Modern Aryne Chemistry
Modern Aryne Chemistry
Edited by
Akkattu T. Biju
Editor
Prof. Akkattu T. Biju
Department of Organic Chemistry
Indian Institute of Science
Bangalore – 560012
India
Cover
Cover Image: (background)
PublicDomainPictures/Pixabay
(inset) Courtesy of Akkattu T. Biju
All books published by WILEY-VCH
are carefully produced. Nevertheless,
authors, editors, and publisher do not
warrant the information contained in
these books, including this book, to
be free of errors. Readers are advised
to keep in mind that statements, data,
illustrations, procedural details or other
items may inadvertently be inaccurate.
Library of Congress Card No.:
applied for
British Library Cataloguing-in-Publication
Data
A catalogue record for this book is
available from the British Library.
Bibliographic information published by
the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists
this publication in the Deutsche
Nationalbibliografie; detailed
bibliographic data are available on the
Internet at <http://dnb.d-nb.de>.
© 2021 WILEY-VCH GmbH, Boschstr.
12, 69469 Weinheim, Germany
All rights reserved (including those of
translation into other languages). No
part of this book may be reproduced in
any form – by photoprinting,
microfilm, or any other means – nor
transmitted or translated into a
machine language without written
permission from the publishers.
Registered names, trademarks, etc.
used in this book, even when not
specifically marked as such, are not to
be considered unprotected by law.
Print ISBN: 978-3-527-34646-2
ePDF ISBN: 978-3-527-82307-9
ePub ISBN: 978-3-527-82309-3
oBook ISBN: 978-3-527-82308-6
Typesetting
SPi Global, Chennai, India
Printed on acid-free paper
10 9 8 7 6 5 4 3 2 1
v
Contents
Foreword xv
Preface xix
1
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.7.1
1.7.1.1
1.7.1.2
1.7.1.3
1.7.1.4
1.7.1.5
1.7.1.6
1.7.1.7
1.7.1.8
1.7.1.9
1.7.2
1.8
1.8.1
1.8.2
1.8.3
1.8.4
1.8.5
1.8.6
1.9
1.10
Introduction to the Chemistry of Arynes 1
Tony Roy, Avishek Guin, and Akkattu T. Biju
Introduction 1
History of Arynes 1
Characterization of the Aryne Intermediates 3
Ortho-Arynes with Substitution 5
Ortho-Arynes of Heterocycles 6
Other Arynes 7
Methods of Aryne Generation 9
Selected Methods of Aryne Generation 9
Deprotonation of Aryl Halides 9
Metal–Halogen Exchange/Elimination 10
From Anthranilic Acids 10
Fragmentation of Amino Benzotriazoles 10
From Phenyl(2-(trimethylsilyl)phenyl)iodonium Triflate 10
Using Hexadehydro Diels–Alder (HDDA) Reaction 11
From ortho-Borylaryl Triflates 11
Pd(II)-Catalyzed C–H Activation Strategy Starting from Benzoic
Acids 11
via Grob Fragmentation 12
Kobayashi’s Fluoride-Induced Aryne Generation 12
Possible Reactivity Modes of Arynes 13
Pericyclic Reactions 14
Arylation Reactions 17
Insertion Reactions 17
Transition-Metal-Catalyzed Reactions 18
Multicomponent Couplings (MCCs) 18
Molecular Rearrangements 18
Domino Aryne Generation 19
Arynes for the Synthesis of Large Polycyclic Aromatic Compounds 19
vi
Contents
1.11
1.12
Arynes in Natural Product Synthesis
Concluding Remarks 21
References 21
2
Aryne Cycloadditions for the Synthesis of Functional
Polyarenes 27
Fátima García, Diego Peña, Dolores Pérez, and Enrique Guitián
Introduction 27
Aryne Cycloaddition Reactions: General Considerations 29
[4+2] Aryne Cycloadditions 29
[2+2] Aryne Cycloadditions 30
[2+2+2] Aryne Cycloadditions 31
Aryne-Mediated Synthesis of Functional Polyarenes 32
Synthesis of Acenes 32
Synthesis of Perylene Derivatives 43
Synthesis of Triptycenes 48
Synthesis of π-Extended Starphenes or Angular PAHs 48
Synthesis of Helicenes 54
Functionalization of Carbon Nanostructures 58
References 63
2.1
2.2
2.2.1
2.2.2
2.2.3
2.3
2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
3
3.1
3.2
3.2.1
3.2.1.1
3.2.1.2
3.2.1.3
3.2.1.4
3.2.1.5
3.2.1.6
3.2.1.7
3.2.1.8
3.2.1.9
3.2.2
3.2.2.1
3.2.2.2
3.3
3.3.1
3.3.2
3.4
20
Dipolar Cycloaddition Reactions of Arynes and Related
Chemistry 69
Pan Li, Jingjing Zhao, and Feng Shi
Introduction 69
1,3-Dipolar Cycloaddition Reactions of Arynes 70
[3+2] Dipolar Cycloaddition Reactions of Arynes with Linear
1,3-Dipoles 72
Reactions with Diazo Compounds 72
Reactions of Arynes with Azides 75
Reactions of Arynes with Nitrile Oxides 79
Reactions of Arynes with Nitrile Imines 80
Reactions of Arynes with Nitrones 80
Reactions of Arynes with Azomethine Imines and Ylides 83
Reactions of Arynes with Pyridinium N-Oxides 85
Reactions of Arynes with Pyridinium N-Imides 87
Reactions of Arynes with Pyridinium Ylides 89
[3+2] Dipolar Cycloaddition Reactions of Arynes with Cyclic
1,3-Dipoles 90
Reactions of Arynes with Sydnones 90
Reactions of Arynes with Münchnones 92
Other [n+2] Dipolar Cycloaddition Reactions of Arynes 92
Cycloaddition with Other Dipoles 92
Cycloaddition of Extended Scope of Arynes 95
Formal Cycloaddition Reactions of Arynes 97
Contents
3.4.1
3.4.2
3.4.3
3.5
4
4.1
4.2
4.2.1
4.2.2
4.2.3
4.2.4
4.3
4.3.1
4.3.2
4.3.3
4.3.4
4.4
4.5
4.5.1
4.5.2
4.5.3
4.6
4.6.1
4.6.2
4.7
5
5.1
5.2
5.3
5.3.1
Formal Cycloaddition with N–C–C Systems Forming
Indole/Indoline/Oxyindole Scaffolds 97
Formal Cycloaddition with Hydrazone-Derived N–N–C Systems 99
Formal Cycloaddition and with Sulfur-Containing Substrates 102
Summary 104
List of Abbreviations 104
References 104
Recent Insertion Reactions of Aryne Intermediates 111
Suguru Yoshida and Takamitsu Hosoya
Introduction 111
Amination and Related Transformations 111
Transformations Involving the Formation of C—N and C—H
Bonds 111
Transformations Involving the Formation of C—N and C—Mg
Bonds 115
Transformations Involving the Formation of C—N and C—C
Bonds 116
Transformations Involving the Formation of C—N and C—S, C—P,
C—Cl, or C—Si Bonds 118
Transformations Involving Bond Formation with Nucleophilic
Carbons 121
Transformations Involving Carbometalation 121
Benzocyclobutene Synthesis by [2+2] Cycloaddition 122
Acylalkylations and Related Transformations 124
Transformations Involving C—C and C—H Bond Formations 128
Etherification and Related Transformations 129
Sulfanylation and Related Transformations 133
Hydrosulfanylation of Arynes 133
Transformations Involving C—S and C—C Bond Formations 135
Other Transformations Involving C—S and C—X Bond Formations 136
Transformations Involving Bond Formation with Other Heteroatom
Nucleophiles 140
Transformations Involving C—P Bond Formation 140
Transformations Involving C—B, C—I, or C—Cl Bond Formations 142
Conclusions 142
References 144
Multicomponent Reactions Involving Arynes and Related
Chemistry 149
Hiroto Yoshida
Introduction 149
Classification of Multicomponent Reactions 150
Carbon Nucleophile–Based Multicomponent Reactions 150
Isocyanide 150
vii
viii
Contents
5.3.2
5.4
5.4.1
5.4.2
5.4.3
5.4.4
5.4.5
5.5
5.5.1
5.5.2
5.5.3
5.5.4
5.6
5.7
5.8
5.9
5.10
Active Methylene Compounds 153
Nitrogen Nucleophile–Based Multicomponent Reactions 153
Amine 153
Imine 159
N-Heteroarene 163
Diazene 164
Nitrite 165
Oxygen Nucleophile–Based Multicomponent Reactions 165
Dimethylformamide 165
Sulfoxide 169
Cyclic Ether 172
Trifluoromethoxide 173
Phosphorus Nucleophile–Based Multicomponent Reactions 174
Sulfur Nucleophile–Based Multicomponent Reactions 176
Halogen Nucleophile–Based Multicomponent Reactions 177
Miscellaneous 179
Conclusive Remarks 179
References 180
6
Transition-Metal-Catalyzed Reactions Involving Arynes and
Related Chemistry 183
Kanniyappan Parthasarathy, Jayachandran Jayakumar, Masilamani
Jeganmohan, and Chien-Hong Cheng
Introduction 183
Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes 184
Palladium-Catalyzed Cyclotrimerization and Cocyclization with
Arynes 184
Ni-Catalyzed Cyclotrimerization and Cocyclization with Benzynes 193
Au-Catalyzed Cyclotrimerization of Arynes 197
Au-Catalyzed [4+2] Cycloaddition of o-Alkynyl(oxo)benzenes with
Arynes 198
Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond
Activation 201
Palladium-Catalyzed Carbocyclization Reaction by C–H Activation 201
Palladium-Catalyzed Arynes in C–X Annulations (X = N, O) 215
Ni-Catalyzed C–N Annulations by Denitrogenative Process 222
Cu-Catalyzed C–H and N–H Annulations of Arynes 224
Transition-Metal-Catalyzed Three-Component Coupling Reactions 225
Palladium-Catalyzed Three-Component Coupling in Arynes 225
Nickel-Catalyzed Three-Component Coupling in Arynes 230
Copper-Catalyzed Three-Component Coupling in Arynes 230
Silver-Catalyzed Three-Component Coupling in Arynes 239
Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X
bonds into Arynes 240
Palladium-Catalyzed C—Sn Bond Addition to Arynes 240
6.1
6.2
6.2.1
6.2.2
6.2.3
6.2.4
6.3
6.3.1
6.3.2
6.3.3
6.3.4
6.4
6.4.1
6.4.2
6.4.3
6.4.4
6.5
6.5.1
Contents
6.5.2
6.5.3
6.5.4
6.5.5
6.5.6
6.5.7
6.5.8
6.5.9
6.5.10
6.5.11
6.5.12
6.6
6.6.1
6.7
6.7.1
7
7.1
7.2
7.2.1
7.2.2
7.3
7.3.1
7.3.2
7.3.3
7.3.4
7.3.5
7.3.6
7.4
7.5
7.5.1
7.5.2
7.6
Palladium-Catalyzed Sn—Sn/Si—Si Bond Addition to Arynes 241
Palladium-Catalyzed Ar—SCN Bond Addition to Arynes 241
Platinum-Catalyzed Boron–Boron Bond Addition to Arynes 243
Copper-Catalyzed B—B Bond Addition to Arynes 244
Copper-Catalyzed Ar—Sn Bond Addition to Arynes 244
Copper-Catalyzed sp C—H Bond Addition to Arynes 247
Gold/Copper-Catalyzed sp C—H Bond Addition to Arynes 247
Copper-Catalyzed C—Br Bond Addition to Arynes 249
Copper-Mediated 1,2-Bis(trifluoromethylation) of Arynes 249
Copper- and Silver-Catalyzed Hexadehydro-Diels–Alder-Cycloaddition of a Triyne (or) Tetrayne (HDDA Arynes) with Terminal
Alkynes 251
Copper-Catalyzed P—H Bond Addition to arynes 253
Metal-Catalyzed CO Insertion Reactions of Arynes 255
Cobalt-, Rhodium-, and Palladium-Catalyzed CO Insertion of
Arynes 255
Metal-Catalyzed [3+2] Cycloaddition of Arynes 260
Silver-Catalyzed [3+2] Cycloaddition of Arynes 260
Abbreviations 261
References 262
Molecular Rearrangements Triggered by Arynes 267
Lu Han and Shi-Kai Tian
Introduction 267
Rearrangements Involved in the Monofunctionalization of Arynes 268
Reactions of Arynes with Nitrogen Nucleophiles 268
Reactions of Arynes with Sulfur Nucleophiles 275
Rearrangements Involved in the 1,2-Difunctionalization of Arynes 278
Formal Insertion of Arynes into Carbon–Carbon Bonds 278
Formal Insertion of Arynes into Carbon–Heteroatom Bonds 281
Formal Insertion of Arynes into Heteroatom–Heteroatom Bonds 288
Vicinal Carbon–Carbon/Carbon–Carbon Bond-Forming Reactions of
Arynes 289
Vicinal Carbon–Carbon/Carbon–Heteroatom Bond-Forming Reactions
of Arynes 292
Vicinal Carbon–Heteroatom/Carbon–Heteroatom Bond-Forming
Reactions of Arynes 302
Rearrangements Involved in the 1,2,3-Trifunctionalization of
Arynes 303
Rearrangements Involved in the Multicomponent Reactions with Two or
More Aryne Molecules 305
Three-Component Reactions with Two Aryne Molecules 305
Four-Component Reactions with Three Benzyne Molecules 308
Conclusions 309
References 310
ix
x
Contents
8
8.1
8.2
8.2.1
8.2.2
8.2.3
8.3
8.3.1
8.3.2
8.3.3
8.4
8.4.1
8.4.2
8.4.3
8.4.4
8.4.5
8.5
9
9.1
9.2
9.3
9.4
9.4.1
9.4.2
9.4.3
9.4.4
9.4.5
9.4.6
9.4.7
9.4.7.1
9.4.7.2
9.4.7.3
9.4.7.4
9.4.8
9.4.8.1
9.4.8.2
9.4.8.3
9.4.8.4
9.4.8.5
9.4.9
New Strategies in Recent Aryne Chemistry 315
Yang Li
Introduction 315
New Aryne Generation Methods 315
Revisiting ortho-Deprotonative Elimination Protocols 316
Arynes from ortho-Difunctionalized Precursors 320
Catalytic Aryne Generation Methods 323
Aryne Regioselectivity 326
Steric Effect 327
Electronic Effect 330
Regioselectivity on Small Ring-Fused Arynes 335
Recent Advances in Aryne Multifunctionalization 336
1,2-Benzdiyne 336
1,3-Benzdiyne 342
1,4-Benzdiyne 345
1,3,5-Benztriyne 349
Benzyne Insertion, C–H Functionalization Cascade 351
Conclusions 354
References 354
Hetarynes, Cycloalkynes, and Related Intermediates 359
Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju
Introduction to Hetarynes 359
Challenges in Hetarynes 359
Different Types of Hetarynes 361
Methods of Preparation 362
2,3-Benzofuranyne Generation 362
2,3-Indolyne Generation 363
2,3-Benzothiophyne Generation 363
3,4-Pyrrolyne Generation 364
2,3-Thiophyne Generation 364
3,4-Thiophyne Generation 364
2,3-Pyridyne Generation 365
2,3-Pyridyne from 3-Halopyridine 365
2,3-Pyridyne from Dihalide Precursor 366
From N-Aminotriazolo-Pyridine 366
2,3-Pyridyne from 3-(Trimethylsilyl)pyridin-2-yl
Trifluoromethanesulfonate 367
3,4-Pyridyne Generation 367
3,4-Pyridyne from Thermolysis of Diazonium Carboxylates 367
From 3-Halopyridine 367
From Oxidation of N-Aminotriazolo-pyridine 368
From 3-Bromo-4-(phenylsulfinyl)pyridine 368
From ortho-Trialkylsilyl Pyridyl Triflates 368
4,5-Indolyne Generation 369
Contents
9.4.9.1
9.4.9.2
9.4.9.3
9.4.9.4
9.4.10
9.4.11
9.4.11.1
9.4.11.2
9.4.11.3
9.4.12
9.4.12.1
9.4.12.2
9.4.12.3
9.4.12.4
9.4.13
9.4.14
9.4.15
9.4.16
9.5
9.5.1
9.5.2
9.5.3
9.6
9.6.1
9.6.2
9.7
9.8
9.9
9.10
9.10.1
9.10.1.1
9.10.1.2
9.10.1.3
9.10.1.4
9.10.1.5
9.10.1.6
9.10.2
9.10.2.1
9.10.2.2
9.10.2.3
9.10.2.4
9.11
9.11.1
9.11.1.1
From 5-Bromoindole 369
From 4-Chloroindole Derivative 369
From Dibromoindole 369
From Silyltriflate Precursor 370
5,6-Indolyne Generation 370
6,7-Indolyne Generation 371
From Dichloroindole Precursor 371
Through Proton–lithium Exchange 371
From 7-Bromoindole Derivative 371
Quinolynes Generation 372
3,4-Quinolyne from Halo Derivatives 372
5,6- and 7,8-Quinolynes 372
7,8-Quinolyne from Quinoline 4-Methylbenzenesulfonate
Derivatives 372
3,4-Isoquinolyne Generation 373
3,4-Dehydro-1,5-Naphthyridine 373
4,5-Pyrimidyne Generation 373
Pyridyne-N-oxides Generation 374
Indolinyne Generation 375
Reactions of Hetarynes 375
Cycloaddition Reactions 375
Nucleophilic Addition Reaction 377
Insertion Reaction 379
Applications in Synthesis 380
Application of Pyridyne 381
Application of Indolyne 382
Introduction to Cycloalkynes 384
History of Cycloalkynes 385
Different Types of Cycloalkynes 387
Methods of Cycloalkyne Generation 387
Traditional Methods of Cycloalkyne Generation 388
Base-Induced 1,2-Elimination 388
Metal–Halogen Exchange/Elimination 389
Fragmentation of Aminotriazoles 389
Fragmentation of Diazirine 390
Oxidation of 1,2-Bis-hydrazones 390
Rearrangement of Vinylidenecarbenes 390
Fluoride-Induced Cycloalkyne Generation 390
Generation of 3,4-Oxacyclohexyne 391
Generation of 2,3-Piperidyne 392
Generation of 3,4-Piperidyne 392
Generation of Cyclohexenynone 392
Reactions of Cycloalkynes 393
Cycloaddition Reactions 393
Diels–Alder Reaction 393
xi
xii
Contents
9.11.1.2
9.11.1.3
9.11.2
9.11.3
9.12
9.13
9.13.1
9.13.1.1
9.13.1.2
9.13.1.3
9.13.2
9.13.2.1
9.13.2.2
9.13.2.3
9.14
[2+2] Cycloaddition 393
1,3-Dipolar Cycloaddition 394
Alkenylation Reactions 395
Insertion Reactions 395
Application in Synthesis 396
Strained Cyclic Allenes 396
Generation of 1,2-Cycloalkadienes 396
Base-Induced 1,6-Elimination 397
Rearrangement of Cyclopropylidenes 398
Fluoride-Induced Elimination 398
Reaction of 1,2-Cycloalkadienes 400
Diels–Alder Addition 400
[2+2] Cycloaddition 401
1,3-Dipolar Cycloaddition 401
Conclusions 402
References 402
10
Hexadehydro Diels–Alder (HDDA) Route to Arynes and
Related Chemistry 407
Rachel N. Voss and Thomas R. Hoye
Introduction 407
History 407
Overview of the Family of Dehydro-Diels–Alder Reactions 407
First Example of a Tetradehydro-Diels–Alder (TDDA) Reaction 408
Earliest Triyne to Benzyne Cycloisomerization (i.e., HDDA)
Reactions 409
First Minnesota Examples (and the Naming) of the “HDDA”
Reaction 411
Early Demonstration of New Modes of Aryne-Trapping Reactivity:
Ag- and B-Promoted Carbene Chemistry 412
De novo Construction of Arenes: A New Paradigm for Synthesis of
Highly Substituted Benzenoid Natural Products 413
Diradical Mechanism of the HDDA Cycloisomerization of Triyne to
Benzyne 414
Additional Contributions from the Lee Group (University of Illinois,
Chicago (UIC)) 416
Additional Notable Modes of Aryne Reactivity 416
HDDA Benzynes as Dienophiles in Diels–Alder [4π+2π] Cycloaddition
Reactions with Aromatic Dienes 416
Trapping of Natural Products: Phenolics 416
Trapping of Natural Products: Colchicine and Quinine 420
New Reaction Modes and New Mechanistic Understanding 421
Three-Component Reactions 421
Dihydrogen Transfer Reactions 422
Aromatic ene, Silyl Ether, Thioamide, and Diaziridine Reactions 423
10.1
10.2
10.2.1
10.2.2
10.2.3
10.2.4
10.3
10.4
10.5
10.6
10.7
10.7.1
10.7.2
10.7.3
10.8
10.8.1
10.8.2
10.8.3
Contents
10.9
10.9.1
10.9.2
10.10
10.10.1
10.10.2
10.11
10.11.1
10.11.2
10.12
10.12.1
10.12.2
10.12.3
10.12.4
10.12.5
10.12.6
10.13
10.13.1
10.13.2
10.13.3
10.13.4
10.13.5
11
11.1
11.2
11.3
11.3.1
11.3.2
11.3.3
11.3.3.1
11.3.3.2
11.4
11.5
11.6
11.7
11.8
New Routes to Polycylic, Highly Fused Aromatic Products 424
Naphthynes via Double-HDDA, Intramolecular-HDDA, and Highly
Functionalized Naphthalenes 424
Trapping with Perylene, Domino HDDA, and Tandem
HDDA/TDDA 426
One-Offs 427
Enal, Formamide, Diselenide, and (N-heterocyclic carbene) NHC-Borane
Trapping 427
Cu(I)-Catalyzed Hydroalkynylation, Ether vs. Alcohol Competition,
Photo-HDDA, and a Kobayashi Benzyne as an HDDA Diynophile 428
Outgrowths from HDDA Chemistry 428
Processes that Outcompete Aryne Formation in Potential HDDA
Substrates 428
Aza-HDDA Reaction 430
Guidelines and Practical Issues: Strategic Considerations 431
Complementarity of Classical vs. HDDA Benzyne Chemistries 431
Regioselectivity Issues and the Nature of the Nucleophilic Trapping
Agent 432
Limitations Imposed by Trapping Agents 433
Formal Equivalent of the Elusive Bimolecular HDDA Reaction 433
Aspects of Substrate Design 434
Limitations Imposed by Substituents on the Diynophile 434
Guidelines and Practical Issues: Experimental Considerations 435
Pristine Reaction Conditions (and Solvent Choices) 435
Reaction Conditions: Tolerance for Water and Oxygen 435
Reaction Conditions: Temperature, Pressure, and Alkyne Stability 436
Reaction Conditions: Substrate Concentration 437
The Value of Half-Life Measurements 437
References 438
Applications of Benzynes in Natural Product Synthesis 445
Hiroshi Takikawa and Keisuke Suzuki
Introduction 445
General Reactivities of Benzynes 445
Strategies Based on Nucleophilic Additions to Benzynes 446
Additions of Nitrogen Nucleophiles 447
Additions of Oxygen Nucleophiles 450
Addition of Carbon Nucleophiles 452
Carbanions 452
π-Nucleophiles: Enamines and Enolates 453
Addition–Fragmentation Reactions 454
Strategies Based on [4+2] Cycloadditions 457
Strategies Based on [2+2] Cycloadditions 464
Strategies Based on Benzyne–Ene Reactions 470
Recent Advances 471
xiii
xiv
Contents
11.8.1
11.8.2
11.8.3
Strategies Based on Multiple Use of Benzyne 471
Strategies Based on Transition-Metal-Catalyzed Reactions 474
Benzyne Generation via Hexadehydro-Diels–Alder Reaction 477
References 479
Index 487
xv
Foreword
Arynes as fleeting intermediates in organic reactions were first recognized by
Stoermer and Kahlert in 1902, but the solid experimental evidence of their (benzyne) involvement came through the seminal 14 C tracer studies by J. D. et al. (1953)
on the amination of haloarenes, and very recently Pavlićek et al. (2015) have directly
observed surface-generated benzyne by atomic force microscopy (AFM). Concurrently, many preparatively useful methods for generating arynes have been devised
and their diverse reactivity landscape has been extensively explored and profiled. A
breakthrough in the exploitation of arynes in wide range of productive applications
in organic synthesis, including total synthesis of natural products, came about
through Kobayashi’s discovery (1983) that stable 2-(trimethylsilyl)aryl triflates
(now commercially available) undergo facile fluoride-mediated 1,2-elimination to
generate arynes safely and efficiently. This convenient access to arynes gave a major
fillip to mapping the diverse and potentially rich synthetic utility of these highly
reactive intermediates in the syntheses of arenes harboring structural complexity
and fostering molecular diversity. The next steps in the advance of aryne arena came
from the hexadehydro-Diels–Alder reaction developed by Hoye, domino generation
of arynes by Li, and the development of heteroarynes by Garg among many other
tactical innovations that have immensely enriched the field and amplified the
expanse of aryne chemistry. Intramolecular variants, domino and tandem reactions
with embellished arynes still offer innovative chemical spaces that await unraveling.
While chemical explorations of aryne reactivity cover a vast and varied arena, they
can be broadly categorized under lead headings like pericyclic reactions, insertion
reactions, multicomponent reactions, transition-metal-catalyzed transformations,
and a variety of unforeseen and interesting molecular rearrangements.
The landscape of aryne chemistry has grown by leaps and bounds since the publication of R. W. Hoffmann’s seminal monograph Dehydrobenzene and Cycloalkynes
over half a century ago in 1967. A recent SciFinder search on “benzyne” and “aryne”
led to −7500 and −4500 hits, respectively – clearly indicative of a fertile field and the
traction it has drawn in the recent decades. These developments in aryne chemistry
have been periodically captured in several timely and authoritative accounts
and reviews covering diverse facets of this growing field. Nevertheless, there is a
much-felt need among students and researchers in the field for an authoritative
book that provides a broad, up-to-date coverage of multifaceted advances in aryne
xvi
Foreword
chemistry with a nuanced lens on developments that are of topical interest and
likely to dominate future directions and activities and also provide a fuller flavor of
the field.
Against this background and to fill a widely felt void, Akkattu T. Biju, an
accomplished contributor in the arena, has put together an authoritative and
timely collection of contributions from leading practitioners in the field of aryne
chemistry under the title Modern Aryne Chemistry. This book is primarily aimed at
highlighting some of the recent advances in carbon–carbon and carbon–heteroatom
bond-forming reactions of arynes, as highly reactive and versatile electrophilic
species, with numerous, contextual synthetic applications.
The first chapter of the book introduces the chemistry of arynes. This overarching
contribution by Akkattu T. Biju (IISc Bangalore) describes the history of arynes,
various methods for their generation, characterization techniques, and possible
modes of reactivity. A detailed account of the application of arynes in cycloaddition
reactions has been presented in the second chapter by E. Guitián from Universidade
de Santiago de Compostela, Spain. The synthetic potential of arynes for accessing
various polycyclic aromatic hydrocarbons (PAHs) and nanographenes has been
highlighted in this chapter. The focal theme of the third chapter of the book
compiled by F. Shi (WuXi AppTec Co., Ltd. Wuhan), and P. Li (Henan University) is
on dipolar cycloaddition reactions of arynes and provides the interception of arynes
with various dipoles for the synthesis of benzo-fused heterocycles. An overview
“Recent advances in the insertion reactions of arynes” forms the fourth chapter
by S. Yoshida and T. Hosoya from Tokyo Medical and Dental University, Japan.
This chapter provides an interesting feature of aryne intermediates to insert into
various element-to-element bonds to form 1,2-disubstituted arenes. A variety of
nucleophiles can add to arynes and the generated aryl anion can be intercepted
with electrophiles to orchestrate multicomponent reactions. A complete coverage
of transition-metal-free aryne multicomponent reactions for the synthesis of
complex 1,2-disubstituted arenes has been presented by H. Yoshida from Hiroshima
University in the fifth chapter.
The sixth chapter of the book by C.-H. Cheng (National Tsing Hua University,
Taiwan), M. Jeganmohan (IIT Madras), and K. Parthasarathy (University of
Madras) provides a detailed account of the transition-metal-catalyzed reactions
involving arynes. Transition-metal-catalyzed cycloisomerization reactions, C—H
and N—H bond activations involving arynes leading to annulation reactions,
three-component coupling reactions, etc. are described in this chapter. Arynes
serve as versatile precursors for a number of molecular rearrangements, resulting
in the synthesis of diverse and structurally attractive organic compounds that are
otherwise difficult to access. The recent developments in molecular rearrangements
triggered through aryne intermediates are summarized in the seventh chapter by
S.-K. Tian from University of Science and Technology of China, Hefei. The eighth
chapter of the book is dedicated to the new strategies and latest developments in this
field and deals with new methods of aryne generation, addresses the regioselectivity
and multifunctionalization issues in aryne chemistry, and is authored by Y. Li
from Chongqing University. A brief history of hetarynes, cycloalkynes and related
Foreword
potential intermediates, different methods of their generation, various types of
reactions and applications in total synthesis are briefly discussed in the ninth
chapter by Akkattu T. Biju (IISc Bangalore). The penultimate chapter contributed
by T. R Hoye (University of Minnesota) offers the hexadehydro Diels–Alder (HDDA)
route to arynes and related chemistry. Although this reaction was first revealed
in 1997, it received an expansive growth after a report in 2012 demonstrating its
potential as a general strategy for generating reactive benzyne intermediates from
simple triyne precursors. The potential applications of arynes in the synthesis of
natural products and biologically active molecules have been highlighted by K.
Suzuki (Tokyo Institute of Technology) and H. Takikawaa (Kyoto University) in the
last chapter of this monograph.
It is expected that in addition to the pedagogic value of the book for the students
and the general reader, the simplicity and sophistication of the synthetic strategies
using aryne chemistry will also inspire and entice a wide range of organic chemists to
explore new reactivity patterns and imaginative applications in total synthesis, material science, and chemical biology. It is reasonable to believe that aryne chemistry
will continue to flourish and lead to many interesting/serendipitous observations in
the future to enrich organic chemistry. Thus, from a wider perspective, this timely
book is expected to serve many purposes to augment and advance organic chemistry
and its interfaces.
Hyderabad-500046, India
4 December 2020
Goverdhan Mehta,
Dr. Kallam Anji Reddy Chair
School of Chemistry
University of Hyderabad
xvii
xix
Preface
Carbon–carbon and carbon–heteroatom bond-forming reactions constitute the
backbone of synthetic organic chemistry. When it comes to the utilization of the
ring strain in these bond-forming reactions, arynes have always been at the forefront
(having low-lying lowest unoccupied molecular orbital [LUMO] with a strain energy
of 63 kcal mol−1 ). Arynes are highly reactive intermediates, which are generated
in situ due to their high reactivity. The chemistry of this century-old intermediate,
which marked its birth in history with the vague evidence of its existence provided
by Stoermer and Kahlert in 1902, has gained outstanding acceleration toward the
end of the twentieth century. This unstable intermediate has been characterized
using various spectroscopic methods by different research groups. In the course
of time, various research groups have developed several methods for the mild
generation of arynes. However, the procedure became much simpler since 1983
when Kobayashi uncovered a facile and mild method for generation of arynes
from 2-(trimethylsilyl) aryl triflates using simple fluoride sources. Moreover, the
reagent-free and metal-free generation and reactivity of arynes generated utilizing
the concept of intramolecular hexadehydro Diels–Alder reaction (HDDA) of triynes
at elevated temperature has also been studied in detail.
Arynes, being a polarizable intermediate, have a diverse reactivity profile due
to their affinity toward charged and uncharged electron donors. Arynes serve as
excellent dienophile and dipolarophile in pericyclic reactions such as Diels–Alder
reactions, [2+2] cycloadditions and dipolar cycloaddition reactions. Arynes hold
the potential to arylate a number of molecules like alcohols, amines, and thiols and
to insert into various element–element σ-bonds and π-bonds. Transition-metal-free
multicomponent couplings (MCCs) and molecular rearrangements are the
emerging class of reactivity of arynes. Moreover, arynes undergo a variety of
transition-metal catalyzed reactions. A consecutive double nucleophilic addition
realizing the concept of multifunctionalization of aryne using a novel domino
aryne precursor was uncovered recently by Li and coworkers. Cycloaddition
reactions involving arynes give access to the synthesis of large polycyclic aromatic
hydrocarbons (PAHs) that are analogous to nanosized graphene substructures.
The applications of arynes are not only limited to developing novel bond-forming
reactions but also in natural product synthesis. The synthesis and reactivities of
several five- and six-membered hetarynes, and strained cycloalkynes have also been
xx
Preface
a subject of interest for chemists. A book on arynes is a need of the hour as the area
has crossed several milestones ever since the first book on arynes Dehydrobenzene
and Cycloalkynes by R. W. Hoffmann was published in 1967. The lack of an update
to this book incorporating all the developments in the past five decades made us
realize this collection of information on arynes. The focus of the present book is
on the history, diverse reactivity, and application of arynes in organic synthesis.
Moreover, details on hetarynes, domino generation of arynes, and HDDA method
of aryne generation have also been included in the book. As the chemistry of arynes
has achieved considerable growth and continues expanding further, with the strong
support of Wiley-VCH, we decided to bring out a new book under the title Modern
Aryne Chemistry to highlight the developments occurred in this interesting area.
Eleven chapters highlighting the history, different modes of reactivity, and the
application of arynes are presented in this book.
The foundation of this book is based on the excellent contributions of all the
colleagues working in aryne chemistry, and I am thankful to them. Moreover,
I would like to thank all the authors, who have contributed enormously to this
project, for their valuable time, efforts as well as the expertise to make this book
a source of encouragement for beginners as well as advanced chemists practicing synthetic organic chemistry. It is anticipated that the diverse reactivity and
application of arynes will inspire a broad range of organic chemists to explore new
opportunities and creative applications of this concept and thereby unraveling
some of the remaining challenges in this field. I am also thankful to Dr Lifen Yang
(Program Manager, Books & References) and Ms Katherine Wong (Senior Managing
Editor) at Wiley-VCH for their unconditional support and valuable advices in
organizing/developing this book.
India
30 November 2020
Akkattu T. Biju
Associate Professor
Department of Organic Chemistry
Indian Institute of Science,
Bangalore 560012
1
1
Introduction to the Chemistry of Arynes
Tony Roy, Avishek Guin, and Akkattu T. Biju
Indian Institute of Science, Department of Organic Chemistry, Bangalore 560012, India
1.1 Introduction
Arynes are highly reactive electrophilic intermediates proposed more than a
century ago and have encountered an extraordinary resurgence of interest in the
past decades. Chemists have exploited this reactive intermediate for the synthesis of
a broad range of 1,2-disubstituted benzene derivatives and also several benzo-fused
carbocycles and heterocycles, which are otherwise difficult to achieve by conventional methods [1–14]. With the discovery of mild methods of generation by
Kobayashi [15] and Hoye [16, 17], aryne chemistry has been significantly promoted
in recent years in terms of better functional group compatibility as well as accommodation of more reaction modes. The progress in heterocyclic arynes, especially
the pyridynes and indolynes, has added extra aroma to the chemistry of this reactive
species [18]. The development and applications of the hexadehydro-Diels–Alder
(HDDA)-based arynes went parallelly over the last decade and have contributed
seminally to the diversification of this field. Moreover, 1,4-benzdiyne equivalents
are one of the most dependable components for the synthesis of polycyclic aromatic
functional materials at present. A recently exploited domino aryne reagent, the
2-(trimethylsilyl)-1,3-phenylene bis(trifluoromethanesulfonate) (TPBT), is one
of the best precursors available for the synthesis of multifunctional aromatic
derivatives [19]. A discussion on the brief history of arynes, their characterization,
methods of generation, and possible modes of reactivities forms the content of this
introductory chapter.
1.2 History of Arynes
Initial speculation on the existence of aryne intermediate appeared in 1902.
Stoermer and Kahlert provided the first evidence for the existence of arynes
when they observed the formation 2-ethoxybenzofuran in the reaction of
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
2
1 Introduction to the Chemistry of Arynes
3-bromobenzofuran under basic conditions. They postulated the possible intermediacy of a 2,3-didehydrobenzofuran intermediate in this reaction [20]. The
unexpected product formation laid the foundation stone for the development of an
interesting area based on a highly transient intermediate (Scheme 1.1).
Br
Base, EtOH
OEt
O
O via
O
Scheme 1.1 Initial observations by Stoermer and Kahlert. Source: Based on Stoermer and
Kahlert [20].
Later in 1927, Bachmann and Clarke at the Eastman Kodak Co. proposed benzyne
as a reactive intermediate to explain the formation of triphenylene in a reaction, and
it was taken as “decisive in favour of the free radical explanation” (Scheme 1.2) [21].
It was thought that structure 1 was predominant among the three possible structures, where the ylide structure 2 as well as the structure 3 with carbon–carbon triple
bond in a six-membered ring were also considered.
+
–
1
Scheme 1.2
2
3
Proposed structures of benzyne. Source: Based on Bachmann and Clarke [21].
Later, Wittig found that the formation of biphenyl in the reaction of phenyllithium with halobenzenes was fastest with fluorobenzene through nucleophilic
substitution reaction via the displacement of fluoride, which was considered as
a complicated task to perform [22–25]. Thus, the ylide structure 2 was proposed
as a reactive intermediate for the formation of biphenyl. The trimerization of this
zwitterion 2 to triphenylene was also noted under certain conditions. At the same
time, Morton had also postulated the intermediate 2, which “cannot be stabilized by
double bond formation” in their study of the Wurtz reaction of pentylsodium with
chlorobenzene [26]. But the zwitterionic structure failed to explain the observed
regioselectivity in the reaction of substituted arynes, and hence its existence was
questioned (Scheme 1.3). For instance, the reaction of aryne bearing an OMe group
at 3-position with NaNH2 was regioselective affording a single product, whereas
the reaction of arynes having methyl substitution provided a 1 : 1 mixture of
regioisomers.
It was also observed that the substitution only occurred in ipso or ortho position to
that of halide substitution. Halides having no ortho hydrogen did not undergo any
substitution reaction. Robert brought the official introduction of benzyne concept
1.3 Characterization of the Aryne Intermediates
OMe
OMe
+
–
–
+
OMe
NaNH2
NH2
Favored
(Only product observed)
Me
Me
Me
+
–
–
+
Favored
Me
NaNH2
+
NH2
NH2
1 : 1 mixture
Scheme 1.3
Regioselectivity in aryne reactions.
[27, 28]. In 1953 at MIT, Robert performed a classical 14 C labeling experiment, which
confirmed the involvement of a symmetrical, electronically neutral intermediate,
benzyne 3 (Scheme 1.4). Later, Wittig performed the Diels–Alder reaction of benzyne
with furan to give 76% yield of the [4+2] adduct [29].
Cl
KNH2/NH3
NH2
+
NH2
(1 : 1 mixture)
Scheme 1.4
et al. [28].
Robert’s 14 C-labeling experiment. Source: Roberts et al. [27]; Roberts
1.3 Characterization of the Aryne Intermediates
In 1963, Fisher and Lossing provided further insight to the structure 3 using mass
spectrometry. They performed the pyrolysis of diiodobenzenes for all three isomers
and identified 3 based on the measured ionization potential [30]. Confirmation for
structure 3 also came from mass spectra. Berry et al. performed a photoinitiated
benzenediazonium carboxylates decomposition in gas phase and identified the
mass 76 along with other masses [31]. The same group further explained the
structure 3 using UV spectra also. Radziszewsk and coworkers recorded the IR
spectra providing a solid proof for the existence of structure 3. The vibration to
absorption peak emerged at 1846 cm−1 corresponding to o-benzyne, which was
confirmed from different isotopomers of phthalic anhydride (Scheme 1.5) [32].
So from the IR data, it is understandable that unlike unstrained alkyne, benzyne
triple bond is much weaker, as it has the stretching vibrations usually occurring in
the range about 2150 cm−1 . IR data resemble cumulene-type structure. However,
o-benzyne can be better explained by strained alkyne rather than biradical, which
can be confirmed by alkyne-like reactivity and large singlet–triplet splitting [33, 34].
Wenthold and Squires determined the enthalpy of formation of structure 3 as
3
1 Introduction to the Chemistry of Arynes
103.6–109.6 kcal mol−1 . The C—C triple bond length in acetylene falls at 120.3 pm
and C—C double bond in ethylene at 133.9 pm. Experimental C—C triple bond
length for benzyne is 122–126 pm, which is closer to that of alkyne triple bond length
value, which aims at a cyclic alkyne-like structure rather than a cumulene-type
structure [35–38]. Adding strength to all the above evidences, Warmuth was able to
measure the nuclear magnetic resonance spectrum in solution in a hemicarcer and
as a “molecular container” [39].
)
08 nm
hv (3
–CO 2
O
hv
(30
8n
O
m
O
O
2
–C
–C O
O
4
at
he
Scheme 1.5
)+
)
hv
3
8
30
CO
nm
(
48
O
)–
CO
nm
(2
hv
hv
(24
8n
m)
Photochemistry of arynes. Source: Based on Berry et al. [32].
The reported 13 C value of 182 ppm for o-benzyne explains the strained alkyne
character. Hoffman’s demonstration of extended Hückel theory throws light on the
electrophilicity of aryne. The LUMO of aryne is significantly lowered compared to
dimethyl acetylene (5.1 eV) and the HOMO is also higher (0.1 eV) in energy, which
make the aryne triple bond much more accessible toward different nucleophiles
(Figure 1.1) [40].
Because of the high electrophilicity and reactivity of arynes, these intermediates
cannot be isolated. However, stable transition metal complexes of benzynes have
been prepared and analyzed by X-ray crystallography for further proof. Crystal
structure of metal-bound benzyne shows that C1 —C2 bond is more ethene-like
Me
Me
π∗
16.1 eV
π∗
π
π
11.0 eV
Significantly lowered LUMO
0.1 eV
Slightly raised HOMO
0 eV
Figure 1.1
et al. [40].
Reason for the enhanced electrophilicity of arynes. Source: Based on Hoffmann
1.4 Ortho-Arynes with Substitution
(133–136 pm) and all other bond is normal benzene-like (138–140 pm). Thus,
these metallocenes can be better described by metallacyclopropenes [41–43]
(Scheme 1.6).
∗
Cp
Me Ta
Me
Shrock and
coworkers [43]
Cy
Cy
P
Me
P Me
Cy
Me
Ni
Cp Zr
Cp
P
Cy
Bennett and
coworkers [42]
Buchwald and
coworkers [41]
Scheme 1.6 Structures of metal-bound benzyne. Source: Buchwald et al. [41]; Bennett
et al. [42]; Mclain et al. [43].
Due to the presence of a carbon–carbon triple bond in a six-membered ring,
arynes are highly reactive and this also leads to the strained nature of the ring
(∼63 kcal mol−1 ), and consequently, these species have low-lying LUMO, and
hence the energy gap between the HOMO and LUMO is smaller than expected.
In addition, arynes react as highly reactive alkynes in cycloaddition reactions.
Moreover, the low-lying LUMO makes arynes a powerful electrophile for facile
addition of nucleophiles.
1.4 Ortho-Arynes with Substitution
The effect of substitution on benzyne has game-changing effect on the reactivity
of arynes. Numerous reactions go via the formation of benzyne intermediate.
Substitution effect can help to understand the observed regioselectivity. Sometimes,
experimental reactivity cannot be predicted due to the fact that the attack of the
nucleophile is not always charge controlled. Introduction of a polar group at
3-positon influences the selectivity to a greater extent. But due to orthogonal nature
of bond, classical electron-donating groups are withdrawing. Strain also can induce
regioselectivity in benzyne intermediate, demonstrated by Suzuki [44]. Calculation
of charge and LUMO coefficient matches prediction of bond angle strain with
selectivity trend (Scheme 1.7) [45, 46].
Squires and Cramer theoretically studied naphthalynes [47]. Many naphthalyne
syntheses were also reported in early 1970s. Lohmann studied the photochemistry
of the two isomeric naphthalene dicarboxylic anhydrides 4 and 5, using laserflash
photolysis (LFP) and found that the dimerization of 7 is much faster than 3; however, intermediate 6 dimerizes rarely (Scheme 1.8) [48]. Intermediates 6 and 7 are
accessible when the photolysis conditions are chosen carefully [49]. Intermediate 6
can stay as alkyne but for 7, it is more like cumulene. Intermediate 6 can be converted
easily to 8 via photocarbonylation, but the analogous reaction of intermediate 7 to 9
is not observed experimentally.
5
6
1 Introduction to the Chemistry of Arynes
–0.002, 0.390
+0.046, 0.429
N
70%, 5 : 1
+0.021, 0.414
+0.015, 0.405
N
76%, 1 : 1
+0.034, 0.427
+0.015, 0.405
N
85%, 2 : 1
Scheme 1.7 Natural atomic charges (above) and atomic populations of LUMO coefficients
(below) at C1 and C2 calculated with the B3LYP/6-311G(d,p) method. Source: Langenaeker
et al. [45]; Johnson and Cramer [46].
O
O
O
O
O
–CO2
4
8
–CO
+CO
6
O
O –CO, –CO
2
5
O
7
O
9
Scheme 1.8
Studies on naphthynes. Source: Lohmann [48].
1.5 Ortho-Arynes of Heterocycles
Although hetarynes are much older than benzynes, the physical data on hetarynes
were negligible. Different groups reported the generation of five-membered biradicaloid intermediate, but direct spectroscopic evidence for these intermediates was
1.6 Other Arynes
not known due to the elevated ring strain, which helped these five-membered
intermediates go through ring opening [50–53]. Thus, detecting lifetime for
five-membered hetarynes by spectroscopic methods is quite less.
Among the six-membered hetarynes, the main focus was on didehydropyridines.
Among didehydropyridines, the 3,4-pyridyne 11 generated by the photolysis of the
precursor 10 is significantly more stable than the 2,3-isomer 13. The bond length for
the 3,4-pyridyne 11 is comparable with that of benzyne 3 [54]. Berry and coworkers
detected 3,4-pyridyne 11 using mass spectrometry [55]. The trapping of the intermediate 11 in a Diels–Alder reaction attempted previously was not successful [56].
In 1988, Leroi and coworkers successfully trapped the pyridyne in nitrogen matrix
and characterized it by IR spectroscopy [57]. However, the 2,3-didehydropyridine
13 generated from the precursor 12 by heating is less explored. It was assumed
that compound 13 was formed as an intermediate in the gas-phase pyrolysis of
2,3-pyridine dicarboxylic anhydride 12 at 600 ∘ C (Scheme 1.9) [58, 59].
O
H
hv (> 340 nm)
O
N
10
H
11
O
+
H
H
hv (> 210 nm)
N
–CO, CO2
N
H+
H
N
N
O
600°C
O
N
12
–CO, –CO2
O
N
N
13
Scheme 1.9 Generation and dissociation of 3,4-pyridyne and 2,3-pyridyne. Source: Cava
et al. [58]; Dunkin and MacDonald [59].
Recently, much effort has been put on the development and reactivity studies,
including efficient computational model to get insight into the synthetic utility of
heterocyclic arynes [60]. Moreover, different types of hetarynes can be generated
at desired position of the heterocycles, thus leading to a variety of indolynes, pyridynes, benzofuranynes, and so on, which will be discussed in detail in Chapter 9 of
this book.
1.6 Other Arynes
Similar to ortho-benzyne, arynes can also be generated in other positions of
the benzene ring as well. Meta- and para-benzynes 14 and 15, tridehydrobenzenes 16-18, and tetradehydrobenzenes 19 are reported (Scheme 1.10) [61–64].
Tetradehydrobenzene (benzdiynes) can stay in different resonance form as illustrated in Scheme 1.10. Multireference methods are preferable for a proper quantum
mechanical description [65, 66]. Due to high reactivity of 1,4-benzdiynes, it can
form complex with transition metals and these complexes can be isolated in many
cases [67–69].
7
8
1 Introduction to the Chemistry of Arynes
15
14
16
17
18
19
Scheme 1.10
Possibility of uncommon benzynes. Source: Wenthold [61].
The existence of m-benzyne has been a matter of discussion, partly due to experimental proof for the existence of an isomer, bicycle[3.1.0]hexatriene 21, as a reactive
intermediate formed by the base treatment of the bicyclohexene 20 (Scheme 1.11)
[72]. Likewise, butalene 22 also denotes the existence of p-benzyne (Scheme 1.11)
[70, 71]. However, both reactions are not fully understood due to complex nature of
the reactions.
Br
LiNMe2
TMEDA
–78 °C
Br
20
Cl
NHMe2
NMe2
21
NMe2
NMe2
LiNMe2
NHMe2
–10 °C
Ph
22
Ph
O
NMe2
O
Ph
Ph
Scheme 1.11 Possible formation of m-benzyne and p-benzyne intermediates. Source:
Breslow et al. [70]; Breslow and Khanna [71].
Early Hückel theory indicates that 21, being a nonalternant “azulenoid” 6π
electron system, maintains benzenoid resonance energy [73, 74]. Although it is a
high-energy intermediate, it is resonance stabilized. On the other hand, iscyclobutadiene derivative 22 possesses antiaromatic character, and hence it is a high-energy
species. General valence bond calculations estimated that the lowest energy forms
of the 1,3- and 1,4-dehydrobenzenes are monocyclic structures having considerable
biradical character [75]. In general, m-benzyne has much less biradical character
and a larger singlet–triplet splitting than p-benzyne [76]. Gas-phase experimental
1.7 Methods of Aryne Generation
studies and matrix isolation IR spectra are also consistent with monocyclic structure, and they do not correspond with 21 and 22. Thus, the intermediate generated
from the reactions shown in Scheme 1.11 is not clarified completely.
The Bergman cyclization (Scheme 1.12) is biologically a very important reaction
because various natural products with antitumor and/or antibiotic properties contain such enediyne moieties 23 and their biological activity can be rationalized in
terms of formation of transient p-benzynes. If p-benzyne abstracts hydrogen, it will
generate phenyl radical, which can abstract hydrogen from DNA leading to the DNA
cleavage [77–81]. The feasible interconversion of the o-, m-, and p-benzynes has been
investigated theoretically. The experiments also indicated that the o- and m-isomers
may rearrange to the p-isomer by H-atom tunneling and then the p-isomer undergoes the Bergman ring opening.
23
15
Scheme 1.12
The Bergman cyclization.
1.7 Methods of Aryne Generation
Due to the highly elevated reactivity, arynes are generated in situ in solution and
cannot be isolated. However, ever since realizing the potential of this intermediate,
different research groups have developed a number of methods for the mild aryne
generation in solution. Selected methods are discussed as follows.
1.7.1
Selected Methods of Aryne Generation
1.7.1.1
Deprotonation of Aryl Halides
Deprotonation of aryl halides 24 followed by the dehalogenation of the anionic
intermediate generated arynes in solution. However, the use of strong bases
such as sodamide or n-BuLi limits the practical utility of this method [82]. Many
base-sensitive functional groups were not compactable under the reaction conditions. Hence, this protocol is considered as a harsh method for the generation of
arynes although this is traditionally important (Scheme 1.13).
X
24
Scheme 1.13
Strong base
3
Aryne generation from halobenzene. Source: Based on Kitamura [82].
9
10
1 Introduction to the Chemistry of Arynes
1.7.1.2
Metal–Halogen Exchange/Elimination
Another approach involves the metal–halogen exchange/elimination of 1,2disubstituted haloarenes 25 or haloaryl triflates mediated by metals (Mg or Li) or
organometallic reagents derived from Cu, Li, and Mg [83, 84]. Many side products
formed via the nucleophilic addition of the organometallic reagents itself made this
route less practical (Scheme 1.14).
X
25
20 °C/0 °C
Li/MgBr
3
Scheme 1.14 Metal–halogen exchange/elimination route to arynes. Source: Ebert et al.
[83]; Matsumoto et al. [84].
1.7.1.3
From Anthranilic Acids
The zwitterionic benzenediazonium 2-carboxylates 26 generated from anthranilic
acid derivatives form arynes in the reaction course. Benzenediazonium
2-carboxylate decomposes upon heating, generating aryne with the liberation
of nitrogen and carbon dioxide [85, 86]. Although the method has advantages, e.g.
the side products are gases, the explosive nature of diazonium compounds limits
the practical application of the method (Scheme 1.15).
N2
26
CO2
3
Scheme 1.15 Arynes from anthranilic acid derivatives. Source: Stiles and Miller [85];
Friedman and Logullo [86].
1.7.1.4
Fragmentation of Amino Benzotriazoles
Benzo[d][1,2,3]thiadiazole 1,1-dioxide 27 and amino benzotriazoles 28, upon fragmentation, produce arynes with the evolution of nitrogen gas. The use of explosive
precursor and the requirement of lead tetraacetate as oxidant appear to be the demerits of this method. Moreover, the method suffers from less functional group tolerance
and hence is not widely used (Scheme 1.16) [87].
1.7.1.5
From Phenyl(2-(trimethylsilyl)phenyl)iodonium Triflate
Fluoride-induced elimination of the aryne precursor phenyl(2-(trimethylsilyl)
phenyl)iodonium triflate 29 is an additional process for the generation of
aryne. However, the preparation of starting material involves a complex process
(Scheme 1.17) [88].
1.7 Methods of Aryne Generation
N
0 °C
N
S
O
27 O
3
N
Pb(OAc)4
N
N
NH2
28
3
Scheme 1.16 Arynes from benzothiadiazole dioxide and amino benzotriazole. Source:
Based on Campbell and Rees [87].
I
Ph OTf
TBAF
TMS
29
3
Scheme 1.17 Arynes from phenyl(2-(trimethylsilyl)phenyl)iodonium triflates. Source:
Based on Kitamura and Yamane [88].
1.7.1.6
Using Hexadehydro Diels–Alder (HDDA) Reaction
Recently, Hoye and coworkers developed a new metal-free method for aryne
generation using the concept of intramolecular HDDA reaction of triynes 30, which
diversified the reactivity profile of the aryne intermediate. This method allows
reagent-free and metal-free thermal generation of arynes 31; however, in some
cases, it requires elevated temperature for the formation of arynes (Scheme 1.18)
[16, 17].
O
O
Heat
O
O
31
30
Scheme 1.18
1.7.1.7
Arynes using HDDA strategy. Source: Hoye et al. [16]; Yun et al. [17].
From ortho-Borylaryl Triflates
In 2013, Hosoya and coworkers developed the generation of aryne intermediates from ortho-borylaryl triflate 32 mediated by sec- or tert-BuLi at low temperature.
However, the use of strong base limits its potential applications (Scheme 1.19)
[89].
1.7.1.8
Pd(II)-Catalyzed C–H Activation Strategy Starting from Benzoic Acids
Greaney and coworkers developed a Pd(II)-catalyzed C–H activation strategy for
the formation of Pd-aryne intermediate, and applied this strategy for the synthesis
11
12
1 Introduction to the Chemistry of Arynes
Bpin
t-BuLi, –33 °C
OTf
32
3
Scheme 1.19
Arynes from ortho-borylaryl triflates. Source: Based on Sumida et al. [89].
of triphenylenes starting from benzoic acids 33 (Scheme 1.20). The intermediate is
formed via an ortho-C–H activation of benzoic acid, followed by the decarboxylation
from the palladacycle [90].
Pd(OAc) 2
ligand
Cu(OAc) 2
COOH
Pd
H
33
3-Pd
Scheme 1.20
1.7.1.9
Arynes via Pd(II)-catalyzed C–H activation. Source: Based on Cant et al. [90].
via Grob Fragmentation
The [2+2] cycloadducts of 3-triflyloxy arynes 34 can undergo a chemoselective ring
opening to generate 2,3-aryne intermediate 35 via Grob fragmentation, which could
be derivatized to trisubstituted arenes (Scheme 1.21) [91].
OTf
OTBS
OR1
R2
R3
34
O
CsF
R2 R3
OR1
35
Scheme 1.21
Arynes via Grob fragmentation. Source: Based on Shi et al. [91].
All the methods outlined above require either metals or stoutly basic or harsh reaction conditions. The use of metals, strongly basic conditions, and high temperature
are not compatible with a large number of functional groups, which considerably
restricted the scope of aryne reactions in organic synthesis. The breakthrough for
a mild method of aryne generation came in 1983 when Kobayashi and coworkers
demonstrated a practical method for the generation of aryne intermediates.
1.7.2
Kobayashi’s Fluoride-Induced Aryne Generation
In 1983, Kobayashi and coworkers, through a pioneering work, uncovered a route
for the generation of arynes, which is base-free and could be carried out under
mild reaction conditions. The strategy involves a fluoride-induced 1,2-elimination
of 2-(trimethylsilyl)aryl triflates 36 to generate arynes in solution. This influential
discovery led to a swift development in the field of aryne chemistry (Scheme 1.22)
1.8 Possible Reactivity Modes of Arynes
[15]. This precursor could easily be synthesized from 2-bromophenol in three
steps. Moreover, a one-pot method also could be employed for the synthesis of the
precursor.
Br
OH
Scheme 1.22
et al. [15].
(i) HMDS (1.2–1.6 equiv)
80 °C, 45–90 min
(ii) n-BuLi (1.1 equiv)
THF, –100 °C to –80 °C
20 min
(iii) Tf2O (1.2 equiv)
–80 °C, 20 min
TMS
OTf
36
F source
rt
3
Kobayashi’s method of aryne generation. Source: Based on Himeshima
Kobayashi’s method, unlike conventional routes, was compatible with a range of
functional groups and reagents. KF (with 18-crown-6 as additive) in THF, CsF in
CH3 CN, TBAT in THF, and tetrabutyl ammonium fluoride (TBAF) in THF are generally used as fluoride sources for the generation of aryne from the silyl triflate 36.
The kinetic control in the aryne reaction can be attained with cautious selection
of fluoride source and solvent combination. This selection of the fluoride sources
controls not only the rate of aryne generation but also the regioselectivity in the product formation. Kobayashi’s method is highly preferred by synthetic chemists over
traditional methods for aryne generation in recent decades. Many traditional aryne
reactions were revisited to enhance the scope and yield after the establishment of
mild and efficient Kobayashi’s procedure of aryne generation.
1.8 Possible Reactivity Modes of Arynes
Due to their low-lying LUMO, arynes have been widely used as electrophiles in various reactions (Scheme 1.23). Arynes are well explored by synthetic organic chemists
as they found that the intermediate is capable for unparallel transformations. The
diverse reactivity profile of this transient intermediate is noteworthy. Aryne reactivity can be classified into:
Pericyclic reactions
Arylation reactions
Insertion reactions
Transition-metal-catalyzed reactions
Multicomponent couplings (MCCs)
Molecular rearrangements
Owing to their well-defined electrophilic nature, arynes are excellent dienophile
and dipolarophile in pericyclic reactions such as Diels–Alder reactions, [2+2]
cycloaddition, and dipolar cycloaddition reactions. Arynes hold the ability to
arylate a number of molecules like alcohols, amines, and thiols leading to efficient
13
14
1 Introduction to the Chemistry of Arynes
+ X
Y
Nu
+
H
Insertion
reaction
Arylation
reaction
Pericyclic reactions
R
E
Multicomponent
reaction
Metal catalyzed
reaction
Scheme 1.23
N
+
Nu
M
R
Molecular
rearrangements
Possible modes of reactivity of arynes.
X–H (X = O, S, and NH) insertion reactions. Arynes are well known to insert into
various element–element σ-bonds and π-bonds, resulting in the formation of a
library of functionalized 1,2-disubstituted arenes. Arynes have also been efficiently
utilized as the electrophilic component in various transition-metal-free multicomponent couplings (MCCs). Molecular rearrangements are the emerging class of
reactivity of arynes, where initial aryne addition is followed by unique molecular
rearrangements (Scheme 1.23).
1.8.1
Pericyclic Reactions
Due to high electrophilicity of the carbon–carbon triple bond in arynes, they are
excellent dienolphiles in pericyclic reactions. Many times, pericyclic reactions of
arynes are utilized for the detection of the aryne generation in solution. Moreover, these reactions could result in the formation of complex arenes in one step
under mild conditions. The Diels–Alder reaction of arynes began with the successful trapping of the in situ–generated aryne intermediate 3 by Wittig and Pohmer
with furan 37 via a [4+2] cycloaddition reaction furnishing epoxynaphthalene
derivative in good yields (Scheme 1.24) [29]. Independently, Huisgen and Knorr
F
O
37
N
N
Li
or
O
S
O2
F
CO2
MgBr
N2
3
38
Scheme 1.24 Wittig and Huisgen’s aryne cycloaddition experiment. Source: Wittig and
Pohmer [29]; Huisgen and Knorr [92].
1.8 Possible Reactivity Modes of Arynes
have utilized aryne as an electrophilic dienophile when they demonstrated the reaction of aryne generated from different precursors with furan 37 or cyclohexadiene
38 [92].
The Diels–Alder reaction of tropones 39 with arynes generated from the Kobayashi
precursor 36 using CsF resulted in the convenient method for the synthesis of
benzobicyclo[3.2.2]nonatrienones 40 in good yield and broad scope (Scheme 1.25)
[93]. Although tropones can react as 4π, 6π, or 8π components in cycloaddition
reactions, the reactivity in this case as diene (4π component) is noteworthy.
O
R2
+
O
TMS
O
CsF
TfO
R1
39
36
Scheme 1.25
R2
+
CH3CN, 30 °C
12 h
R2
R1
R1
40
Diels–Alder reactions of tropones with arynes. Source: Thangaraj et al. [93].
The poor yield and limited scope in the Diels–Alder reaction of styrene with
arynes, known as early as 1966, has been revisited recently in a reaction of
styrenes 41 with arynes generated from 36 using CsF in CH3 CN affording the
9-aryl dihydrophenanthrene derivatives 42 (Scheme 1.26) [94]. Electronics decided
the products in this transformation as electron-rich and neutral styrenes reacted
with arynes to form 9-aryldihydrophenanthrenes, whereas electron-poor styrenes
afforded the dihydrophenanthrenes (1,1 adducts).
R1
TMS
TfO
CsF
+
R2
R1
41
36
CH3CN, 30 °C, 12 h
R2
42
R1
Scheme 1.26
Reaction of styrenes with arynes. Source: Bhojgude et al. [94].
However, similar reactivity was not observed when indene/benzofuran was
treated with arynes under identical conditions. Using indene 43 as the diene
component, reaction afforded the dihydrobenzocyclobutaphenanthrenes 44 in
moderate-to-good yields (Scheme 1.27) [95]. The reaction features a unique [4+2]
cycloaddition followed by a diastereoselective [2+2] cycloaddition to afford the
desired product.
Due to their high electrophilicity and strong dienophilic nature, arynes are
well known to participate in [2+2] cycloaddition reactions with electron-rich
carbon–carbon double bonds. For instance, a tandem stereoselective aryne [2+2]
15
16
1 Introduction to the Chemistry of Arynes
R1
TMS
+
CsF
R1
TfO
43
H
CH3CN, 30 °C, 12 h
dr > 20:1 in all cases
36
R1
44
Scheme 1.27 Tandem [4+2]/[2+2] cycloaddition involving arynes and indene. Source:
Bhojgude et al. [95].
cycloaddition reaction with enamides 45 for the synthesis of benzocyclobutanes 46
has been uncovered by Hsung and coworkers (Scheme 1.28) [96].
Ts
N
TMS
CsF
R1
Bn +
TfO
45
Ts
N Bn
Dioxane, 110 °C
46
36
Scheme 1.28 [2+2] Cycloaddition involving arynes and enamides. Source: Based on
Feltenberger et al. [96].
Apart from [4+2] and [2+2] cycloaddition reactions, arynes are well known to
participate in dipolar cycloaddition reactions. Arynes are excellent dipolarophiles
and can add to various 1,3-dipoles for the synthesis of benzo-fused five-membered
rings. The commonly used 1,3-dipoles that can conveniently add to arynes are
nitrones, nitrile oxides, nitrile imines, azomethine imines, azides, diazo compounds,
etc. (Scheme 1.29).
Dipolar
a
Cycloaddition
c
a
+
b+
–c
3
b
1,3-dipole
Scheme 1.29
1,3-Dipolar cycloaddition of arynes.
For example, the 1,3-dipolar cycloaddition of arynes with diazomethane derivatives for the synthesis of N-unsubstituted indazoles 47 has been reported by Larock
and coworkers (Scheme 1.30) [97].
R1
TMS
+
N2
OTf
36
R1 = H, Aryl, alkyl
R1 = Aryl, TMS, CO2Et
R2
KF, 18-crown-6
THF, rt
R1
R1
N
H
N
N
R2
N
47
R2
Scheme 1.30 [3+2] Cycloaddition reaction of diazo compounds with arynes. Source: Based
on Liu et al. [97].
1.8 Possible Reactivity Modes of Arynes
1.8.2
Arylation Reactions
Arynes are highly electrophilic species; hence, they react with a number of charged
as well as uncharged nucleophiles, resulting in the in situ generation of aryl
anions, which can be protonated, thus leading to efficient arylation reactions.
Thus, arynes can be used as the aryl source for the arylation of OH, SH, and NH
bonds under transition-metal-free conditions. In 2003, Larock and coworkers
developed a mild strategy for the N-arylation of primary and secondary amines 48
by making use of the arylating property of arynes generated from the precursor 36
(Scheme 1.31) [98].
R1
TMS
+
R
HN
OTf
CsF (2.0 equiv)
R2
48
36
CH3CN, rt
5–72 h
R1
N
R
R2
49
R = H, Me, OMe
R1 = alkyl, aryl, sulfonyl
R2 = H, alkyl, aryl
Scheme 1.31
1.8.3
N-Arylation of amines. Source: Based on Liu and Larock [98].
Insertion Reactions
Arynes have the exceptional ability to insert into various element–element
σ-bonds and π-bonds. This insertion phenomenon of arynes has been extensively
employed for the synthesis of functionalized 1,2-disubstituted arenes. For example,
Shirakawa, Hiyama and coworkers utilized the benzyne insertion strategy for
the synthesis of 2-aminobenzamides 50 via a N—CO bond insertion of ureas
(Scheme 1.32) [99]. Also, the insertion of arynes into a carbon–carbon σ-bond of
acyclic and cyclic β-ketoesters led to the one-step synthesis of 1,2-disubstituted
arenes 51 as demonstrated by Stoltz and coworkers in 2005 (Scheme 1.32) [100].
Aryne insertion reactions
Nu E
Nu E
Nu
Insertion
Reactions
E
O
O
NR′2
R
NR′2
50
O
NR′2
O
R2O
TMS
NR′2
CsF (2.0 equiv)
20 °C, 2–19h
R = H, Me, OMe, –(CH)4 –, Ph
R
OTf
36
O
R1
R3
CsF (2.5 equiv)
CH3CN, 80 °C
45–60 min
R1
R2O2C
R
R3
51
R = H, Me, OMe, O(CH2)O, R1 = Me, Et, i-Pr, Bn, Ph
R2 = Me, Et, R3 = Me, (CH2)3, (CH2)5
Scheme 1.32 Insertion of arynes to amides and β-keto esters. Source: Yoshida et al. [99];
Tamber and Stoltz [100].
17
18
1 Introduction to the Chemistry of Arynes
1.8.4
Transition-Metal-Catalyzed Reactions
The development of o-(trimethylsilyl)aryl triflate by Kobayashi and coworkers
helped to discover many novel transition-metal-catalyzed reactions involving
arynes [101]. Metal-catalyzed aryne-based insertion, annulations, cycloadditions,
and multicomponent reactions are well known. In 2009, Biehl and coworkers
reported the coupling of a terminal alkyne 52 and aryne in the presence of CuI for
the synthesis of phenyl acetylene derivatives 53 (Scheme 1.33) [102].
TMS
R
R1
52
OTf
R1
CuI
CsF, 150 °C
MW, CH3CN, Toluene
36
R
53
R = H, Me, F,C4H4
R1 = alkyl
Scheme 1.33 Metal-catalyzed coupling reaction of arynes. Source: Based on Akubathini
and Biehl [102].
1.8.5
Multicomponent Couplings (MCCs)
Transition-metal-free MCCs involving arynes have received considerable attention in the past two decades. A number of 1,2-disubstituted arenes are synthesized
using the MCCs involving arynes in one step. In a typical aryne MCC, the nucleophiles having no acidic proton are added to the in situ–generated arynes forming
the aryl anion intermediate, which is subsequently intercepted by an electrophilic
third component to form complex 1,2-disubstituted arenes. If the nucleophile
and the electrophile do not belong to the same molecule, these reactions result
in unique MCCs. For instance, Yoshida, Kunai, and coworkers reported a facile
three-component reaction of arynes with isocyanides 54 and aldehydes 55 under
mild reaction conditions for the efficient synthesis of iminoisobenzofurans 56 in
good yields (Scheme 1.34) [103]. The variation on all the three components is well
tolerated, and the use of other third components such as activated imines and
electron-poor olefins is also possible.
1.8.6
Molecular Rearrangements
Molecular rearrangements involving arynes are of high interest in recent years.
These rearrangement reactions have provided a number of structurally important
motifs, which is otherwise complicated to synthesize. Many well-known conventional molecular rearrangements were applied in aryne chemistry to make the
aryne version of the same. Using arynes as the aryl source, many of these rearrangements proceed under mild conditions in broad scope. For example, Greaney and
coworkers developed an aza-Claisen rearrangement to synthesize functionalized
anilines 57 using various piperidine and morpholine-derived tertiary allylic amines
58 (Scheme 1.35) [104].
1.10 Arynes for the Synthesis of Large Polycyclic Aromatic Compounds
Multicomponent coupling employing arynes
Nu
Nu
Multicomponent
coupling
E
E
TMS
R
+
1
CN R +
OTf
36
H
KF (4.0 equiv),
O 18-Crown-6 (4.0 equiv)
R2
THF, 0 °C, 5–24 h
1
N R
R
55
54
O
56
R2
R = H, Me, (CH2)3, OMe, F
R1 = CMe2-CH2-CMe3, t-Bu, 1-Ad
R2 = Et, t-Bu, Ph, Ar
Scheme 1.34 MCCs involving arynes, isocyanides, and aldehydes or activated imines.
Source: Based on Yoshida et al. [103].
R2
TMS
N
R1
R
OTf
57
36
CsF
CH3CN, Toluene
(i) rt, 12 h
(ii) reflux 48 h
R
N R1
2
58 R
R = H, Me, (CH2)3, F
R1 = alkyl
Scheme 1.35
Aryne aza-Claisen rearrangement. Source: Based on Cant et al. [104].
1.9 Domino Aryne Generation
The concept of multifunctionalization of aryne materialized with the realization
of the concept of domino aryne generation by Li and coworkers [105]. A novel
domino aryne precursor 59 has been developed (Scheme 1.36), which has vicinal
electrophilic centers, capable of receiving consecutive double nucleophilic addition
onto it. Utilizing this concept, a methodology for the nucleophilic addition-ene
reaction end for the construction of indoline scaffolds 60 was developed by the
same group [106]. A detailed discussion on the domino aryne strategy is provided
in Chapter 8 of this book.
1.10 Arynes for the Synthesis of Large Polycyclic
Aromatic Compounds
Cycloaddition reactions involving arynes give access to the synthesis of large
polycyclic aromatic hydrocarbons (PAHs) containing five or more fused benzene
rings. This strategy is of high value since the products find applications in the
19
20
1 Introduction to the Chemistry of Arynes
E
OTf
OTf
–
TMS
F
Nu2
Nu2, E
Nu1
Nu1
Nu1
OTf
59
Domino Aryne
Precursor
Trifunctionalized
arene
R2
OTs
R1
TMS
+
R
OTf
R3
R = H, aryl, alkyl, Cl, TBS
R1 = R2 = alkyl
R3 = H, alkyl, Aryl
R2
K2CO3 or KF
18-crown-6
R1
R3
R
PhCl, 130 °C
60
Nu
Nu
Scheme 1.36 Domino aryne strategy and the indoline synthesis. Source: Shi et al. [105];
Xu et al. [106].
field of materials science. Moreover, several PAHs are analogous to nanosized
graphene substructures. The benzodiyne precursor has been efficiently utilized for
the synthesis of a number of symmetrical and unsymmetrical PAHs. For example,
Wudl and coworkers reported the synthesis of the stable large PAH 63, in a reaction
of cyclopentadienone 61 with benzodiyne precursor 62 (Scheme 1.37) [107]. The
two-fold Diels–Alder reaction of aryne generated from 62 with the diene 61 is
followed by the elimination of two molecules of CO resulting in the formation of
the PAH 63 in one step.
Ph
O
61
Ph
+
TMS
Ph
Ph
Ph
TBAF
DCM
OTf
TMS
TfO
Ph
63, 22%
62
Scheme 1.37 Polycyclic aromatic hydrocarbons (PAHs) synthesis using arynes. Source:
Based on Duong et al. [107].
1.11 Arynes in Natural Product Synthesis
Arynes are not only exploited in developing novel carbon–carbon and carbon–
heteroatom bond-forming reactions but also in natural product synthesis
References
(Scheme 1.38). The motifs with new carbon–carbon or carbon–heteroatom
bonds formed on the aromatic rings in the aryne reactions form the backbone
for several biologically important molecules. For example, biologically important
molecules such as trisphaeridine, dacarine, eupolauramine, and neuvamine could
be easily synthesized using the aryne strategy. More details on application of arynes
in natural products synthesis have been provided in Chapter 11 of the book.
O
O
O
O
N
N
OMe
OMe
OMe
Trisphaeridine
Scheme 1.38
N
N
MeO
O
HO
O
N Me
Decarine
Eupolauramine
Neuvamine
O
O
Selected examples of natural product synthesized using the aryne concept.
1.12 Concluding Remarks
Arynes are century-old transient intermediates, which can now be accessed using
simple precursors in mild and convenient ways. This has considerably broadened the diverse range of applications using this reactive intermediate. Ever
since the development of Kobayashi’s mild protocol for aryne generation, the
field has revolutionized significantly. The reactivity of arynes can be classified
into cycloaddition reactions, insertion reactions, multicomponent reactions,
transition-metal-catalyzed transformations, and aryne-induced molecular rearrangements. Recent developments in the area have shown rapid emergence of a new
class of reactions under molecular rearrangement employing arynes as aryl source.
The potential synthetic utility of a variety of heterocyclic arynes has also been
uncovered recently by synthesizing various heterocycle-fused ring systems. The
generation of benzynes through the HDDA reaction has allowed this intermediate
to explore new modes of intrinsic reactivities. The trifunctionalization of arynes
and the domino aryne strategies are new concepts emerging recently in this field.
Moreover, aryne methodologies have widely been employed for the synthesis of
several natural products. It is expected that the mild and transition-metal-free
method for the generation of arynes will inspire synthetic chemists to explore new
reactions and potential applications using the concept of arynes.
References
1 Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112: 3550–3577.
2 Gampe, C.M. and Carreira, E.M. (2012). Angew. Chem. Int. Ed. 51: 3766–3778.
3 Bhunia, A., Yetra, S.R., and Biju, A.T. (2012). Chem. Soc. Rev. 41: 3140–3152.
21
22
1 Introduction to the Chemistry of Arynes
4 Dubrovskiy, A.V., Markina, N.A., and Larock, R.C. (2013). Org. Biomol. Chem.
11: 191–218.
5 Wu, C. and Shi, F. (2013). Asian J. Org. Chem. 2: 116–125.
6 Pérez, D., Peña, D., and Guitián, E. (2013). Eur. J. Org. Chem.: 5981–6013.
7 Roy, T. and Biju, A.T. (2018). Chem. Commun. 54: 2580–2594.
8 Sanz, R. (2008). Org. Prep. Proced. Int. 40: 215–291.
9 Takikawa, H., Nishii, A., Sakai, T., and Suzuki, K. (2018). Chem. Soc. Rev. 47:
8030–8056.
10 Wenk, H.H., Winkler, M., and Sander, W. (2003). Angew. Chem. Int. Ed. 42:
502–528.
11 Pellissier, H. and Santelli, M. Tetrahedron 9: 701–730.
12 Chen, Y. and Larock, R.C. (2009). Arylation reactions involving the formation
of arynes. In: Modern Arylation Methods (ed. L. Ackermann), 401, 401–473, 473.
Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA.
13 Karmakar, R. and Lee, D. (2016). Chem. Soc. Rev. 45: 4459–4470.
14 Bhunia, A. and Biju, A.T. (2014). Synlett 25: 608–614.
15 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett. 12:
1211–1214.
16 Hoye, T.R., Baire, B., Niu, D. et al. (2012). Nature 490: 208–212.
17 Yun, S.Y., Wang, K.-P., Lee, N.-K. et al. (2013). J. Am. Chem. Soc. 135:
4668–4671.
18 Goetz, A.E., Shah, T.K., and Garg, N.K. (2015). Chem. Commun. 51: 34–45.
19 Shi, J., Li, Y., and Li, Y. (2017). Chem. Soc. Rev. 46: 1707–1719.
20 Stoermer, R. and Kahlert, B. (1902). Dtsch. Chem. Ges. 35: 1633–1640.
21 Bachmann, W.E. and Clarke, H.T. (1927). J. Am. Chem. Soc. 49: 2089–2098.
22 Wittig, G. (1942). Naturwiss. 30: 696–703.
23 Wittig, G. and Pohmer, L. (1956). Chem. Ber. 89: 1334–1351.
24 Huisgen, R. and Rist, H. (1955). Ann. Chem. 594: 137–158.
25 Huisgen, R. and Rist, H. (1954). Naturwiss. 41: 358–359.
26 Morton, A.A., Davidson, J.B., and Hakan, B.L. (1942). J. Am. Chem. Soc. 64:
2242–2247.
27 Roberts, J.D., Simmons, H.E., Carlsmith, L.A., and Vaughan, C.W. (1953).
J. Am. Chem. Soc. 75: 3290–3591.
28 Roberts, J.D., Semenow, D.A., Simmons, H.E., and Carlsmith, L.A. (1956).
J. Am. Chem. Soc. 78: 601–611.
29 Wittig, G. and Pohmer, L. (1955). Angew. Chem. Int. Ed. 67: 348.
30 Fisher, I.P. and Lossing, F.P. (1963). J. Am. Chem. Soc. 85: 1018–1019.
31 Berry, R.S., Clardy, J., and Schafer, M.E. (1964). J. Am. Chem. Soc. 86:
2738–2739.
32 Berry, R.S., Spokes, G.N., and Stiles, M. (1962). J. Am. Chem. Soc. 84:
3570–3577.
33 Radziszewski, J.G., Hess, B.A.J., and Zahradnik, R. (1992). J. Am. Chem. Soc.
114: 52–57.
34 Leopold, D.G., Stevens-Miller, A.E., and Lineberger, W.C. (1986). J. Am. Chem.
Soc. 108: 1379–1384.
References
35 Wenthold, P.G., Squires, R.R., and Lineberger, W.C. (1998). J. Am. Chem. Soc.
120: 5279–5290.
36 Wenthold, P.G. and Squires, R.R. (1994). J. Am. Chem. Soc. 116: 6401–6412.
37 Wenthold, P.G., Paulino, J.A., and Squires, R.R. (1991). J. Am. Chem. Soc. 113:
7414–7415.
38 Riveros, J.M., Ingemann, S., and Nibbering, N.M.M. (1991). J. Am. Chem. Soc.
113: 1053.
39 Warmuth, R. (1997). Angew. Chem. Int. Ed. 36: 1347–1350.
40 Hoffmann, R., Imamura, A., and Hehre, W.J. (1968). J. Am. Chem. Soc. 90:
1499–1509.
41 Buchwald, S.L., Watson, B.T., and Huffman, J.C. (1986). J. Am. Chem. Soc. 108:
7411–7413.
42 Bennett, M.A., Hambley, T.W., Roberts, N.K., and Robertson, G.B. (1985).
Organomet. 4: 1992–2000.
43 Mclain, S.J., Schrock, R.R., Sharp, P.R. et al. (1979). J. Am. Chem. Soc. 101:
263–265.
44 Hamura, T., Ibusuki, Y., Sato, K. et al. (2003). Org. Lett. 5: 3551–3554.
45 Langenaeker, W., De Proft, F., and Geerlings, P. (1998). J. Phys. Chem. A 102:
5944–5950.
46 Johnson, W.T.G. and Cramer, C.J. (2001). J. Am. Chem. Soc. 123: 923–928.
47 Squires, R.R. and Cramer, C.J. (1998). J. Phys. Chem. A 102: 9072–9081.
48 Lohmann, J. (1972). J. Chem. Soc., Perkin Trans. 168: 814.
49 Sato, T., Niino, H., and Yabe, A. (2001). J. Phys. Chem. A 105: 7790–7798.
50 Kauffmann, T. (1965). Angew. Chem. Int. Ed. 4: 543–557.
51 Kaufmann, T. and Wirthwein, R. (1971). Angew. Chem. Int. Ed. 10: 20–33.
52 Reinecke, M.G. (1982). Five membered hetarynes. In: Reactive Intermediates,
vol. 2 (ed. R.A. Abramovitch), 367–526. New York, Chapter 5: Plenum.
53 van der Plas, H.C. (1982). The chemistry of triple bonded groups. In:
Supplement C of "The Chemistry of Functional Groups" (eds. S. Patai and
Z. Rappoport). New York: Wiley-Interscience.
54 Cramer, C.J. and Debbert, S. (1998). Chem. Phys. Lett. 287: 320–326.
55 Kramer, J. and Berry, R.S. (1972). J. Am. Chem. Soc. 94: 8336–8347.
56 Sasaki, T., Kanematsu, K., and Uchide, M. (1971). Chem. Soc. Jpn. 44: 858–859.
57 Nam, H.-H. and Leroi, G.E. (1988). J. Am. Chem. Soc. 110: 4096–4097.
58 Cava, M.P., Mitchell, M.J., DeJongh, D.C., and van Fossen, R.Y. (1966). Tetrahedron Lett. 4: 2947–2951.
59 Dunkin, I.R. and MacDonald, J.G. (1982). Tetrahedron Lett. 23: 4839–4842.
60 Goetz, A.E., Bronner, S.M., Cisneros, J.D. et al. (2012). Angew. Chem. Int. Ed.
51: 2758–2762.
61 Wenthold, P.G. (2010). Aust. J. Chem. 63: 1091–1098.
62 Winkler, H. and Sander, W. (2010). Aust. J. Chem. 63: 1013–1047.
63 Sato, T. and Niino, H. (2010). Aust. J. Chem. 63: 1048–1065.
64 Sander, W. (1999). Acc. Chem. Res. 32: 669–676.
65 Diau, E.W.-G., Casanova, J., Roberts, J.D., and Zewail, A.H. (2000). Proc. Natl.
Acad. Sci. U.S.A 97: 1376–1379.
23
24
1 Introduction to the Chemistry of Arynes
66 Moskaleva, L.V., Madden, L.K., and Lin, M.C. (1999). Phys. Chem. Chem. Phys.
1: 3967–3972.
67 Buchwald, S.L. and Nielsen, R.B. (1988). Chem. Rev. 88: 1047–1058.
68 Bennett, M.A. and Schwemlein, H.P. (1989). Angew. Chem. Int. Ed. 28:
1296–1320.
69 Frid, M., Pérez, D., Peat, A.J., and Buchwald, S.L. (1999). J. Am. Chem. Soc. 121:
9469–9470.
70 Breslow, R., Napierski, J., and Clarke, T.C. (1975). J. Am. Chem. Soc. 97:
6275–6276.
71 Breslow, R. and Khanna, P.L. (1977). Tetrahedron Lett. 18: 3429–3432.
72 Washburn, W.N., Zahler, R., and Chen, I. (1978). J. Am. Chem. Soc. 100:
5863–5874.
73 Roberts, J.D., Streitwieser, A. Jr., and Regan, C.M. (1952). J. Am. Chem. Soc. 74:
4579–4582.
74 Evleth, E.M. (1967). Tetrahedron Lett. 8: 3625–3628.
75 Dewar, M.J.S. and Li, W.-K. (1974). J. Am. Chem. Soc. 96: 5569–5571.
76 Jagau, J.-C., Prochnow, E., Evangelista, F.A., and Gauss, J. (2010). J. Chem.
Phys. 132: 144110–144119.
77 Nicolaou, K.C. and Dai, W.-M. (1991). Angew. Chem. Int. Ed. 30: 1387–1416.
78 Nicolaou, K.C. and Smith, A.L. (1995). Modern Acetylene Chemistry (eds.
P.J. Stang and F. Diederich). VCH: Weinheim.
79 Polukhtine, A., Karpov, A.G., Pandithavidana, D.R. et al. (2010). Aust. J. Chem.
63: 1099–1107.
80 Guo, X.-F., Zhu, X.-F., Shang, Y. et al. (2010). Clin. Cancer Res. 16: 2085–2094.
81 Roy, S. and Basak, A. (2010). Chem. Commun. 46: 2283–2285.
82 Kitamura, T. (2010). Aust. J. Chem. 63: 987–1001.
83 Ebert, G.W., Pfennig, D.R., Suchan, S.D., and Donovan, T.A. Jr., (1993). Tetrahedron Lett. 34: 2279–2282.
84 Matsumoto, T., Hosoya, T., Katsuki, M., and Suzuki, K. (1991). Tetrahedron Lett.
32: 6735–6736.
85 Stiles, M. and Miller, R.G. (1960). J. Am. Chem. Soc. 82: 3802.
86 Friedman, L. and Logullo, F.M. (1963). J. Am. Chem. Soc. 85: 1549.
87 Campbell, C.D. and Rees, C.W. (1969). J. Chem. Soc. C 1969: 742–747.
88 Kitamura, T. and Yamane, M. (1995). J. Chem. Soc., Chem. Commun. 1995:
983–984.
89 Sumida, Y., Kato, T., and Hosoya, T. (2013). Org. Lett. 15: 2806–2809.
90 Cant, A.A., Roberts, L., and Greaney, M.F. (2010). Chem. Commun. 46:
8671–8673.
91 Shi, J., Xu, H., Qiu, D. et al. (2017). J. Am. Chem. Soc. 139: 623–626.
92 Huisgen, R. and Knorr, R. (1963). Tetrahedron Lett. 16: 1017–1021.
93 Thangaraj, M., Bhojgude, S.S., Bisht, R.H. et al. (2014). J. Org. Chem. 79:
4757–4762.
94 Bhojgude, S.S., Bhunia, A., Gonnade, R.G., and Biju, A.T. (2014). Org. Lett. 16:
676–679.
References
95 Bhojgude, S.S., Thangaraj, M., Suresh, E., and Biju, A.T. (2014). Org. Lett. 16:
3576–3579.
96 Feltenberger, J.B., Hayashi, R., Tang, Y. et al. (2009). Org. Lett. 11: 3666–3669.
97 Liu, Z., Shi, F., Martinez, P.D.G. et al. (2008). J. Org. Chem. 73: 219–226.
98 Liu, Z. and Larock, R.C. (2003). Org. Lett. 5: 4673–4675.
99 Yoshida, H., Shirakawa, E., Honda, Y., and Hiyama, T. (2002). Angew. Chem.
Int. Ed. 114: 3381–3383.
100 Tamber, U.K. and Stoltz, B.M. (2005). J. Am. Chem. Soc. 127: 5340–5341.
101 Dhokale, R.A. and Mhaske, S.B. (2018). Synthesis 50: 1–16.
102 Akubathini, S. and Biehl, E. (2009). Tetrahedron Lett. 50: 1809–1811.
103 Yoshida, H., Fukushima, H., Ohshita, J., and Kunai, A. (2004). Angew. Chem.
Int. Ed. 43: 3935–3938.
104 Cant, A.A., Bertrand, G.H.V., Henderson, J.L. et al. (2009). Angew. Chem. Int.
Ed. 48: 5199–5202.
105 Shi, J., Qiu, D., Wang, J. et al. (2015). J. Am. Chem. Soc. 137: 5670–5673.
106 Xu, H., He, J., Shi, J. et al. (2018). J. Am. Chem. Soc. 140: 3555–3559.
107 Duong, H.M., Bendikov, M., Steiger, D. et al. (2003). Org. Lett. 5: 4433–4436.
25
27
2
Aryne Cycloadditions for the Synthesis of Functional
Polyarenes
Fátima García, Diego Peña, Dolores Pérez, and Enrique Guitián
Universidade de Santiago de Compostela, Departamento de Química Orgánica and CiQUS, Jenaro de la
Fuente s/n, 15782, Santiago de Compostela, Spain
2.1 Introduction
The origin of aryne chemistry can be traced back to 1902, when 2,3-didehydrobenzofuran was formulated by Stoermer and Kahlert as a reaction intermediate [1].
However, arynes did not reappear in the literature as such until the middle of last
century. In 1953, Roberts et al. established the structure 1 for benzyne based on
their famous isotopic labeling experiments [2]. A further period of 60 years had
to elapse before an image of an aryne, generated on a surface under ultra-high
vacuum (UHV) conditions at cryogenic temperature, was obtained by atomic force
microscopy (AFM, Figure 2.1), which curiously suggests a dominant contribution
of the cumulene resonance structure (2a) for this particular aryne under these
conditions [3, 4].
Soon after the experiments by Roberts, several groups initiated studies on the generation and reactivity of arynes. In the context of this chapter, the development of
aryne Diels–Alder (D–A) reactions by Wittig and Pohmer is particularly relevant
[5]. They reported the first aryne cycloaddition, the reaction between benzyne (1)
and furan (4) to yield adduct 5, which represents a fundamental milestone in the
development of aryne chemistry. The formation of epoxynaphthalene 5 constitutes
the first example of an aryne cycloaddition reaction or, more specifically, a [4+2]
cycloaddition or D–A reaction (Scheme 2.1). Over the following decades, cycloaddition reactions involving arynes have experienced impressive progress, including a
great variety of processes, such as [2+2], [4+2], [2+2+2] cycloadditions, etc. [6–11].
The increasing availability of generation methods is of utmost importance in the
progress of aryne chemistry and its synthetic applications. Scheme 2.2 outlines the
most commonly used methods in the 1950–1990 period for the generation of benzyne
and derivatives for synthetic purposes: dehydrohalogenation of aryl halides 6 with
strong base [5, 12]; treatment of o-dihaloaryls 7 with metals [13, 14] or organolithium
compounds [15], or o-haloaryltosylates 8 with organolithium compounds [16]; thermal decomposition of an arenediazonium carboxylate 10 previously isolated [17] or
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
28
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
1
2a
2b
Figure 2.1 Structure of benzyne (1) and AFM image of o-aryne 2. Source: Image adapted
with permission from Pavliček et al. [3]. Copyright 2015, Springer Nature.
Br
+
3
O
PhLi
O
via 1
5
4
Scheme 2.1
1
Wittig’s first aryne cycloaddition. Source: Based on Wittig and Pohmer [5].
generated in situ by diazotization of the corresponding anthranilic acid 9 [18]; thermal decomposition of a 2-diphenyliodonium carboxylate 11 [19] and oxidation of a
1-aminobenzotriazole 12 with Pb(OAc)4 [20].
X
CO2–
Δ
Base
6
10
X
7
Y
OTs
8
N2+
9
1
n-BuLi
X
NH2
CO2–
Δ
RLi, Mg
COOH
i-Am-ONO
11
N
Δ
N
13
I+
Ph
N
Pb(OAc)4
N
N
12
N
N
NH2
X, Y: halogen
Scheme 2.2
Classical methods for aryne generation.
In 1983, Kobayashi and coworkers described a new synthetic methodology
for the preparation of arynes, based on the fluoride-induced decomposition of
o-(trimethylsilyl)phenyl triflate (14) (Scheme 2.3) [21]. This is a mild, efficient, and
safe procedure for the generation of arynes. It does not require the use of oxidants
or strong bases, and it is compatible with most substrates and reaction conditions.
Despite these clear advantages, this method went unnoticed for 15 years, being
reported only in three publications between 1983 and 1998.
In 1998, Guitián and Pérez’s research group described the first example in the
participation of benzyne, generated from triflate 14, in a metal-catalyzed reaction,
specifically in a [2+2+2] cycloaddition catalyzed by palladium(0) [22]. This, together
with the establishment of a general approach for the synthesis of functionalized and
2.2 Aryne Cycloaddition Reactions: General Considerations
Me
Si Me
Me
F
–
OTf
1
14
Scheme 2.3
et al. [21].
Kobayashi’s method for aryne generation. Source: Based on Himeshima
polycyclic o-(trimethylsilyl)aryl triflates developed by the same group [23], demonstrated the versatility of Kobayashi’s method and, since then, aryne chemistry has
experienced a reawakening.
2.2 Aryne Cycloaddition Reactions: General
Considerations
This section provides an overview of the utility of [2+2], [4+2], and [2+2+2] aryne
cycloaddition reactions for the preparation of extended polycyclic aromatic hydrocarbons (PAHs), which are relevant as functional organic compounds and appear
in examples selected from the last 40 years’ literature. The 1,3-dipolar cycloaddition
reactions will be discussed in Chapter 3. General aspects of cycloaddition reactions
involving arynes are described in Sections 2.2.1–2.2.3.
2.2.1
[4+2] Aryne Cycloadditions
Concerted D–A reactions involving arynes are symmetry-allowed [π4s+π2s]
cycloadditions, usually controlled by the interaction between the lowest unoccupied molecular orbital (LUMO) of aryne, i.e. the Csp –Csp antibonding orbital, and the
highest occupied molecular orbital (HOMO) of the diene. Therefore, aryne and diene
must approach in almost perpendicular planes, as shown in Scheme 2.4. In this
classic example, benzyne (1) reacts with tetraphenylcyclopentadienone (15),
presumably through transition state 18, to afford adduct 16, which undergoes a
cheletropic extrusion of CO to give 17 [14].
Ph
O
Ph
Ph
Ph
+ O
1
15
Ph
–CO
Ph
Ph
Ph
Δ
Ph
Ph Ph
16
17
Ph
Ph
Ph
O
Ph
Ph
18
Scheme 2.4 [4+2] Cycloaddition of benzyne (1) and cyclopentadienone 15. Source: Based
on Wittig and Knauss [14].
The regioselectivity of [4+2] cycloadditions with nonsymmetric partners depends
on the position and nature of the substituents on aryne and diene and has been
attributed either to electronic [24], steric [25, 26], or distortion effects [27].
29
30
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
D–A reactions of arynes have been extensively used for the synthesis of PAHs [28,
29], heterocycles [30–33], natural products [34–37], and molecular materials (see
references for Section 2.3).
2.2.2
[2+2] Aryne Cycloadditions
[π2s+π2s] Aryne cycloadditions are forbidden processes according to the
Woodward–Hoffmann rules. However, there are numerous examples of [2+2]
cycloadditions of arynes described in the literature, particularly with ketene acetals
[6–12, 38–40].
When substituted olefins were used as reaction partners, mixtures of stereoisomers were usually observed. For example, the reaction of benzyne (1) and
1,2-dichloroethylene led to mixtures of stereoisomers 19 and 20 (Scheme 2.5) [41].
Cl
Cl
Cl
Cl
or
Cl
1
19
Scheme 2.5
Levin [41].
Cl
+
Cl
20
Cl
Reaction of benzyne (1) and 1,2-dichloroethylene. Source: Jones and
These findings led to the conclusion that nonconcerted radical mechanisms are in
operation, and this was supported by density functional theory (DFT) calculations
[42, 43]. However, some examples of stereospecific [2+2] cycloadditions have been
reported (Scheme 2.6) [39].
OBn
OBn
TBDMSO
I
OEt
+
Me
OTf
21
Scheme 2.6
et al. [39].
H
22
n-BuLi
87%
via 23
OTBDMS
OEt
H
Me
24
OBn
23
Suzuki’s stereospecific [2+2] cycloaddition. Source: Based on Hosoya
[2+2] Aryne cycloadditions have been used for the synthesis of natural products
[37, 44] and to obtain rather complex structures, such as 25 (Figure 2.2), prepared
through an iterative process of aryne generation/[2+2] cycloaddition [40]. For [2+2]
cycloadditions leading to insertion reactions, see Chapter 4.
R
R
R
R
R R
R
R
R
R
R R
25, R = OMe
Figure 2.2 Compound 25 obtained by three consecutive
[2+2] cycloadditions. Source: Based on Hamura et al. [40].
2.2 Aryne Cycloaddition Reactions: General Considerations
A particular case of [2+2] cycloaddition is the formation of biphenylenes, such as
26, by dimerization of arynes (Scheme 2.7) [17]. Examples of [2+2] cycloadditions
between arynes and carbon-rich structures will be discussed in Section 2.3.6.
+
1
1
Scheme 2.7
et al. [17].
2.2.3
26
Dimerization of benzyne to yield biphenylene (26). Source: Based on Logullo
[2+2+2] Aryne Cycloadditions
Despite [π2s+π2s+π2s] cycloadditions being allowed according to Woodward–
Hoffmann rules, the participation of three reactants in a concerted reaction is
entropically disfavored. The examples on the formation of triphenylene (27) by
formal cyclotrimerization of benzyne described until the late 1990s are supposed to
occur stepwise rather than in a concerted manner.
In their pioneering work, Guitián, Pérez, and coworkers explained in 1998
that benzyne is able to react in the presence of catalytic amounts of palladium(0)
complexes, affording triphenylene (27) (Scheme 2.8) [22]. Experimental evidences supported a mechanism for this reaction similar to that of the well-known
metal-catalyzed [2+2+2] cycloaddition of alkynes. This work represented the first
example of the participation of arynes in metal-catalyzed reactions, broadening
the scope and utility of these short-lived species for their application in organic
synthesis.
OTf
TMS
14
Scheme 2.8
[22].
CsF
[2+2+2]
CH3CN
1
Pd(PPh3)4
10 mol%
27
First palladium-catalyzed [2+2+2] cycloaddition of arynes. Source: Peña et al.
The authors found that the slow, controlled generation of benzyne was a crucial
factor for the success of the reaction. This can be achieved by treating 14 with a fluoride source (typically, CsF) in acetonitrile or in an alternative solvent (and additives,
if necessary). The reaction allows the efficient synthesis of triphenylenes, which constitutes the core of an important family of discotic liquid crystals [45], as well as the
fundamental structure to access extended PAHs with trigonal symmetry, which are
discussed in Section 2.3.4.
Guitián, Pérez, and coworkers also explained that the [2+2+2] cycloaddition reactions of arynes could be extended to include alkynes as reaction partners. Thus, the
31
32
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
Pd(0)-catalyzed cocycloaddition of benzynes with electron-deficient alkynes, such as
dimethyl acetylenedicarboxylate (28, DMAD), was reported [46]. Surprisingly, these
reactions are highly chemoselective and the product distribution depends on the
choice of the catalyst. Thus, the use of Pd(PPh3 )4 as catalyst allows to obtain the
product 29, bearing two units of aryne and one of alkyne, while the use of Pd2 (dba)3
affords 30, resulting from the reaction of one aryne moiety and two molecules of
alkyne (Scheme 2.9).
CO2Me
Pd
+
1
+
CO2Me
CO2Me
28
Pd(PPh3)4
Pd2(dba)3
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
29
30
84
10
7
83
Scheme 2.9 First palladium-catalyzed [2+2+2] cocyclotrimerization of arynes and
alkynes. Source: Based on Peña et al. [46].
Later, Yamamoto and coworkers developed an alternative catalytic system,
Pd(OAc)2 /P(o-tol)3 , which allows the [2+2+2] cocycloaddition with electron-rich
alkynes [47]. Subsequently, it was demonstrated that alkenes and allenes could also
participate in [2+2+2] cocycloaddition with arynes [48–50].
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Cycloaddition reactions of arynes have been used for the preparation of π-functional
materials following a bottom-up approach as well as for the functionalization of
materials obtained by other aryne-free methodologies. In Sections 2.3.1–2.3.6,
aryne-based methodologies for the synthesis of families of compounds with
potential application in materials science will be described.
2.3.1
Synthesis of Acenes
Acenes, such as rubrene and pentacene, are characterized by their low band gap and
high charge carrier mobility and, therefore, are potentially useful as organic semiconductors, although their practical application is hampered by their instability and
the difficulties in preparing them. To improve their properties, intensive research
has been done for preparing and studying new substituted and heterocyclic acenes.
In this context, [4+2] cycloadditions involving arynes as dienophiles are used for
increasing the length of the acene skeleton [29]. On the other hand, it was established that the introduction of substituents or nonlinearly fused benzene rings can
improve the stability of acenes [51].
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Seminal work in this field was reported by Thummel et al. on the synthesis of
tetracene (35) [52]. The [4+2] cycloaddition reactions between benzyne (1), generated from benzenediazonium 2-carboxylate (10), and 1,2-dimethylenecyclobutane
(31) led to the formation of adduct 32 (Scheme 2.10). Furthermore, they demonstrated that 32 could be transformed into tetracene (35) through three reaction
steps: a first electrocyclic opening at 300 ∘ C providing the exocyclic diene
33, followed by reaction with benzyne (1), and a final dehydrogenation with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
CO 2
300 °C
+
10
N2
25%
via 1
31
32
33
10
27% via 1
1
DDQ
35
Scheme 2.10
34
Thummel’s synthesis of tetracene (35). Source: Based on Thummel et al. [52].
In a related but more sophisticated approach, Herwig and Müllen described
the synthesis of stable pentacene precursors 41a,b, which can be converted in the
solid state into pentacene (42) through heating (Scheme 2.11) [53]. The synthetic
pathway started with the reaction of bisdiene 37 with two benzyne units, generated
from o-dibromobenzene (36) in the presence of n-BuLi, to form bisadduct 38
in 54% yield. Dehydrogenation of 38 with chloranil afforded 39. Then, 39 was
reacted with tetrachlorothiophenedioxide (40a) or its bromo-analogue 40b to yield
adducts 41a,b, which are soluble and easily processable as films. Finally, heating
up to 180 ∘ C, films of 41a,b afforded pentacene (42) quantitatively by a retro-D–A
reaction. This is a practical approach to pentacene films for the construction of
field-effect transistors.
Br
n-BuLi
+
36
Br
Chloranil
54%
via 1
37
75%
38
39
X
X
X
X
70–75%
X
X
SO2
X
X
40a,b
Δ
100%
1
Scheme 2.11
[53].
42
41a,b
a: X = Cl
b: X = Br
Müllen’s synthesis of pentacene (42). Source: Based on Herwig and Müllen
A similar strategy to yield hexacene (47) was implemented by Neckers’s group in
2007 [54]. Sequential reaction of both dienes of bisdiene 37 with benzyne (1) and
33
34
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
2,3-naphthyne (44) yielded bisadduct 45 in 54% yield (Scheme 2.12). Then, dehydrogenation with chloranil followed by dihydroxylation with OsO4 and oxidation with
trifluoroacetic anhydride (TFAA) and dimethyl sulfoxide (DMSO) afforded diketohexacene 46, which was transformed into hexacene (47) by irradiation at 395 nm.
Br
(1)
3
n-BuLi, via 1
(2)
Br
37
43
n-BuLi, via 44
45 (54%)
Br
48%
hν
(1) Chloranil
(2) OsO4, NMO
(3) DMSO, TFAA
CO
CO
47
Scheme 2.12
1
46
44
Neckers’s synthesis of hexacene (47). Source: Based on Mondal et al. [54].
Jancarick, Gourdon, and Levet described a general methodology for the synthesis
of long acenes [55]. The key step in the synthetic route is a double D–A cycloaddition
reaction between bisdiene 48 and two units of 2,3-naphthyne (44), generated either
from 2,3-dibromonaphthalene (43) or from triflate 49 (Scheme 2.13). Treatment of
the corresponding biscycloadduct with DDQ and deprotection of the ketal groups
yielded the CO-bridged acene precursor 50, which, upon heating in the solid state at
c. 200 ∘ C, allowed the preparation of heptacene (51). Other acenes, such as 52 and
53, could be obtained when using 1,2-naphthyne (54) as dienophile.
O
O
(1) 49, CsF
or 43, n-BuLi
via 44
(2) DDQ
(3) TMSI
48
CO
50 (60–63%)
Δ
44
TMS
OTf
51 (100%)
49
52
53
54
Scheme 2.13 Gourdon’s synthesis of heptacene (51) and benzo-fused acenes 52, 53.
Source: Based on Jancarik et al. [55].
Gribble and coworker succeeded in the generation of the tetracyclic skeleton of
tetracenes in just one reaction step by a D–A reaction of 2,3-didehydronaphthalene
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
(44), generated from 2,3-dibromonaphthalene (43) in the presence of phenyllithium,
and 2-methylisoindoles 55a,b (Scheme 2.14) [56]. The unsubstituted and tetrafluorinated adducts 56a,b were deaminated by treatment with m-chloroperbenzoic acid
(m-CPBA) to yield tetracenes 35 and 57 in excellent yields.
X
Br
X
X
+ Me N
Br
X
43
55a,b X
X
PhLi
a: 52%
b: 68%
via 44
NMe
X
56a,b
X
m-CPBA
X
a: X = H
b: X = F
X
44
X
35: X = H (85%)
57: X = F (92%)
Scheme 2.14
Gribble [56].
X
Gribble’s synthesis of tetracenes 35 and 57. Source: Based on LeHoullier and
Rickborn and coworkers also used a [4+2] cycloaddition of 2,3-didehydronaphthalene (44) with isobenzofuran 58 to yield adduct 59 with the tetracyclic skeleton
of tetracene (Scheme 2.15) [57]. The adduct 59, obtained in a 78% yield, was transformed into tetracene (35) by treatment with acetic acid, to yield ketone 60 in 90%
yield, followed by its reduction with LiAlH4 and dehydration with HCl.
+
O
Br
43
TMS
TMS
Br
TMS 58
RLi
78%
via 44
O
59
TMS
AcOH
90%
(1) LiAlH4
44
Scheme 2.15
35
(2) HCl
83%
60
O
Rickborn’s synthesis of tetracene (35). Source: Based on Netka et al. [57].
Hamura and coworkers obtained a substituted pentacene 69 by successive
D–A cycloadditions (Scheme 2.16) [58]. Epoxynaphthalene 5 was reacted with
dibromoisobenzofuran 61 through a [4+2] cycloaddition to afford adduct 62, which,
in the presence of n-BuLi, can generate aryne 63 and react with furan through
another D–A to generate endoxide 64 in 76% yield. Endoxide 64 was reacted with
3,6-di-2-pyridyl-1,2,4,5-tetrazine (65) and fumaronitrile to afford adduct 67. This
one-pot transformation involves a sequence of reactions, starting with a D–A
reaction between 64 and tetrazine 65, followed by a N2 extrusion, and a final
retro-D–A reaction to yield isobenzofuran 66, which is reacted in situ with
35
36
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
fumaronitrile. Adduct 67 by treatment with LiI and 1,8-diazabicyclo(5.4.0)undec-7ene (DBU) was converted into diepoxypentacene 68, which, by epoxide opening
and Lewis acid–promoted aromatization, afforded pentacene 69 in 49% yield.
Ph
O
+O
Ph
5
H
Br
O
65%
Br
Br
O
H
61
Ph
Br
Ph 62
H
n-BuLi
O
Furan
via 63
76%
Ph
O
H
O
Ph 64
via 66
H
O
AlBr 3
CsI
49%
Ph
H
CN
LiI, DBU
O
H
Ph
H
CN
O
CN
Ph
Scheme 2.16
[58].
69
H
Ph 63
CN
O
CN
67 (89%)
Ph
Ph
O
Py
N N 65
CN
O
H
68
N N
(2) NC
Ph
93%
CN
Ph
O
(1)
Py
H
O
Ph
O
H
O
Ph 66
Hamura’s synthesis of substituted pentacene 69. Source: Based on Eda et al.
In a seminal work published in 1979, Hart’s group introduced a convergent
methodology based on the use of bisarynes (Scheme 2.17) [59]. These species
formally contain two arynic triple bonds in the same molecule, but both triple
bonds most probably do not coexist. In Hart’s work, the transformation of 70 into
bisadduct 75 can be formally represented as a double D–A over the bisaryne synthon
72, but this process presumably involves the generation of a first monoaryne 73,
its D–A reaction with tetramethylpyrrole 71, the generation of a second aryne 74
and its reaction with 71 to yield bisadduct 75 in 57% yield. Finally, dodecamethyltetracene (76) was obtained by oxidation of bisadduct 75 with m-CPBA and thermal
elimination of the N-oxide in 15% yield.
A slightly modified procedure for the generation of a bisnaphthyne was
implemented by Gribble et al., based on the use of tosylates as leaving groups
(Scheme 2.18) [60]. For a similar synthesis using Kobayashi’s method, see [61, 62].
Rickborn and coworkers followed a similar methodology for the synthesis of pentacene (42) (Scheme 2.19) [57]. Starting from 1,4-dibromobenzene (82), a formal
double D–A reaction of the bisaryne synthon 83 with furan 58 yielded bisadduct 84.
This reaction is highly regioselective, observing the formation of linear pentacene
derivative 84 as the only reaction product, which suggests that reaction through
synthon 85 does not occur. Bisadduct 84 was subjected to a treatment with trifluoroacetic acid (TFA) followed by LiAlH4 to obtain pentacene (42).
Luo and Hart designed an original methodology for the construction of
acenes based on iterative [4+2] cycloadditions (Scheme 2.20) [63]. Starting from
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Me
Me
Me Me Me Me
NR
Me Me
Br
Br
Br
Br
Me
71 Me
Me
NR
NR
n-BuLi
57%
Me
Me Me
Me Me Me Me
Me m-CPBA Me
Me
Me Me Me Me 75
Me Me 70
15%
Me
Me
Me
Me Me Me Me 76
Me Me Me
Me Me
Br
Me
NR
Br
Me Me
37
Me Me
72
Me
Me Me Me
73
R = n-Bu
74
Scheme 2.17 Hart’s bisaryne synthesis of dodecamethyltetracene (76). Source: Based on
Sy and Hart [59].
R
TsO
OTs
+
Br
Br
77
O
PhLi
40–44%
via 79
R
4: R = H
78: R = Me
R
R
O
O
R
80a: R = H
80b: R = Me
R
R
R
(1) H2, Pd/C
(2) TFA/CHCl3
or
HCl/MeOH
R
35: R = H
81: R = Me
79
Scheme 2.18 Gribble’s bisaryne synthesis of tetracenes 35 and 81. Source: Based on
Gribble et al. [60].
TMS
TMS
Br
+
LTMP
O
39%
Br
82
TMS
58
via 83
TMS
O
O
84 TMS
TMS
(1) TFA
(2) LiAlH4
83
Scheme 2.19
85
42
Rickborn’s synthesis of pentacene (42). Source: Based on Netka et al. [57].
1,2,4,5-tetrabromobenzene (86a) in the presence of butyllithium, bisaryne 87a was
generated and reacted with excess of furan through two D–A reactions, yielding
bisadduct 88a in a 71% yield. Then, 88a was reacted with tetraphenylcyclopentadienone (15) through another [4+2] cycloaddition, affording bisadduct 89a in high
yield. Heating bisadduct 89a to 190–200 ∘ C generates bisdiene 91a, which can be
trapped by dienophiles. This process presumably involves two retro-D–A reactions
R
38
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
to give norbornadienone 90 and bisfuran 91a. Schlüter and coworkers extended
this methodology to the synthesis of oligomers 92 [64, 65]. Generation of 91b in the
presence of 88b afforded oligomers 92 with almost monomodal weight distributions
(M n = 16 500; M w = 29 000) [64]. Reaction of polymer 92 with trimethylsilyliodide
gave a deoxygenated material, which was not fully characterized [65].
R
O
Br
Br
Br
R
O
30%
Br
via 87
O
R
86a,b
R
Ph
O
Ph
n-BuLi
Ph
Ph
R
R
Ph
Ph
15 Ph
Ph
O
CO
90–92%
O
CO
Ph
Ph
Ph
88a,b
Hex
89a,b
R
Ph
Ph
Δ
R
Ph
88b
O
R
O
Hex
92
87a,b
O
O
Ph
90 Ph
R
n
CO
91a,b
a: R = H; b: R = Hex
Scheme 2.20 Hart’s and Schlüter’s synthesis of epoxyacenes. Source: Luo and Hart [63];
Blatter and Schlüter [64]; Vogel et al. [65].
Wudl and coworkers synthesized the stable, substituted heptacene 98 [66]. Dibromoanthracene 94, prepared by standard procedures from quinone 93, was treated
with lithium tetramethylpiperidide (LTMP), in the presence of diphenylisobenzofuran 95 to afford bisendoxide 97. Reduction of 97 with Zn provided the expected
functionalized heptacene 98 (Scheme 2.21).
Ph
R
O
O
Br
Br
LTMP
32%
via 96
Br
Br
93
O
94
R
Ph
R
Ph
95 Ph
O
Ph
O
97
R
Ph
Zn, HOAc
73%
Ph
R
R=
96
R
Scheme 2.21
R
Ph
R
Ph
TIPS
Ph
98
Wudl’s synthesis of heptacene 98. Source: Based on Chun et al. [66].
Hamura’s group developed a second methodology based on bisaryne and furan
[4+2] cycloadditions to obtain pentacene 105 (Scheme 2.22) [67]. Selective generation of aryne 99 from 1,2,4,5-tetrabromobenzene (86a) by addition of n-BuLi and
trapping with 61 yielded adduct 100, which can also act as a formal bisbenzyne
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
precursor (synthon 101) in the presence of n-BuLi and can be trapped again with
two furan units to afford triepoxypentacene 102 in 41% yield. Triepoxypentacene
102 was reacted with tetrazine 65 to give bisisobenzofuran 103, which, in the
presence of dimethyl maleate, afforded bisadduct 104. This one-pot transformation
involves a sequence of reactions, starting with a D–A reaction between terminal
alkenes present in 102 and tetrazine 65, followed by a N2 extrusion, and a final
retro-D–A reaction to yield bisisobenzofuran 103, which is reacted in situ with
dimethyl maleate. In the last step of the synthesis, triepoxypentacene 104 was
transformed into pentacene 105 by treatment with H2 SO4 .
Ph
Ph
Br
Br
Br
+ O
Br
Br
86a
Br
Ph
n-BuLi
via 99
Br
Ph
Br
n-BuLi
Furan
Br
41%
via 101
O
Br
61
100 Ph
Ph
CO2Me
MeO2C
CO2Me
cat. H2SO4
MeO2C
Toluene
71%
MeO2C
O
99
Scheme 2.22
et al. [67].
CO2Me
CO2Me
O
CO2Me
104
Ph
Ph
N
N N
O
N N
101 Ph
Ph
65
58%
via 103
O
Ph
Br
O
CO2Me
O
Ph
Br
O
102
Ph
MeO2C
105
O
65
O
O
N
103 Ph
Hamura’s synthesis of substituted pentacene 105. Source: Based on Haneda
Peña and coworkers modified Hamura’s methodology by using Kobayashi’s
method for the generation of arynes and developed a methodology for the generation of acenes by combining solution chemistry with on-surface synthesis. As a
proof of concept, stable bisepoxytetracene and trisepoxyhexacene were synthesized
through successive D–A cycloaddition reactions between arynes and furans.
Then, these epoxyacenes were deposited on Cu(111) under UHV conditions and,
upon annealing at 393 K or by tip-induced manipulation with a scanning probe
microscope, tetracene [68] and hexacene [69], respectively, were generated. With
these precedents, the authors decided to try the generation and characterization
of unknown decacene [70]. Tetraepoxydecacene (114) was selected as a stable precursor for decacene (115) (Scheme 2.23). The synthesis of 114 involved a three-step
iterative sequence of four aryne cycloadditions. Bistriflate 106 by treatment with
stoichiometric CsF presumably led to the formation of monoaryne 108, which was
trapped by means of a first D–A cycloaddition with highly reactive substituted
isobenzofuran 107 to give a mixture of regioisomers 109a,b in 42% yield. Further
reaction of this mixture with more CsF generated aryne 110, which, in the presence
39
40
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
of isobenzofuran 107, afforded regioisomers 111a,b in 34% yield by means of a
second [4+2] cycloaddition. Then, the mixture 111a,b was treated with an excess
of CsF and in situ–formed isobenzofuran 112 to obtain decacene precursor 114
in 33% yield by two consecutive aryne D–A cycloadditions. Finally, tetraepoxydecacene 114 was deposited on Au(111) under UHV conditions and transformed into
decacene (115) by annealing at 220 ∘ C or by voltage pulses from the scanning probe
microscope tip.
TfO
O
TfO
OTf
TMS
TMS
106
TMS
R
107
CsF, 42%
via 108
R
OTf
O
R′
TMS
109a,b
107
CsF, 34%
via 110
OTf
O
R′
O
a: R = OTf, R′ = TMS
b: R = TMS, R′ = OTf
TMS
111a,b
O
112
CsF, 33%
via 113
O
O
O
O
114
On-surface
deoxygenation
Au(111)
Decacene
115
OTf
OTf
O
O
108
TMS
110
TMS
O
113
Scheme 2.23 Peña’s synthesis and STM image of decacene (115). Source: Image adapted
with permission from Krüger et al. [70]. Copyright 2017, John Wiley and Sons.
Aryne intermediates have also been used for the synthesis of undecacene – the
longest unsubstituted acene prepared to date – by Bettinger and coworkers [71]. The
synthesis started with the trapping of one unit of 2,3-naphthyne (44), generated from
2,3-dibromonaphthalene 43 in the presence of n-BuLi, with bisdiene 37, generating monoadduct 116 in 47% yield (Scheme 2.24). Sequential generation of arynes
from 1,2,4,5-tetrabromobenzene (86a) with methyllithium and trapping with two
units of diene 116 afforded bisadduct 117, bearing the undecacene skeleton in 19%
yield. Bisadduct 117 was dehydrogenated with chloranil, dihydroxylated with OsO4 ,
oxidized with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and, finally, photoirradiated (𝜆 > 395 nm) on a polystyrene matrix under cryogenic conditions (8 K) to
generate undecacene (118).
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Br
n-BuLi
+
43
Br
37
47%
via 44
Br
Br
Br
86a
Br
116
MeLi
19%
via 83
44
117
hv
Matrix, 8 K
83
118
Scheme 2.24
Bettinger’s synthesis of undecacene (118). Source: Based on Shen et al. [71].
Acenes that consist of more than four units are unstable and very reactive
molecules with respect to photo-oxidation. Two main strategies have been implemented to improve their stability. The first of them entails the expansion of the
conjugated system of the acene by introducing fused rings, such as phenanthrene
or pyrene units. The second strategy is to introduce substituents, blocking the more
reactive positions. Additionally, substituents and fused rings can create a distortion
of the planarity (twistacene), improving the solubility and processability of the
corresponding acenes. In this context, in 2004, Pascal and coworkers synthesized
hexaphenyltetrabenzopentacene 123, which, due to the steric constraint, is not
planar, exhibiting an end-to-end twist of the pentacene skeleton of 144∘ [72].
The synthesis of this pentacene 123 starts with two D–A cycloadditions between
p-diphenylbisbenzyne 121 synthon, generated from tetrabromoterphenyl 119 in the
presence of n-BuLi, and 1,3-diphenylphenanthrofuran 120, yielding bisendoxypentacene 122. This compound was converted into hexaphenyltetrabenzopentacene
123 by treatment with low-valent titanium (TiCl3 /n-BuLi) in 27% isolated yield
(Scheme 2.25). Moreover, the authors were able to resolve both enantiomers of
hexaphenyltetrabenzopentacene 123 by preparative chiral high performance liquid
chromatography (HPLC).
Very recently, Zhang, Liu, and coworkers described the synthesis of dodecatwistacene 127 by the reaction of aryne 126, generated in situ from anthranilic
acid 124 upon treatment with i-Am-ONO, and biscyclopentadienone 125, followed
by thermolysis of the bisadduct to force its decarbonylation (Scheme 2.26) [73].
However, 127, although having six benzene rings fused to the dodecacene scaffold
and six pendant phenyl rings, was found to be unstable on air, presumably due to
the high energy of its HOMO orbital.
Wudl and coworkers used a bisbenzyne approach for the synthesis of tetraphenyltetrabenzoheptacene 130, another twistacene [74]. Sequential aryne generation
from bistriflate 128, triggered by fluoride, followed by trapping with two units
41
42
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
Ph
Br
Ph
Ph
Br
n-BuLi
+ O
Br
Br
Ph
O
26%
via 121
Ph
119
Ph
O
Ph
122
120
Ph
Ph
Ph
TiCl 3, n-BuLi
27%
Ph
Ph
Ph
121
Ph
Ph
Ph Ph
123
Ph
Scheme 2.25 Pascal’s synthesis of twisted substituted pentacene 123. Source: Based on
Lu et al. [72].
t-Bu
Ph
CO2H
t-Bu
t-Bu
NH2
Ph
t-Bu
+
(2) 300 °C
t-Bu
O
O
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
127
t-Bu
t-Bu
Ph
Ph
t-Bu
Ph
t-Bu
Ph
Ph
Ph
(1) i-Am-ONO
23%
via 126
124
Ph
t-Bu
125
Ph
t-Bu
Scheme 2.26
[73].
126
Zhang’s synthesis of dodecatwistacene 127. Source: Based on Chen et al.
of cyclopentadienone 129, afforded tetraphenyltetrabenzoheptacene 130 as stable orange solid in 22% reaction yield (Scheme 2.27). In contrast with 127, this
relatively short twistacene is stabilized by four fused benzene rings and four phenyl
substituents.
In 2015, Pérez, Peña, and coworkers described the synthesis of a series of large
acenes by a sequence of two D–A cycloadditions of the 2,6-naphthodiyne synthon
79 with dienones (Scheme 2.28) [75]. Treatment of bistriflate 106 with tetrabutylammonium fluoride (TBAF) in the presence of cyclopentadienone 129 afforded acene
131. These authors also showed that, using a controlled amount of TBAF, the
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Ph
TMS
OTf
TfO
TMS
+
128
O
Ph
Ph
Ph
Ph
Ph
TBAF
22%
via 83
129
83
130
Scheme 2.27 Wudl’s synthesis of benzo-fused substituted heptacene 130. Source: Based
on Duong et al. [74].
reaction of bistriflate 106 with cyclopentadienone 15 can be stopped after only
one cycloaddition to isolate 132. Then, the generation of the second aryne 134
in the presence of a different cyclopentadienone 133 afforded the asymmetric
acene 135.
Another approach to yield substituted pentacenes involving three [4+2] aryne
cycloadditions was used by Nuckolls’s group (Scheme 2.29) [76]. Aryne 138 was
generated from the iodonium triflate 136 in the presence of TBAF, and reacted
with cyclopentadienones 137 or 15 to yield bis(trimethylsilyl)naphthalenes 139a
or 139b, respectively. These naphthalenes 139a,b were converted into iodonium
triflates 140a,b by treatment with PhI(OAc)2 and TfOH. The reaction of 140a,b
with TBAF generates the corresponding arynes 142a,b, which, in the presence
of electron-deficient diene 2,5-diaryl-6H-1,3,4-oxadiazine-6-one (141), afforded
phenylated pentacenes 144a,b. This transformation involves a D–A aryne cycloaddition followed by N2 extrusion and another D–A cycloaddition to the resulting
α-pyrone 143a,b, followed by CO2 extrusion.
Palladium-catalyzed [2+2+2] cocyclizations have also been used for the synthesis
of functionalized acenes, as shown in Scheme 2.30 [77]. The reaction of bisaryne precursor 106 and dialkylacetylene dicarboxylates 145a–c in the presence of Pd2 (dba)3
afforded tetracene octaesters 146a–c in one pot in 16% yield.
2.3.2
Synthesis of Perylene Derivatives
[4+2] Cycloaddition of arynes to the bay region of perylenes is an interesting one-pot
synthetic strategy for extending the π-conjugation of such compounds. This transformation involves a D–A reaction followed by a spontaneous dehydrogenation.
Fort and Scott reported the cycloaddition of benzyne to perylene (147) in the gas
phase (Scheme 2.31) [78]. They used phthalic anhydride (148), which can generate
benzyne (1) in the gas phase after eliminating CO2 and CO above 650 ∘ C. By mixing
solid phthalic anhydride with perylene and, then, cosublimating the mixture at
1000 ∘ C under reduced pressure in a quartz tube, naphtho[1,2,3,4-ghi]perylene
(149) is obtained in 5% yield, compared with the 45% yield when the reaction is
performed in solution and using triflate as aryne precursor.
Peña and coworkers reported the addition to perylene of substituted arynes 150
and 153, generated from triflates 128, and 152, respectively, to afford the corresponding adducts 151 [79] and 154 [3] in moderate yields (Scheme 2.32).
43
Ph
O
129
TBAF
18%
via 79
OTf
TfO
TMS
Ph
Ph
Ph
Ph
131
TMS
Ph
Ph
106
Ph
Ph
O
Ph
15
Ph
O
Ph
TBAF
40%
via 108
Ph
OTf
Ph
TMS
Ph
132
133
Ph
TBAF
42%
via 134
Ph
Ph
Ph
Ph
Ph
135
Ph
79
Scheme 2.28
108
OTf
Ph
TMS
Ph
Ph
134
Pérez–Peña’s synthesis of benzo-fused substituted acenes. Source: Based on Rodríguez-Lojo et al. [75].
Ph
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
TMS
+
I
Ph
TMS
136
Ph
Ph
R
TMS
TBAF
O
R
OTf
via 138
R
O
Ph
Ph
O
Ph
O
R
via 142a,b
–N2
15%
Ph
TMS
R
I
OTf
Ph
140a,b
143a,b
142a,b
139a,b
PhI(OAc)2, TfOH
Ph 141
O
R
TMS
Ph
N
N
Ph
TMS
R
Ph
137: R = H
15: R = Ph
Ph
R
–CO2
Ph
Ph
Ph
Ph
R
R
R
R
Ph
Scheme 2.29
et al. [76].
TfO
TMS
Ph
144a,b
TMS
R
138
R
Ph 142a,b
Ph
a: R = H
b: R = Ph
Nuckolls’s synthesis of substituted pentacenes 144. Source: Based on Miao
OTf
106
TMS
TMS
ROOC
COOR
145a–c
Pd2(dba)3
KF/18-crown-6
via 79
COOR
ROOC
ROOC
COOR
COOR
COOR
COOR
COOR
79
146a, 16%
146b, 16%
146c, 16%
a: R = Me
b: R = Et
c: R = n-Pr
Scheme 2.30 Kitamura’s synthesis of substituted tetracenes 146. Source: Based on
Kitamura et al. [77].
O
O
148
O
147
147
650 °C
via 1
5%
TBAF
via 1
45%
149
OTf
14
TMS
1
Scheme 2.31 Cycloadditions of benzyne to the bay region of perylene (147). Source:
Based on Fort and Scott [78].
45
46
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
TMS
OTf
OTf
TfO
TMS
I
TMS
TMS
I
TfO
128
152
CsF
45%
via 150
CsF
20%
via 153
151
OTf
147
TMS
150
I
I
154
I
I
153
Scheme 2.32 Cycloadditions of arynes to the bay region of perylene (147). Source:
Pavliček et al. [3]; Schuler et al. [79].
In 2013, Kubo and coworkers reported the [4+2] cycloaddition of arynes, such as
157 and 99, to bisanthene 155, leading to the formation of extended derivatives 158
and 159 in moderate yields (Scheme 2.33) [80].
Mes
Br
156
Mes
NaNH2
40%
via 157
157
Mes
158
Mes
Br
Mes
155
Br
Br
86a
Br
Br
n-BuLi
51%
via 99
Br
Mes
Br
99
Br
159
Scheme 2.33 Cycloadditions of arynes to the bay region of bisanthene 155. Source: Based
on Konishi et al. [80].
Very recently, Itami and coworkers implemented this methodology for generating
π-extended perylenebisimides (PBIs) 161, 162, or 164 in only one reaction step
from PBIs 160, in contrast to the classical approach consisting of three reaction
steps involving bromination, Suzuki–Miyaura C–C coupling, and a final cyclization
(Scheme 2.34) [81].
Peña, Guitián, and coworkers described a strategy to obtain extended perylenes
on a two-step synthetic route involving tandem [4+2] cycloadditions (Scheme 2.35)
[82, 83]. The reaction of 1,8-difurylnaphthalene (165) with benzyne (1), generated by
Kobayashi’s method, afforded only the exo,exo diastereomer 166 in 99% yield. This
key transformation involves two tandem cascade D–A reactions in a domino mode,
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
O
R
N
O
O
R
N
O
OTf
O
TMS
14
R
N
O
+
R = Mes
via 1
KF
O
N
R
160
O
OTf
O
O
N
R
O
O
161 (63%)
R
N
N
R
O
162 (13%)
O
TMS
163
R = Mes, 54%
R = 6-Undecyl, 54%
via 157
1
157
O
N
R
O
164
Scheme 2.34 Cycloadditions of arynes to the bay region of perylenebisimides. Source:
Based on Nakamuro et al. [81].
1
HCl
H
99%
O
O
165
O
O
H
EtOH
72%
166
167
R1
R2
Ph
44
157
Ph
R3
168
169a, R1 = OMe, R2 = R3 = H
169b, R1 = H, R2 = R3 = F
169c, R1 = H, R1 + R2 = OCH2O
169d, R1 = H, R2 + R3 = (CH2)3
Scheme 2.35 Synthesis of perylene derivatives by tandem aryne cycloadditions. Source:
Criado et al. [82]; Criado et al. [83].
with the creation of four new C—C bonds and six new stereogenic centers. Final
treatment of adduct 166 with concentrated aqueous HCl in refluxing EtOH led to
perylene derivative 167 in 72% yield. This methodology has been extended to more
complex arynes, such as 44, 157, 168, and 169, allowing the synthesis of extended
perylene derivatives.
47
48
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
2.3.3
Synthesis of Triptycenes
Aryne intermediates have also been used in [4+2] cycloaddition reactions with
positions 9 and 10 of anthracene derivatives to yield triptycenes. Triptycenes are not
planar, exhibiting a paddle-wheel configuration. Kelly et al. conceived triptycenes
endowed with helicenes as molecular ratchets, where the triptycene acts as the
wheel and the helicenes serve as pawls and springs [84–86]. With this goal in mind,
they synthesized triptycene 172 endowed with a [4]helicene (Scheme 2.36). To
obtain triptycene 172, they reacted benzyne (1), generated from anthranilic acid 9 in
the presence of i-Am-ONO, with anthracene derivative 170. Afterwards, triptycene
171 was derivatized to the functionalized triptycene 172a endorsed with amino
and butanol groups. To yield unidirectional rotary motion, chemical energy was
used for activating and biasing a thermally induced isomerization reaction, which
yielded rotamer 172b after several steps.
Me
O
Me
H
CO2H
+
NHAc
NH2
9
170
i-Am-ONO
H
56%
O
NHAc
via 1
171
Me
Me
1
H2N
NH2
O
(CH2)3OH
O
(CH2)3OH
172b
172a
Scheme 2.36 Kelly’s synthesis of molecular ratchet 172. Source: Kelly et al. [84]; Kelly
et al. [85]; Kelly et al. [86].
In 2012, iptycene-based molecules 176 were described as fluorescent sensors
for explosives such as nitroaromatics and trinitrotoluene (TNT) [87, 88]. To synthesize the iptycene sensors 176, cycloaddition reactions between bisaryne 175,
generated from haloarene 173 and t-BuOK, and anthracene (174) were employed
(Scheme 2.37).
Other examples of the use of arynes for building triptycenes with specific functions include a spur gear [89], a molecular gyroscope [90], porous triptycene-based
molecules [91], and microporous polymers [92].
2.3.4
Synthesis of 𝛑-Extended Starphenes or Angular PAHs
Starphenes, star-shaped PAHs having a central aromatic core with a variable
number of branches, have attracted the attention of synthetic chemists due to
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
Ar
Cl
+
Ar
Ar
Ar
via 175
Cl
173
Ar
t-BuOK
Ar
174
176
175
Scheme 2.37 Synthesis of triptycene sensors for explosives. Source: Based on
Anzenbacher et al. [87].
their interesting properties and potential uses in electronic devices [93, 94].
Aryne cycloadditions, particularly the palladium-catalyzed [2+2+2] cycloaddition,
have proved to be a useful tool for the synthesis of three-branched starphenes, also
known as cloverphenes, due to their clover-like structure [95] or supertriphenylenes
[96]. In 2006, our group described the synthesis of [13]cloverphenes 179a,b by
a palladium-catalyzed [2+2+2] cyclotrimerization of arynes 178a,b. This was
accomplished by the successful synthesis of novel triflates 177a,b in four reaction
steps, which can serve as precursors of arynes 178a,b (Scheme 2.38) [97, 98]. It has
been reported that [13]cloverphene 179b exhibit columnar mesophases [96].
R
R
R
R
R
R
R
R
OTf
TMS
R
TBAF
Pd(PPh3)4
via 178a,b
R
R
R
R
177a,b
Scheme 2.38
R
R
R
a: R = H
b: R = OC6H13
179a, 18%
179b, 28%
R
R
178a,b
R
R
Synthesis of starphenes 179. Source: Romero et al. [97]; Romero et al. [98].
Moreover, the palladium-catalyzed cocyclotrimerization of arynes 178b,c,
equipped with alkoxy chains, with acetylenedicarboxylates 145a,d,e, gave rise to
tetrabenzopentaphenes 180 equipped with alkyl chains that exhibit liquid crystal
behavior (Scheme 2.39) [98].
Lynett and Maly reported the synthesis of a series of substituted trinaphthylenes
183a–c through the Pd-catalyzed [2+2+2] cyclotrimerization of substituted
2,3-naphthynes 182a–c, generated from triflates 181a–c (Scheme 2.40) [99].
Although no mesophases were observed for alkyl-substituted trinaphthylenes
183a–c, in the case of 183b, its aggregation in solution was inferred from the
concentration-dependent 1 H NMR (nuclear magnetic resonance).
Recently, Bunz and coworkers showed that the synthesis of trinaphthylenes
183b,d–h from dibromonaphthalenes 184b,d–h is also possible by using
Ni(0)-promoted Yamamoto coupling (Scheme 2.40) [100].
49
50
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
R′
R′
R′
R′
R′
R′
R′
R′
CO2R
OTf
CO2R
CsF
+
TMS
CO2R
Pd(PPh3)4
via 178
CO2R
R′
R′
R′
177b: R′ = OC6H13
177c: R′= OC12H25
Scheme 2.39
[98].
R′
R′
R′
145a: R = Me
145d: R = t-Bu
145e: R = (S)-2-Octyl
178b: R′ = OC6H13
178c: R′ = OC12H25
R′
R′
180ba: R′ = OC6H13, R = Me (65%)
180bd: R′ = OC6H13, R = t-Bu (54%)
180be: R′ = OC6H13, R = (S)-2-Octyl (72%)
180ca: R′ = OC12H25, R = Me (57%)
Synthesis of mesogenic tetrabenzopentaphenes 180. Source: Romero et al.
R
R
R
OTf
R
TMS
181a–c
X +F –
via 182a–c
R
182a–c
Excess Ni(COD)2
bipy
COD
R
a: R = H (41%)
b: R = Hex (45%)
c: R = C8H17 (45%)
R
R
cat. Pd(PPh3)4
R
Br
R
Br
184b,d–h
183a–h
R
R
b: R = Hex (65%)
d: R = Me (38%)
e: R = Et (57%)
f: R = i-Pr (52%)
g: R = Pr (65%)
h: R = Bu (50%)
Scheme 2.40 Synthesis of trinaphthylenes 183 by Maly and coworker. Source: Lynett and
Maly [99]; Rüdiger et al. [100].
Later on, Soe et al. studied the trinaphthylene 183a deposited on Au surface by
scanning tunneling microscopy (STM). They found that this molecule, when connected to Au atoms, behaves as a molecular logic gate [101].
Peña and coworkers expanded the limits of aryne cycloaddition reactions to build a
clover-shaped cata-condensed nanographene 189, known as [16]cloverphene, with
102 sp2 carbons (Scheme 2.41) [95]. The synthesis of [16]cloverphene started with a
first D–A cycloaddition between aryne 186, generated from triflate 185 by reaction
with TBAF, and dienone 133, followed by cheletropic extrusion of CO to afford 187.
o-Bromophenol 187 was then converted into the corresponding o-silylaryltriflate
188, precursor of aryne 168. The generation of this aryne in the presence of Pd(PPh3 )4
led to the formation of cloverphene 189 in a 22% yield.
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
TMS
+
O
Br
TfO
Ph
Ph
OH
185
133
OH
TBAF
via 186
OH
Br
Ph
Ph
186
187
(1) HMDS
(2) i. n-BuLi
ii. Tf2O
30%
Ph
Ph
Ph
Ph
Ph
Ph
OTf
Pd(PPh3)4
Ph
189
Br
CsF
22%
via 168
Ph 168
TMS
Ph
188
Ph
Scheme 2.41
[95].
Synthesis of twisted [16]cloverphene 189. Source: Based on Alonso et al.
A couple of years later, our group described the synthesis of a threefold symmetric C78 H36 PAH with 22 fused benzene rings within its structure in only two
reaction steps starting from commercially available compounds (Scheme 2.42) [79].
The synthesis of such clover-shaped nanographene 190 began with the preparation
of triflate 151 (see Scheme 2.32). Then, aryne 2, generated from triflate 151, was
transformed into cloverphene 190 by a palladium-catalyzed [2+2+2] cycloaddition.
Due to its insolubility, the structure of cloverphene 190 was unambiguously
elucidated by AFM on an ultrathin insulating film (Scheme 2.42b).
OTf
TMS
CsF
Pd(PPh3)4
via 2
46%
151
190
(a)
2
(b)
Scheme 2.42 (a) Synthesis and (b) AFM image of threefold symmetric nanographene 190.
Source: Image adapted with permission from Schuler et al. [79]. Copyright 2014, John Wiley
and Sons.
51
52
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
More recently, our group described the synthesis of a dendritic starphene 194
with 19 cata-fused benzene rings distributed in six branches. This [19]dendriphene
194 was prepared in solution by a palladium-catalyzed cyclotrimerization of
aryne 193, being the largest unsubstituted cata-condensed PAH synthesized to
date (Scheme 2.43) [102]. Triflate 192 was prepared in 19% yield by means of a
palladium-catalyzed annulation of aryne 150 and iodobinaphthalene 191.
I
CsF
Pd2(dba)3
P(o-tol)3
TfO
CsF
Pd2(dba)3
19%
via 150
TMS
13%
via 193
191
192
194
TfO
TMS
150
193
Scheme 2.43 Synthesis and AFM image of dendriphene 194. Source: Image adapted with
permission from Vilas-Varela et al. [102]. Copyright 2018, John Wiley and Sons.
The scope of the palladium-catalyzed [2+2+2] cycloaddition methodology is evidenced by the large number and diversity of molecular structures
obtained. In this regard, Pérez and coworkers described the synthesis of
tris(benzocyclobutadiene)triphenylenes 197a,b, molecules consisting of three
biphenylene units (bearing antiaromatic cyclobutadiene rings) fused to a central benzene ring, distorting the central triphenylene unit (Scheme 2.44) [103].
R
R
R
OTf
R
TMS
195a,b
CsF, Pd(PPh3)4
a: 58%
b: 65%
via 196a,b
R
R
R
R
197a,b
a: R = H
b: R = n-Hex
196a,b
R
R
Scheme 2.44
Synthesis of biphenylene-based starphenes 197. Source: Iglesias et al. [103].
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
53
Trimers 197a,b were synthesized through Pd-catalyzed [2+2+2] cycloadditions of
didehydrobiphenylenes 196a,b, which were generated in good yields from their
corresponding triflate precursors 195a,b by addition of CsF. Recently, trimer 197a
was used to selectively functionalize hydrogen-passivated Ge(001):H surfaces
through reversible [4+2] cycloaddition between trimers and dangling-bond Ge
dimers [104].
Hamura and coworkers reported the synthesis of a star-shaped polycyclic aromatic
ketone 206 involving a Pd-catalyzed [2+2+2] cyclotrimerization of aryne 202 to give
203 (Scheme 2.45) [105]. What is important about this trimer 203 is that it acts as a
synthetic equivalent of isobenzofuran trimer 205, which can be transformed into
the star-shaped polycyclic ketone 206 by cycloaddition with dienophiles such as
naphthoquinones 204.
Ph
Ph
Ph
O
TBDMSO
OTs
I
5 steps
via 199
I
Ph
TfO
O
198
15 Ph
91%
TMS
Ph
TfO
O
CO
201
Ph
Ph
TMS
200
R
R
CsF
Pd2(dba)3
72%
via 202
Ph
Ph
O
Ph
CO
O
Ph
O
O
R
O
R
O
R
206
O
O
O
O
204
Ph
R
Ph
O
131 °C
80%
via 205
CO
Ph
203
O
Ph
R = C12H25
Ph
CO
O
O
O
Ph
Ph
Ph
R
R
Ph
O
TBDMSO
199
Scheme 2.45
I
O
205
Ph
O
CO
202
Ph
Ph
Hamura’s synthesis of starphenes 206. Source: Based on Tozawa et al. [105].
In recent years, many organic reactions traditionally run in solution have been
performed on metallic surfaces under UHV conditions [106, 107]. On-surface reactions can be promoted either by thermal annealing or by the application of voltage
pulses from STM tips. For example, aryl radicals have been generated from aryl
halides by using these procedures. The related on-surface generation of arynes from
54
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
o-dihalides has already been cited in the introduction [3, 4]. With these precedents,
Fasel, Meunier, and coworkers described the formation of oligomeric structures
209–211, presumably through aryne 208, by heating 2,3-dibromotetracene (207) on
a Ag(111) surface (Scheme 2.46) [108].
Br
207
Br
208
209
211
210
Trimers
Linear dimers
Tetramers
Scheme 2.46 Generation and coupling of aryne 208 on Ag(111). Source: Images adapted
with permission from Sánchez-Sánchez et al. [108]. Copyright 2017 American Chemical
Society.
2.3.5
Synthesis of Helicenes
Helicenes are polycyclic aromatic compounds with nonplanar helically shaped
skeletons formed by ortho-fused aromatic rings. As helical chiral structures,
they can adopt two enantiomeric configurations. Among the several methods
developed for the synthesis of helicenes, organometallic catalysis plays a growing
role [109]. Soon after the discovery of Pd-catalyzed [2+2+2] aryne cycloadditions,
the first example of the application of this methodology to the synthesis of an
helicene was reported. Guitián, Pérez, and coworkers described the preparation
of the highly twisted triple-helicene 212 in 68% yield by cyclotrimerization of
9,10-didehydrophenantrene (157) catalyzed by Pd2 (dba)3 (Scheme 2.47) [110]. The
synthesis of hexabenzotriphenylene (212) had been previously reported but in very
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
low yields (5–13%) [112, 113]. The authors reported experimental and computational studies on the conformational stability of this interesting triple-helicene 212,
observing the formation of the C2 -conformers, which, upon heating, evolved to the
D3 molecular propeller, which is the thermodynamic isomer [111].
OTf
TMS
CsF, Pd 2(dba)3
Δ
68%
via 157
163
157
C2 - 212
D3 - 212
Scheme 2.47 Synthesis of hexabenzotriphenylene (212) and their conformers. Source:
Peña et al. [110]; Peña et al. [111]; Barnett et al. [112]; Hacker et al. [113].
Our group described the preparation of triflate 213 as precursor of 3,4-didehydrophenantrene 214 (Scheme 2.48) [114]. Pd-catalyzed reaction of triflate 213 under
aryne-forming conditions led to the formation of trimer 215 in 26% yield, with the
other cyclization product, the C3 -symmetric trimer 216 – a triple [5]helicene – not
being detected. Compound 216 was later synthesized by Watanabe and coworkers,
but using oxidative photocyclization reactions, not involving arynes [115]. Pérez,
Peña, and coworkers also described the cocyclizations of 3,4-didehydrophenantrene
214 and 1,2-didehydrotriphenylene with alkynes through Pd-catalyzed [2+2+2]
reactions to yield other sterically congested PAHs [116].
TMS
OTf
CsF, Pd2(dba)3
via 214
213
Scheme 2.48
215-PM
26%
216
Not detected
214
Synthesis of double helicene 215. Source: Based on Peña et al. [114].
The introduction of chiral ligands can lead to the formation of nonracemic
[2+2+2] palladium-catalyzed cycloaddition products, as exemplified by Guitián, Pérez, and coworkers [117]. In this contribution, naphthalene triflate 217
is reacted with Pd(PPh3 )4 in the presence of CsF, yielding the three possible
products of the cycloaddition of two units of aryne 218 and one of DMAD (28)
(Scheme 2.49). Even though [5]helicene 219 is not the major product from
the reaction, the isolated yield (25%) was found to be satisfactory considering
55
56
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
the limited availability of synthetic approaches to pentahelicenes. When using
(2,2′ -bis(diphenylphosphino)-1,1′ -binaphthyl) (BINAP) as a ligand for the Pd catalyst in the reaction, they found enantioselectivity in the formation of [5]helicene
219 with reasonable enantiomeric excess. This contribution represented the first
example of an enantioselective, metal-catalyzed cycloaddition involving arynes.
CO2Me
CO2Me
MeO
OTf
TMS
217
Scheme 2.49
et al. [117].
5% Pd2(dba)3,
MeO2C
(R)-BINAP, TBAF, rt
+
via 218
CO2Me
28
H
H
OMe
OMe
219, 16%, 67% ee
MeO
218
Enantioselective synthesis of pentahelicene 219. Source: Based on Caeiro
Three groups independently described the synthesis of hexapole pentahelicene
222 containing six [5]helicenes (Scheme 2.50). Kamikawa, Tsurusaki, and coworkers synthesized this hexapole helicene 222 in 54% yield by a Pd2 (dba)3 -catalyzed
[2+2+2] cycloaddition of aryne 221, generated from triflate 220 by treatment with
CsF [118]. X-ray diffraction of 222 reveals the highest degree of twisting angle
per benzene unit (35.7∘ ) reported so far. Gingras, Coquerel, and coworkers used
(a)
Kamikawa
(2017)
OTf
TMS
220
Gingras
(2017)
Pd2(dba)3
CsF
Ni(COD)2
54%
via 221
56%
222
Au(111)
380 °C
Br
Br
223
Peña (2018)
(b)
221
224
4.3 Å
Scheme 2.50 Synthesis of hexapole pentahelicene 222. Source: Hosokawa et al. [118];
Berezhnaia et al. [119], and AFM image of 224. Image adapted from Zuzak et al. [120].
Copyright 2018, The Royal Society of Chemistry.
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
a Ni(0)-mediated trimerization of 7,8-dibromo[5]helicene (223) to yield hexapole
222 in one reaction step in 56% yield [119]. Our group independently prepared
compound 222 by Pd-catalyzed cyclotrimerization of aryne 221, and then 222
was deposited on Au(111) and transformed into the threefold symmetric C66 H24
nanographene (224) by on-surface cyclodehydrogenation. This compound was
characterized with submolecular resolution by AFM with functionalized tip (inset
in Scheme 2.50) [120].
Sygula and coworkers synthesized helical corannulene trimers by trimerization of
corannulyne 226. Treatment of triflate 225 with CsF in the presence of Pd2 (dba)3 led
to hydrocarbon C60 H24 227 in 40% yield (Scheme 2.51) [121].
OTf
CsF, Pd2(dba)3
TMS
40%
via 226
226
225
227
Scheme 2.51
Synthesis of triscoranylene 227. Source: Based on Yanney et al. [121].
Garg, Houk, and coworkers reported the synthesis of helicenes containing indole
moieties by palladium-catalyzed cyclotrimerization of indolynes (Scheme 2.52)
[122]. For example, 3,4-indolyne 229, generated from 228, was trimerized using
Pd2 (dba)3 and BINAP to form a 1 : 2 mixture of regioisomers 230 and 231 in
93% yield. Similarly, 5,6-indolyne undergoes cyclotrimerization to give a mixture
of regioisomeric cyclotrimers in 80% yield. However, the cyclotrimerization of
6,7-indoline only works in 9% yield, presumably due to steric hindrance.
N
Me
Me
N
TMS
TfO
CsF, Pd2(dba)3
228
N
Me
BINAP
93%
via 229
+
Me
Me
N
230
1
Scheme 2.52
N
Me
N
231
:
N
Me
229
N
Me
2
Synthesis of heterocyclic helicenes. Source: Based on Lin et al. [122].
Finally, Pérez and coworkers reported the synthesis of [4]helicenes and other sterically congested PAHs by means of a double [4+2] cycloaddition reaction of the novel
1,7-naphthodiyne synthon 233 with different dienes (Scheme 2.53) [123]. Bistriflate
232 was reacted with furan 95 in the presence of CsF to give bisadduct 234 in 69%
57
58
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
yield. This bisendoxide 234 was reduced with Zn in AcOH to afford [4]helicene 235
in 45% yield. Bistriflate 232 was also reacted with cyclopentadienone 15 and CsF to
afford highly congested 237 after spontaneous decarbonylation of bisadduct 236 in
23% yield.
Ph
TMS TMS
TfO
OTf
O
Ph
CsF
15
Ph
Ph
via 233
Ph Ph
Ph
Zn, AcOH
100 °C
45%
Ph
Ph
235
234
Ph
Ph
Ph
236
O
Ph
CO
CO
Ph Ph
Ph
Ph
O
Ph
Ph 95
CsF
69%
via 233
232
Ph
Ph Ph
O
60 °C
–CO
23%
Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph
233
237
Scheme 2.53 Pérez’s synthesis of angular and congested PAHs 235 and 237. Source:
Based on Pozo et al. [123].
2.3.6
Functionalization of Carbon Nanostructures
The first reports on the cycloaddition of benzyne to fullerene were published in
1992 [124, 125]. In both cases, a series of cycloadducts of benzyne, generated from
anthranilic acid, and C60 , [C60 + (C6 H4 )n ], were detected by mass spectrometry
and NMR. Cooks, Kahr, and coworkers proposed structure 238 for the isolated
monoadduct, which results from the [2+2] cycloaddition (Scheme 2.54) [124]. But it
was not until 1995 that the X-ray structure of the [2+2] monoadduct was elucidated,
proving that the cycloaddition process takes place at the (6,6) double bond of the
fullerene sphere, generating a benzocyclobutene structure attached to a closed (6,6)
bond of C60 [126].
In 2001, Nishimura and coworkers reported the isolation of all eight possible regioisomers (241) of [2+2] bisadducts from cycloaddition to C60 of
4,5-dimethoxybenzyne (240a), generated from the 4,5-dimethoxyanthranilic
acid (239) in the presence of i-Am-ONO (Scheme 2.54) [127].
In 2013, Yang and coworkers claimed the formation of an open cage (5,6)
monoadduct (243) by addition of aryne 240b to C60 based on NMR, UV–vis
spectroscopy, and cyclic voltammetry (Scheme 2.54) [128]. They suggested the
formation of this open (5,6) monoadduct stemming from the rearrangement of the
previously formed (6,6) closed-cage monoadduct. However, a recent reinvestigation
of this reaction led to the conclusion that the reaction product is the (6,6) closed
C60 -fused δ-lactone 244 [129].
Additions of up to 10 units of benzyne to C70 were firstly detected in 1994 by
Walton and coworkers by means of mass spectrometry [130]. Shortly after, the same
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
NH2
i-Am-ONO
+ C60
9
CO2H
via 1
MeO
MeO
NH2
MeO
+ C60
CO2H
239
OMe
OMe
i-Am-ONO
via 240a
OMe
241
OR
OR
240a:
: R = Me
240b: R = n-Bu
OC4H9
OC4H9
OC4H9
C4H9O
NH2
C4H9O
CO2H
+ C60
242
1
238
i-Am-ONO
OC4H9
via 240b
O
243
O
244
Scheme 2.54 Functionalization of C60 by aryne cycloadditions. Source: Hoke et al. [124];
Ishida et al. [126]; Nakamura et al. [127]; Kim et al. [128]; Mizunuma et al. [129].
group isolated the monoadducts as a mixture of four isomers according to their 1 H
NMR spectra [131]. Three of them corresponded to [2+2] additions to (6,6) bonds
and one was the result of a [4+2] cycloaddition. In 1998, Meier et al. were able to
separate the four isomers and confirmed that one of them was a close monoadduct
resulting from the addition of benzyne to a (6,6) bond in C70 , according to the X-ray
crystal structure [132]. The other two were considered as other (6,6) cycloadditions,
and one of them as a (5,6) according to their NMR spectra.
Arynes react with endohedral fullerenes to give [2+2] adducts, and the regioselectivity of the process depends on the metal inside the cage. While La@C82 gives (5,6)
adducts [133], Sc3 N@I h -C80 gives both (5,6) and (6,6) adducts [134].
Computational studies on the cycloaddition of benzyne to fullerenes [135] and
endohedral fullerenes [136] support nonconcerted radical mechanisms.
In 2016, Martín, Pérez, and coworkers described the synthesis of the first aryne
precursor comprising a C60 (245) (Scheme 2.55) [137]. They reacted C60 with
monoaryne 150, generated from bistriflate 128 and TBAF, to afford the [2+2]
monoadduct 245 in 21% yield. Furthermore, upon subjecting monoadduct 245 to
the presence of TBAF and a diene, such as furan, fullerobenzyne 246 was generated
and trapped through a [4+2] cycloaddition to give 247 in 43% yield.
In 1998, it was suggested that addition of arynes to single-walled carbon nanotubes
(SWCNTs) could produce paddle-wheel nanostructures, in which the stiff benzene
fragments produced after multiple aryne cycloaddition to the SWCNTs act as teeth
(Figure 2.3) [138].
59
60
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
O
TMS
OTf
+ C60
TfO
TMS
OTf
TBAF
21%
via 150
128
TMS
TBAF
O
43%
via 246
245
247
OTf
150
Scheme 2.55
TMS
246
Synthesis of a fullerobenzyne precursor. Source: Based on García et al. [137].
Figure 2.3 Molecular models of paddle-wheel nanostructures. Source: Globus et al. [138].
© 1998 IOP Publishing Ltd.
Langa, Guitián, and coworkers described the first functionalization of SWCNTs by
aryne cycloadditions. Arynes 1 and 249b,c were generated either by thermal decomposition of benzenediazonium 2-carboxylate (10) or by fluoride-induced decomposition of triflates 14, 248, or 163 in the presence of SWCNTs to give polyadducts,
represented as monoadducts 250 and 251 for the sake of clarity (Scheme 2.56) [139].
Later on, they extended the functionalization strategy by using different arynes with
microwave (MW) irradiation, increasing the functionalization up to 1 functional
group per 64–120 carbon atoms (Scheme 2.56) [140].
Due to the lack of crystalline structures and NMR data caused by the high
insolubility of carbon nanotubes (CNTs), it is difficult to determine whether
the aryne reacts with CNT through a [2+2] or a [4+2] cycloaddition. Therefore,
computational studies are essential for establishing the chemoselectivity of the
cycloaddition reaction. Nagase, Zhao, and coworker reported DFT-based calculations describing the energy profiles for the [2+2] and [4+2] cycloaddition of
benzyne to armchair SWCNTs [141]. They concluded that the [2+2] product is
always more thermodynamically stable than the [4+2] cycloadduct, although the
latter becomes kinetically favored as the diameter of the SWCNT increases. Solá,
Osuna, and coworkers investigated the effect of the curvature of zigzag SWCNTs
on the cycloadditions of benzyne and concluded that, as far as zigzag SWCNTs
are concerned, the sidewall [4+2] cycloaddition of benzyne to SWCNTs in parallel
position is the preferred reaction pathway, both kinetically and thermodynamically
[135]. If zigzag SWCNT diameter increases, the energy barrier increases and the
2.3 Aryne-Mediated Synthesis of Functional Polyarenes
COO–
10
R
OTf
TMS
R
SWCN, 80 °C
via 1
N2+
14 or 248b,c
R
R
R
R
SWCN, CsF
249b,c
Δ or MW
250a–c
via 1 or 249b,c
a: R = H; b: R = OC6H13; c: R = F
OTf
TMS
SWCNT, CsF
Δ or MW
via 157
157
163
251
Scheme 2.56 Functionalization of carbon nanotubes by aryne cycloadditions. Source:
Criado et al. [139]; Criado et al. [140].
exothermicity of the reaction decreases. Therefore, it is clear that cycloadditions of
benzyne can produce both [2+2] and [4+2] adducts depending on the shape and
curvature of the nanotube, as well as on their intrinsic electronic nature.
Reaction with arynes has also been used to functionalize novel carbon nanostructures such as carbon nanohorns. Thus, in 2013, Tagmatarchis and coworkers
used cycloaddition of benzynes to functionalize this nanostructure (Scheme 2.57)
[142]. Two different precursors were used for the generation of benzyne: anthranilic
X
X
NH2
i-Am-ONO
CO2H
253
9 (X = H)
252 (X = I)
OTf
14
TMS
Δ or MW
via 1 or 254
CsF
X
1 (X = H)
254 (X = I)
255a (X = H)
255b (X = I)
Scheme 2.57 Functionalization of carbon nanohorns by aryne cycloadditions. Source:
Based on Chronopoulos et al. [142].
61
62
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
acid (9) or triflate 14, respectively, either by normal heating or MW. Aryne
cycloaddition was proved by Raman spectroscopy (increase in the D/G band
intensity ratio). By using iodo anthranilic acid 252 as starting material for aryne
254, iodine-functionalized carbon nanohorns 255b were obtained and further
derivatized to endocyclic disulfides that can immobilize gold nanoparticles.
Graphene is currently the most widely studied carbon-based material due to its
outstanding properties, such as lightness, strength, stiffness, and electrical and heat
conductivity. Therefore, functionalization of this material is nowadays a key issue in
materials science [143].
The first aryne cycloaddition to graphene was reported in 2010 by Ma and
coworkers (Scheme 2.58) [144]. Benzyne (1), generated by Kobayashi’s procedure,
in the presence of multilayered graphene afforded highly functionalized and
aryne-modified graphene sheets that could be dispersed in a variety of organic
solvents. Similar results were obtained by addition of some substituted arynes such
as 4,5-difluorobenzyne (249c).
1
256
Graphene
F
F
249c
44
157
257
258
Scheme 2.58 Functionalization of graphene by aryne cycloadditions. Source: Zhong et al.
[144]; Sulleiro et al. [145].
Very recently, Prato, Criado, and coworkers described the functionalization
of few-layer graphene (FLG) by cycloaddition with arynes 44, 157, 257, or 258
(Scheme 2.58), generated by MW-promoted decomposition of the corresponding
phthalic anhydrides. Simply by MW irradiation of homogeneous powder mixtures of
phthalic anhydrides and FLG, functionalization was achieved, yielding dispersions
of the functionalized graphene, characterized by a number of techniques (X-ray
photoelectron spectroscopy [XPS], Raman, thermogravimetric analysis [TGA], and
transmission electron microscopy [TEM]) [145].
In 2016, Martín, Pérez, and coworkers described the preparation of [60]fullerenebenzyne building block 246, which they used for functionalizing exfoliated FLG
(Scheme 2.59) [137]. Triflate 245 was reacted with TBAF in the presence of FLG to
yield an all-carbon hybrid material 259 comprising C60 and graphene. The authors
carried out computational studies, which indicated that both [2+2] and [4+2]
References
cycloadditions were feasible. Denis [146] and Zhao’s [147] groups conducted other
theoretical studies on cycloadditions of arynes to graphene.
OTf
TMS
245
+
TBAF
28%
via 246
246
259
Graphene
Scheme 2.59
Synthesis of C60 -graphene hybrids 259. Source: Based on García et al. [137].
References
1 Stoermer, R. and Kahlert, B. (1902). Ber. Dtsch. Chem. Ges. 35 (2): 1633–1640.
2 Roberts, J.D., Simmons, H.E., Carlsmith, L.A., and Vaughan, C.W. (1953).
J. Am. Chem. Soc. 75 (13): 3290–3291.
3 Pavliček, N., Schuler, B., Collazos, S. et al. (2015). Nat. Chem. 7 (8): 623–628.
4 Pavliček, N., Majzik, Z., Collazos, S. et al. (2017). ACS Nano 11 (11):
10768–10773.
5 Wittig, G. and Pohmer, L. (1955). Angew. Chem. 67 (13): 348.
6 Hoffmann, R.W. (1967). Dehydrobenzene and Cycloalkynes. New York:
Academic Press.
7 Gilchrist, T.L. (1983). Arynes. In: The Chemistry of Triple-Bonded Functional
Groups (eds. S. Patai and Z. Rappoport), 383–419. Wiley.
8 Winkler, M., Wenk, H.H., and Sander, W. (2003). Arynes. In: Reactive Intermediate Chemistry (eds. R.A. Moss, M.S. Platz and J.M. Jones), 741–794. Wiley.
9 Pellissier, H. and Santelli, M. (2003). Tetrahedron 59 (6): 701–730.
10 Sanz, R. (2008). Org. Prep. Proced. Int. 40 (3): 215–291.
11 Yoshida, S. and Hosoya, T. (2015). Chem. Lett. 44 (11): 1450–1460.
12 Caubere, P. (1993). Chem. Rev. 93 (6): 2317–2334.
13 Wittig, G. and Pohmer, L. (1956). Chem. Ber. 89 (5): 1334–1351.
14 Wittig, G. and Knauss, E. (1958). Chem. Ber. 91 (5): 895–907.
15 Gilman, H. and Gorsich, R.D. (1957). J. Am. Chem. Soc. 79 (10): 2625–2629.
16 Tochtermann, W., Stubenrauch, G., Reiff, K., and Schumacher, U. (1974).
Chem. Ber. 107 (10): 3340–3352.
17 Logullo, F.M., Seitz, A.H., and Lester, F. (1968). Org. Synth. 48: 12–16.
18 Friedman, L. and Logullo, F.M. (1969). J. Am. Chem. Soc. 85 (10): 3089–3092.
19 Le Goff, E. (1962). J. Am. Chem. Soc. 84 (19): 3786.
63
64
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
20 Campbell, C.D. and Rees, C.W. (1969). J. Chem. Soc. C (5): 752–756.
21 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett. 12 (8):
1211–1214.
22 Peña, D., Escudero, S., Pérez, D. et al. (1998). Angew. Chem. Int. Ed. 37 (19):
2659–2661.
23 Peña, D., Cobas, A., Pérez, D., and Guitián, E. (2002). Synthesis (10):
1454–1458.
24 Díaz, M.T., Cobas, A., Guitián, E., and Castedo, L. (1998). Synlett 1998 (02):
157–158.
25 Akai, S., Ikawa, T., Takayanagi, S. et al. (2008). Angew. Chem. Int. Ed. 47 (40):
7673–7676.
26 Masson, E. and Schlosser, M. (2005). Eur. J. Org. Chem. 2005 (20): 4401–4405.
27 Medina, J.M., Mackey, J.L., Garg, N.K., and Houk, K.N. (2014). J. Am. Chem.
Soc. 136 (44): 15798–15805.
28 Pérez, D., Peña, D., and Guitián, E. (2013). Eur. J. Org. Chem. 2013 (27):
5981–6013.
29 Wu, D., Ge, H., Liu, S.H., and Yin, J. (2013). RSC Adv. 3 (45): 22727–22738.
30 Alam, M.A., Shimada, K., Jahan, A. et al. (2017). Am. J. Heterocycl. Chem.
3 (5): 47–54.
31 Dubrovskiy, A.V., Markina, N.A., and Larock, R.C. (2013). Org. Biomol. Chem.
11 (2): 191–218.
32 Kovalev, I.S., Kopchuk, D.S., Zyryanov, G.V. et al. (2012). Chem. Heterocycl.
Compd. 48 (4): 536–547.
33 Peña, D., Pérez, D., and Guitián, E. (2007). Heterocycles 74 (1): 89–100.
34 Gampe, C.M. and Carreira, E.M. (2012). Angew. Chem. Int. Ed. 51 (16):
3766–3778.
35 Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112 (6): 3550–3577.
36 Zamiraei, Z. (2017). Chem. Biol. Interface 7 (4): 217–223.
37 Takikawa, H., Nishii, A., Sakai, T., and Suzuki, K. (2018). Chem. Soc. Rev.
47 (21): 8030–8056.
38 Stevens, R.V. and Bisacchi, G.S. (1982). J. Org. Chem. 47 (12): 2393–2396.
39 Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K. (1995). Tetrahedron
Lett. 36 (19): 3377–3380.
40 Hamura, T., Ibusuki, Y., Uekusa, H. et al. (2006). J. Am. Chem. Soc. 128 (31):
10032–10033.
41 Jones, M. and Levin, R.H. (1969). J. Am. Chem. Soc. 91 (23): 6411–6415.
42 Ozkan, I. and Kinal, A. (2004). J. Org. Chem. 69 (16): 5390–5394.
43 Maurin, P., Ibrahim-Ouali, M., Parrain, J.-L., and Santelli, M. (2003). J. Mol.
Struct. THEOCHEM 637 (1): 91–100.
44 Ma, Z.-X., Feltenberger, J.B., and Hsung, R.P. (2012). Org. Lett. 14 (11):
2742–2745.
45 Wöhrle, T., Wurzbach, I., Kirres, J. et al. (2016). Chem. Rev. 116 (3): 1139–1241.
46 Peña, D., Pérez, D., Guitián, E., and Castedo, L. (1999). J. Am. Chem. Soc. 121
(24): 5827–5828.
References
47 Radhakrishnan, K.V., Yoshikawa, E., and Yamamoto, Y. (1999). Tetrahedron
Lett. 40 (42): 7533–7535.
48 Jayanth, T.T., Jeganmohan, M., and Cheng, C.-H. (2004). J. Org. Chem. 69 (24):
8445–8450.
49 Quintana, I., Boersma, A.J., Peña, D. et al. (2006). Org. Lett. 8 (15): 3347–3349.
50 Hsieh, J.-C., Rayabarapu, D.K., and Cheng, C.-H. (2004). Chem. Commun. (5):
532–533.
51 Li, J. and Zhang, Q. (2013). Synlett 24 (06): 686–696.
52 Thummel, R.P., Cravey, W.E., and Nutakul, W. (1978). J. Org. Chem. 43 (12):
2473–2477.
53 Herwig, P.T. and Müllen, K. (1999). Adv. Mater. 11 (6): 480–483.
54 Mondal, R., Adhikari, R.M., Shah, B.K., and Neckers, D.C. (2007). Org. Lett.
9 (13): 2505–2508.
55 Jancarik, A., Levet, G., and Gourdon, A. (2019). Chem. Eur. J. 25 (9):
2366–2374.
56 LeHoullier, C.S. and Gribble, G.W. (1983). J. Org. Chem. 48 (14): 2364–2366.
57 Netka, J., Crump, S.L., and Rickborn, B. (1986). J. Org. Chem. 51 (8):
1189–1199.
58 Eda, S., Eguchi, F., Haneda, H., and Hamura, T. (2015). Chem. Commun.
51 (27): 5963–5966.
59 Sy, A. and Hart, H. (1979). J. Org. Chem. 44 (1): 7–9.
60 Gribble, G.W., Perni, R.B., and Onan, K.D. (1985). J. Org. Chem. 50 (16):
2934–2939.
61 Kitamura, C., Abe, Y., Ohara, T. et al. (2010). Chem. Eur. J. 16 (3): 890–898.
62 Kitamura, C., Tsukuda, H., Yoneda, A. et al. (2010). Eur. J. Org. Chem. 2010
(16): 3033–3040.
63 Luo, J. and Hart, H. (1988). J. Org. Chem. 53 (6): 1341–1343.
64 Blatter, K. and Schlüter, A.-D. (1989). Chem. Ber. 122 (7): 1351–1356.
65 Vogel, T., Blatter, K., and Schlüter, A.-D. (1989). Makromol. Chem. Rapid
Commun. 10 (8): 427–430.
66 Chun, D., Cheng, Y., and Wudl, F. (2008). Angew. Chem. Int. Ed. 47 (44):
8380–8385.
67 Haneda, H., Eda, S., Aratani, M., and Hamura, T. (2014). Org. Lett. 16 (1):
286–289.
68 Krüger, J., Pavliček, N., Alonso, J.M. et al. (2016). ACS Nano 10 (4): 4538–4542.
69 Krüger, J., Eisenhut, F., Alonso, J.M. et al. (2017). Chem. Commun. 53 (10):
1583–1586.
70 Krüger, J., García, F., Eisenhut, F. et al. (2017). Angew. Chem. Int. Ed. 56 (39):
11945–11948.
71 Shen, B., Tatchen, J., Sánchez García, E., and Bettinger, H. (2018). Angew.
Chem. Int. Ed. 57 (33): 10506–10509.
72 Lu, J., Ho, D.M., Vogelaar, N.J. et al. (2004). J. Am. Chem. Soc. 126 (36):
11168–11169.
73 Chen, W., Li, X., Long, G. et al. (2018). Angew. Chem. Int. Ed. 57 (41):
13555–13559.
65
66
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
74 Duong, H.M., Bendikov, M., Steiger, D. et al. (2003). Org. Lett. 5 (23):
4433–4436.
75 Rodríguez-Lojo, D., Pérez, D., Peña, D., and Guitián, E. (2015). Chem. Commun.
51 (25): 5418–5420.
76 Miao, Q., Chi, X., Xiao, S. et al. (2006). J. Am. Chem. Soc. 128 (4): 1340–1345.
77 Kitamura, C., Takenaka, A., Kawase, T. et al. (2011). Chem. Commun. 47 (23):
6653–6655.
78 Fort, E.H. and Scott, L.T. (2011). Tetrahedron Lett. 52 (17): 2051–2053.
79 Schuler, B., Collazos, S., Gross, L. et al. (2014). Angew. Chem. Int. Ed. 53 (34):
9004–9006.
80 Konishi, A., Hirao, Y., Matsumoto, K. et al. (2013). Chem. Lett. 42 (6): 592–594.
81 Nakamuro, T., Kumazawa, K., Ito, H., and Itami, K. (2019). Synlett 30 (04):
423–428.
82 Criado, A., Peña, D., Cobas, A., and Guitián, E. (2010). Chem. Eur. J. 16 (32):
9736–9740.
83 Criado, A., Vilas-Varela, M., Cobas, A. et al. (2013). J. Org. Chem. 78 (24):
12637–12649.
84 Kelly, T.R., Sestelo, J.P., and Tellitu, I. (1998). J. Org. Chem. 63 (11): 3655–3665.
85 Kelly, T.R., Silva, R.A., De Silva, H. et al. (2000). J. Am. Chem. Soc. 122 (29):
6935–6949.
86 Kelly, T.R., De Silva, H., and Silva, R.A. (1999). Nature 401: 150–152.
87 Anzenbacher, P. Jr.,, Mosca, L., Palacios, M.A. et al. (2012). Chem. Eur. J.
18 (40): 12712–12718.
88 See also McQuade, D.T., Pullen, A.E., and Swager, T.M. (2000). Chem. Rev.
100: 2537–2574.
89 Frantz, D.K., Linden, A., Baldridge, K.K., and Siegel, J.S. (2012). J. Am. Chem.
Soc. 134 (3): 1528–1535.
90 Godinez, C.E., Zepeda, G., Mortko, C.J. et al. (2004). J. Org. Chem. 69 (5):
1652–1662.
91 Taylor, R.G.D., Carta, M., Bezzu, C.G. et al. (2014). Org. Lett. 16 (7): 1848–1851.
92 Ghanem, B.S., Hashem, M., Harris, K.D.M. et al. (2010). Macromolecules 43
(12): 5287–5294.
93 Kanibolotsky, A.L., Perepichka, I.F., and Skabara, P.J. (2010). Chem. Soc. Rev.
39 (7): 2695–2728.
94 Zhang, H., Wu, D., Hua, L., and Yin, J. (2012). Curr. Org. Chem. 16 (18):
2124–2158.
95 Alonso, J.M., Díaz-Álvarez, A.E., Criado, A. et al. (2012). Angew. Chem. Int. Ed.
51 (1): 173–177.
96 Yatabe, T., Harbison, M.A., Brand, J.D. et al. (2000). J. Mater. Chem. 10 (7):
1519–1525.
97 Romero, C., Peña, D., Pérez, D., and Guitián, E. (2006). Chem. Eur. J. 12 (22):
5677–5684.
98 Romero, C., Peña, D., Pérez, D. et al. (2009). J. Mater. Chem. 19 (27):
4725–4731.
99 Lynett, P.T. and Maly, K.E. (2009). Org. Lett. 11 (16): 3726–3729.
References
100 Rüdiger, E.C., Rominger, F., Steuer, L., and Bunz, U.H.F. (2016). J. Org. Chem.
81 (1): 193–196.
101 Soe, W.-H., Manzano, C., Renaud, N. et al. (2011). ACS Nano 5 (2): 1436–1440.
102 Vilas-Varela, M., Fatayer, S., Majzik, Z. et al. (2018). Chem. Eur. J. 24 (67):
17697–17700.
103 Iglesias, B., Cobas, A., Pérez, D., and Guitián, E. (2004). Org. Lett. 6 (20):
3557–3560.
104 Godlewski, S., Engelund, M., Peña, D. et al. (2018). Phys. Chem. Chem. Phys. 20
(16): 11037–11046.
105 Tozawa, H., Kakuda, T., Adachi, K., and Hamura, T. (2017). Org. Lett. 19 (15):
4118–4121.
106 Lindner, R. and Kühnle, A. (2015). ChemPhysChem 16 (8): 1582–1592.
107 Shen, Q., Gao, H.-Y., and Fuchs, H. (2017). Nano Today 13: 77–96.
108 Sánchez-Sánchez, C., Nicolaï, A., Rossel, F. et al. (2017). J. Am. Chem. Soc. 139
(48): 17617–17623.
109 Shen, Y. and Chen, C.-F. (2012). Chem. Rev. 112 (3): 1463–1535.
110 Peña, D., Pérez, D., Guitián, E., and Castedo, L. (1999). Org. Lett. 1 (10):
1555–1557.
111 Peña, D., Cobas, A., Pérez, D. et al. (2000). Org. Lett. 2 (11): 1629–1632.
112 Barnett, L., Ho, D.M., Baldridge, K.K., and Pascal, R.A. (1999). J. Am. Chem.
Soc. 121 (4): 727–733.
113 Hacker, N.P., McOmie, J.F.W., Meunier-Piret, J., and Van Meerssche, M. (1982).
J. Chem. Soc., Perkin Trans. 1: 19–23.
114 Peña, D., Cobas, A., Pérez, D. et al. (2003). Org. Lett. 5 (11): 1863–1866.
115 Saito, H., Uchida, A., and Watanabe, S. (2017). J. Org. Chem. 82 (11):
5663–5668.
116 Romero, C., Peña, D., Pérez, D., and Guitián, E. (2008). J. Org. Chem. 73 (20):
7996–8000.
117 Caeiro, J., Peña, D., Cobas, A. et al. (2006). Adv. Synth. Catal. 348 (16–17):
2466–2474.
118 Hosokawa, T., Takahashi, Y., Matsushima, T. et al. (2017). J. Am. Chem. Soc.
139 (51): 18512–18521.
119 Berezhnaia, V., Roy, M., Vanthuyne, N. et al. (2017). J. Am. Chem. Soc. 139
(51): 18508–18511.
120 Zuzak, R., Castro-Esteban, J., Brandimarte, P. et al. (2018). Chem. Commun. 54
(73): 10256–10259.
121 Yanney, M., Fronczek, F.R., Henry, W.P. et al. (2011). Eur. J. Org. Chem. 2011
(33): 6636–6639.
122 Lin, J.B., Shah, T.K., Goetz, A.E. et al. (2017). J. Am. Chem. Soc. 139 (30):
10447–10455.
123 Pozo, I., Cobas, A., Peña, D. et al. (2016). Chem. Commun. 52 (32): 5534–5537.
124 Hoke, S.H., Molstad, J., Dilettato, D. et al. (1992). J. Org. Chem. 57 (19):
5069–5071.
125 Tsuda, M., Ishida, T., Nogami, T. et al. (1992). Chem. Lett. 21 (12): 2333–2334.
126 Ishida, T., Shinozuka, K., Nogami, T. et al. (1995). Chem. Lett. 24 (4): 317–318.
67
68
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes
127 Nakamura, Y., Takano, N., Nishimura, T. et al. (2001). Org. Lett. 3 (8):
1193–1196.
128 Kim, G., Lee, K.C., Kim, J. et al. (2013). Tetrahedron 69 (35): 7354–7359.
129 Mizunuma, R., Tanaka, T., Nakamura, Y. et al. (2018). Tetrahedron 74 (5):
544–548.
130 Darwish, A.D., Abdul-Sada, A.K., Langley, G.J. et al. (1994). J. Chem. Soc.,
Chem. Commun. (18): 2133–2134.
131 Darwish, A.D., Avent, A.G., Taylor, R., and Walton, D.R.M. (1996). J. Chem.
Soc., Perkin Trans. 2 (10): 2079–2084.
132 Meier, M.S., Wang, G.-W., Haddon, R.C. et al. (1998). J. Am. Chem. Soc. 120
(10): 2337–2342.
133 Lu, X., Nikawa, H., Tsuchiya, T. et al. (2010). Angew. Chem. Int. Ed. 49 (3):
594–597.
134 Li, F.-F., Pinzón, J.R., Mercado, B.Q. et al. (2011). J. Am. Chem. Soc. 133 (5):
1563–1571.
135 Martínez, J.P., Langa, F., Bickelhaupt, F.M. et al. (2016). J. Phys. Chem. C 120
(3): 1716–1726.
136 Yang, T., Nagase, S., Akasaka, T. et al. (2015). J. Am. Chem. Soc. 137 (21):
6820–6828.
137 García, D., Rodríguez-Pérez, L., Herranz, M.A. et al. (2016). Chem. Commun.
52 (40): 6677–6680.
138 Globus, A., Bauschlicher, C.W., Han, J. et al. (1998). Nanotechnology 9 (3):
192–199.
139 Criado, A., Gómez-Escalonilla, M.J., Fierro, J.L.G. et al. (2010). Chem.
Commun. 46 (37): 7028–7030.
140 Criado, A., Vizuete, M., Gómez-Escalonilla, M.J. et al. (2013). Carbon 63:
140–148.
141 Yang, T., Zhao, X., and Nagase, S. (2013). Org. Lett. 15 (23): 5960–5963.
142 Chronopoulos, D., Karousis, N., Ichihashi, T. et al. (2013). Nanoscale 5 (14):
6388–6394.
143 Georgakilas, V., Otyepka, M., Bourlinos, A.B. et al. (2012). Chem. Rev. 112 (11):
6156–6214.
144 Zhong, X., Jin, J., Li, S. et al. (2010). Chem. Commun. 46 (39): 7340–7342.
145 Sulleiro, M.V., Quiroga, S., Peña, D. et al. (2018). Chem. Commun. 54 (17):
2086–2089.
146 Denis, P.A. and Iribarne, F. (2012). J. Mater. Chem. 22 (12): 5470–5477.
147 Zhao, J., Wang, H., Gao, B. et al. (2012). J. Mol. Model. 18 (6): 2861–2868.
69
3
Dipolar Cycloaddition Reactions of Arynes and Related
Chemistry
Pan Li 1 , Jingjing Zhao 1 , and Feng Shi 2
1
Henan University, Institute of Functional Organic Molecular Engineering, College of Chemistry and
Chemical Engineering, Kaifeng 475004, China
2
WuXi AppTec (Wuhan) Co., Ltd., International Discovery Service Unit, Research Service Division, 666 Gaoxin
Rd, Wuhan East-Lake High-Tech Development Zone, Wuhan 430075, People’s Republic of China
3.1 Introduction
1,n-Dipoles are reactive species bearing separate positive and negative charges, and
therefore exhibit both electrophilic and nucleophilic reactivity, respectively [1].
They easily react with olefins, alkynes, allenes, etc., commonly referred to as
dipolarophiles, to form various rings. Such strategy has been widely used to
construct polycyclic systems. Among the different dipolarophiles, aryne constitutes
an important class owing to its poorly overlapped C—C triple bond that is highly
reactive. Consequently, while many classical dipolar cycloadditions work better
or only with polarized or activated olefins or alkynes, the strain itself of the
“triple bond” of the aryne provides enough driving energy so that plain aryne is
reactive enough toward various dipoles under milder conditions. Hence, aryne
cycloaddition reactions have become a powerful and widely used synthetic method
for constructing benzannulated heterocyclic scaffolds, which are widely found in
various biologically active compounds (Scheme 3.1).
A
+
D
Dipolar cycloaddition
B
n
A
D
B
n
n = 0,1,2
Scheme 3.1
General scheme of 1,n-dipolar cycloaddition of arynes.
Aryne dipolar cycloaddition takes place in either a concerted mechanism or
a stepwise mechanism, the exact nature and the distinction of which have not
been much studied. In an ideal situation, the concerted mechanism involves a
preorganized cyclic transition state with aryne and the dipole orientated perpendicular to each other. On the other side, the stepwise mechanism involves first
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
70
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
the nucleophilic attack of the nucleophilic site of the formal “1,n-dipole” to aryne,
followed by the back attack of the generated aryl anion to the electrophilic site
of the formal “dipole.” In such a situation, the formal “1,n-dipole” may not be
zwitterionic, and any amphiphilic species where the nucleophilic site and the
electrophilic site are tethered but separated by n–2 atoms would suffice. It is worth
mentioning that the nonzwitterionic amphiphiles may still react with arynes in a
concerted mechanism.
To date, aryne dipolar cycloadditions mainly involve 1,3-, 1,5-, and 1,7-dipoles [2].
This chapter will also follow the same classification. In addition, this chapter will
primarily cover the general conceptual knowledge of aryne dipolar cycloadditions,
with the emphasis on demonstrating the scope of dipoles, subsequent events and
mechanism after the cycloaddition, and applications in a broader picture. The
synthetic utility will be briefly mentioned, but the scope and limitation of each
individual reaction type, as well as the reaction conditions and other technical
details, will not be mentioned. Since most recent development of aryne chemistry
uses the Kobayashi aryne precursor (2-silylaryl triflate) [3], this chapter will also
focus on the application of this precursor in dipolar cycloadditions. Other versions
of aryne generation will also be mentioned if necessary.1
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
1,3-Dipolar cycloadditions (1,3-DC) provide an efficient and straightforward route
to synthesize five-membered heterocycles [4]. 1,3-DC of arynes, quickly developed
in the past decade, have been recognized as a powerful tool for the synthesis of benzannulated five-membered heterocycles.
The typical classification of 1,3-dipoles is based on whether or not the three atoms
are embedded into a ring. Thus, 1,3-dipoles such as nitrones, diazo compounds,
azides, azomethine imines, azomethine ylides, nitrile oxides, and nitrile imines are
all classified as linear dipoles (Figure 3.1). They can be further classified to straight
linear (180∘ , such as azides or diazo compounds) where the central atoms adopt
sp-hybridization, and V-shaped (120∘ , such as nitrones) where the central atoms
adopt sp2 -hybridization. Explicitly the former dipoles would react with arynes to
generate new five-membered rings that are unsaturated, while the latter dipoles
would generate new five-membered rings that are saturated (vide infra). In both
cases, the newly generated five-membered ring can undergo subsequent events,
most commonly including rearrangement, elimination, and oxidation, as driven by
gaining aromaticity or formation of stronger bonds after breaking weaker X–X ones
(X being N or O).
Cyclic 1,3-dipoles, so-called mesoionic rings, are generally less known and utilized due to the instability and difficulty to access (Figure 3.2). Those known to
react with arynes include Sydnones and Münchnones [5]. These two are azomethine
imines and ylides in nature, but embedded within lactone rings. Such lactone moiety
1 This chapter will mainly cover literature from year 2000 to August 2019.
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
V-Shaped dipoles (sp2)
Straight linear dipoles (sp)
R1
(Section 3.2.1.1)
N N
2
O
N
R
R3
Nitrones
N N N R
(Section 3.2.1.2)
Azides
N O
N R4
(Section 3.2.1.6)
N
R2
R3
Azomethine imines
R2
Nitrile imines
Figure 3.1
(Section 3.2.1.7)
N
N
R
(Section 3.2.1.8)
Pyridinium N-imides
(Section 3.2.1.3)
(Section 3.2.1.4)
R5
R4
(Section 3.2.1.6)
N
R2
R3
Azomethine ylides
R1
N N
O
Pyridinium N-oxides
R1
Nitrile oxides
R1
N
(Section 3.2.1.5)
2
R
Diazoalkanes
R
R1
N
EWG (Section 3.2.1.9)
Pyridinium N-ylides
Classification of typical linear 1,3-dipoles.
Figure 3.2 Cyclic 1,3-dipoles: Sydnones and
Münchnones.
R1
R1
R1
R2
N
N O
R1
O
N
R1
O
R2
N
O
N O
Sydnone
(Section 3.2.2.1)
R2
N
O
O
R3
R1
O
O
R3
R2
N
N O
R2
R2
N
O
O
Müchnone
(Section 3.2.2.2)
R3
provides added stability as well as additional driving force of decarboxylation after
the 1,3-DC, and thus can produce skeletons similar to those obtained by 1,3-DC of
nitrile imines and ylides but with different electron organization.
Pyridine can be derivatized into a variety of inner salts, constituting a special
class of dipoles. Pyridinium N-oxides, N-imides, and N-ylides should structurally be
classified as equivalents of nitrones, azomethine imines, and ylides (see Figure 3.1).
Despite that parts of the dipole structure are embedded into the pyridine, these
dipoles fall into linear dipoles and are different from cyclic dipoles shown in
Figure 3.2, where all of the dipole structure is embedded into rings. Pyridine can
also be derived to 3-oxido- and 3-imido inner salts (see Section 3.3.1), which can
react as either 1,3-dipoles or 1,7-dipoles (Figure 3.3). Thus, in this chapter, we
discuss pyridinium N-oxides, N-imides, and N-ylides in linear dipole sections, and
71
72
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
O
O
O
N
R
N
R
N
R
O
N
R
N
R
Azomethine ylide
Cyclic 1,3-dipole
Figure 3.3
O
Linear 1,7-dipole
3-Oxidopyridinium dipole.
put the entire content of 3-oxido- and 3-imidopyridinium species (whatever the
periselectivity is) into the 1,7-dipolar cycloaddition section.
3.2.1 [3+2] Dipolar Cycloaddition Reactions of Arynes with Linear
1,3-Dipoles
3.2.1.1 Reactions with Diazo Compounds
Diazo compounds are versatile building blocks in chemical synthesis [6], and
their [3+2] cycloaddition with arynes provides a very attractive and effective
strategy to construct indazoles. In this aspect, Yamamoto and Larock groups [7]
have independently reported [3+2] cycloaddition of arynes and diazomethane
derivatives (Scheme 3.2). The reaction, at the first stage, affords a primary [3+2]
cycloadduct 3H-indazole 1. Clearly spotted, the newly formed five-membered ring
in 1 is not aromatic and thus prone to subsequent events, which heavily depends
on the substitutions of the diazo compounds. When both R1 and R2 are aryl groups,
the reaction stops at the stage of 1, which can be isolated. When R2 is H, hydrogen
shift from C3 to N1 takes place to transform this 3H-indazole intermediate to a more
stable and aromatic 1H-indazole product 2. By controlling the reaction condition
and stoichiometry, reaction can stop at this stage. When excessive aryne exists and
reaction conditions permit, 2 will further react with another equivalent of aryne to
yield 1-arylated 1H-indazole 3.
R1
TMS
+
Z
OTf
N2
R1
Fluoride
R2
R1/R2 ≠ EWG
Scheme 3.2
R1 R2
N
Z
N
1, isolable when
R1/R2 ≠ EWG/H
R1
When R2 = H
Z
Z
N
Z
N
N
N
H
2, isolable
3
Z
[3+2] Cycloaddition of arynes with diazomethane derivatives.
The rearrangement of 1 to 2 takes place not only when R2 is H. It will also occur
when R2 is an acyl group (Scheme 3.3), although acyl group shifts less readily
than H. Such a process affords a 1-acylated indazole 4. Larock and coworkers have
observed that when both R1 and R2 are acyl groups (as in Scheme 3.2), the ketone
moiety migrates more readily than the ester moiety or amide moiety [7c]. It is important to note that the apparent C3 -to-N1 migration may result from two sequential
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
R2
+ R1
Z
OTf
R1
R2
N2
TMS
R1
Fluoride
Thermal
N
Z
N
N
Z
O
O
N
4
May be isolable
Scheme 3.3
R2
O
[3+2] Cycloaddition of arynes with acylated diazomethane derivatives.
1,5-migrations from C3 to N2 first, and then N2 to N1 . This rearrangement has been
exploited for cyclic diazo compounds [8], where the intermediate 3H-indazoles 1A
and 1A′ could be stable and isolable, and further acyl migration under thermal or
acidic conditions led to ring-expanded products (Scheme 3.4a). Note that here the
acyl migration stopped at the N2 -position of the indazole, presumably due to the
unachievable reach of the acyl group to the N1 -position given the cyclic nature of
the diazo compounds.
Z
Z
N2
Z
R1
N
N
O
N
R2
1
N
R2
1A, isolable
O
Z
N2
X
N
R1
O
R
O
R3
Thermal
O
N N
Thermal or acid
N
O
N
3
R3
n
N
R2
N
X
n
Z
R
X
Z
n
1A′, isolable
(a)
TMS
N2
(b)
OH
R4
R5
HO R5
TMS
R4
Z
N
Z
N
1B, rarely isolable
4
R5 R
OH
Brook rearrangement
Z
N
N
H
Scheme 3.4 [3+2] Cycloaddition of arynes with subsequent acyl/silyl migration. (a) Acyl
shift in cyclic diazo compounds and (b) silyl shift via Brook rearrangement. Source: Based on
Hari et al. [8d].
A silyl group can also shift to transform 1 to 2. For example, trimethylsilyl
(TMS)-diazomethane reacted with benzyne in a mixed solvent containing methanol
to afford plain unsubstituted 1H-indazole [7c]. The TMS group was lost likely to the
methoxy group in the solvent. A more complicated silyldiazomethane substrate has
been studied in this context (Scheme 3.4b) [8d]. With an intrinsic hydroxyl group to
accommodate the silyl group, the [3+2] cycloadduct 1B readily underwent a Brook
rearrangement to afford 1H-indazole after hydrolytic workup.
73
74
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
There has been no direct evidence that phosphoryl groups can migrate.
When α-substituted diisopropyl α-diazophosphonates reacted with arynes,
3H-3-phosphoryl indazole 1C could be obtained (Scheme 3.5, path A) [9a]. Under
slightly different conditions, dimethyl α-diazophosphonates directly afforded
1H-indazoles 2 as the final product (Scheme 3.5, path B). Formation of 2 in this
case could be explained by an in situ cleavage of the phosphate by fluoride to
generate a diazomethane derivative prior to its reaction with aryne. Alternatively, it is also possible that dimethyl α-diazophosphonates reacted to afford
the 3H-indazole adduct (as 1C) first, followed by phosphate migration to form
1-phosphoryl-1H-indazole, and subsequent hydrolysis to cleave the phosphate
group. A three-component variant of the latter outcome has been developed to
afford 1-alkyl-1H-indazoles [9b].
R1
2
R = i-Pr
Path A
TMS
+
Z
N2
R1
OTf
O
P
OR2
OR2
N
Z
N
1C, can be isolable
O
P OR2
OR2
R1
R2 = Me
Path B
via
Z
N2
R1
N
N
H
2
H
Scheme 3.5 [3+2] Cycloaddition of arynes with α-substituted α-diazophosphonate.
Source: Based on Chen et al. [9a].
Apart from the aforementioned cases where 1H-indazoles and 3H-indazoles
could be selectively formed, the regio-complementary 2-aryl-2H-indazole species
5 could also be selectively obtained under silver-catalyzed conditions (Scheme 3.6).
The Ag(I) ion could intercept the conjugate base of intermediate 1D to generate
TMS
Z
N2
+
H
OTf
O
H
Fluoride
R1
R1
F
O
N
Z
R1
–
– HF
O
–
Z
N
N
N
1D
R1
O
O
Z
R1
AgOTf
N
Z
2A
Scheme 3.6
N
Ag
Z
N
Z
N
5
Silver-catalyzed [3+2] cycloaddition of arynes with diazo compounds.
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
a possible (1H-indazol-1-yl)silver intermediate 2A [10], leaving only the
N2 -position of the indazole open for further arylation with another equivalent
of aryne.
Diazo compounds without electron-withdrawing groups (EWGs) are unstable and
barely isolable. They can be generated in situ from N-tosylhydrazones under basic
conditions. Such substrates have been indeed employed in aryne cycloaddition
to afford 3-substituted 1H-indazoles with aid of a phase-transfer catalyst [11].
The reaction proceeds, at least in part, through in situ formation of diazo compounds, although a stepwise annulation mechanism may also operate (Scheme 3.7,
see also Section 3.4.2).
TMS
N
+
Z
OTf
R
Fluoride
N
R
H
N
H
Z
[3+2] via
R
Z
N
N2
R
H
H shift
Ts
N
N
H R
H
H
N
Fluoride, PTC
Step-wise via
Ts
N
Scheme 3.7
Ts
N
Z
Z
– Ts
–
N
R H
[3+2] Cycloaddition of arynes with N-tosylhydrazones.
3.2.1.2 Reactions of Arynes with Azides
Azides have found wide applications in synthetic organic chemistry, polymer
chemistry, material sciences, bioconjugation chemistry, and medicinal chemistry
owing to their reactivity in [3+2] cycloaddition with alkynes to afford triazoles,
commonly referred to as the click reaction [12]. While being generally schematic
and straightforward, most click chemistry involving terminal alkynes is slow
and requires either Cu or Ru to facilitate the reaction and offer regioselectivity.
It has been known that strained alkynes can undergo Cu-free [3+2] cycloaddition
with azides under much milder conditions [13]. Aryne, as an extreme example of
“strained” alkyne, was anticipated to do the same thing to generate benzotriazoles.
Pioneering work in this field was reported simultaneously by several groups [14]
using isolated azides, and indeed such [3+2] dipolar cycloaddition worked very
well under mild conditions without Cu (Scheme 3.8). Quite a few studies quickly
followed, including using microwave to promote the reaction [15], different aryne
precursors (see Figure 3.4) [16], and different azides (including sugar-derived
TMS
Z
+
OTf
Scheme 3.8
R N3
Fluoride
N
Z
N
N
R
[3+2] Cycloaddition of arynes with azides in general.
75
76
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
TMS
TMS
Si
O
Si
O
O2S
ref 16a
Oxidation by
PhI(OAc)2+TfOH,
then fluoride
CO2H
O
Bpin
O
O2S
F
ref 16b
Fluoride
N
ref 16c
Fluoride
N
OTf
ref 16d
s-BuLi
N
N
O
O
N
ref 16e
Photolytic
O
I
OTf
O
ref 16f
Photolytic
ref 16g
Iodine-metal
exchange
Figure 3.4 Some selected aryne precursors applied to [3+2] aryne cycloaddition with
azides. Source: Lin et al. [16a]; Chen et al.[16b]; Kovács et al. [16c]; Sumida et al. [16d];
Gann et al. [16e]; Chang et al. [16f]; Yoshida et al. [16g].
azides) [17]. One interesting case worth mentioning is the one developed by Moses
and coworkers [17c], where both arynes and aromatic azides were generated in
situ via diazotization reactions (although sequentially) from anthranilic acids and
anilines, respectively (Scheme 3.9).
N
NH2
NH2
+
Z
CO2H
t-BuONO
Scheme 3.9
azides.
N
R
R
t-BuONO
TMSN3
N3
Z
N
Z
+
[3+2]
R
[3+2] Cycloaddition of in situ–generated arynes with in situ–generated
In the above studies, regioselectivity with respect to unsymmetrical benzynes
had been observed. It is worth the effort here to summarize the regioselectivity of
aryne–azide cycloaddition as part of the general, global picture of aryne cycloaddition, and to discuss the scope and regioselectivity of heteroarynes (such as indolyne
and pyridyne) as well in this section. Even though similar observations have been
obtained with other dipoles, data and the rationale for the cycloaddition with
azides are the richest to facilitate our understanding.
Scheme 3.10 below summarizes the regioselectivity in azide cycloaddition of
benzynes bearing different substitutions [18]. There are many factors that could
influence the regioselectivity. Garg group has previously advanced a computational
model to explain certain aryne reactions using a distortion model [19]. Thus, the
intrinsic selectivity would involve the more nucleophilic atom of the azide, namely
the internal nitrogen (Figure 3.5a), to attack the aryne position bearing a larger
internal angle. Tokiwa and Akai in their report also calculated the natural bond
orbital (NBO) to reveal the difference in the electron density of the two “yne”
carbons (Figure 3.5b). Thus, the nucleophile, again the internal nitrogen of the
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
F
F
F
N
N
R
ref 14a/17c
exclusive
N
N
N
R
Me
Bpin
ref 18a
exclusive
Me
TfO
TfO
N
N
N
TMS R
ref 18b
3:1
N
N
N
N
MeO
R
ref 18b
1:1
Me
N
N
R
MeO
MeO
N
N
Bpin R
N
ref 18a
mostly 3 : 1 to 10 : 1 Me
N
N
R
N
TMS
TMS
N
N
R
N
N
ref 17c
1:1
N
ref 18b
exclusive
Me
Me
OTf
OTf
N
N
R
ref 17c
exclusive
Me
N
R
CF3
CF3
Me
N
N
N
N
R
ref 17c
1:1
OMe
OMe
N
N
N
N
N
N
R
N
N
R
TfO
N
N
R
Scheme 3.10 Regioselectivity of unsymmetrical benzyne in [3+2] cycloaddition with
azides. Source: Ikawa et al. [18a]; Ikawa et al. [18b].
azide, would also prefer to attack the position with smaller value in electron density.
The bigger the difference in the electron density, the better the selectivity. Both
rationales provide the same conclusion, and they are in agreement with empirical
rationale that such EWGs (on σ-skeleton, such as OMe) on benzyne polarize the
“triple” bond so that more electron density resides on the “yne” atom closer to
the EWG. They are also in agreement with most of the observed regioselectivity,
both in trend and in magnitude, and can explain similar regioselectivity in aryne
cycloaddition with nitrile oxide (vide infra). The one that cannot be explained is
the 3-silylbenzyne (Scheme 3.10) [18], where calculation results show that sterics
induced by the big silyl group, which neither of the two rationales shown in
Figure 3.5 considers, are the dictating factor.
Apart from benzynes, pyridynes were also examined in cycloaddition with azides
(Scheme 3.11) [20]. Two observations should be mentioned beforehand. Firstly,
pyridynes are much more reactive and short-lived than benzynes, and therefore
the yields for pyridynes are generally lower. Second, 2,3-pyridyne itself is distorted
and nucleophilic attack is regioselective toward its 2-position [20, 21]. Therefore,
despite low yields, plain 2,3-pyridyne reacts with azide to afford 1-substituted
7-azabenzotriazole. A methoxy substituent at the 4-position reinforces this regioselectivity. In contrast, 3,4-pyridyne is less distorted and reacts to afford mixture of two
regioisomers. A methoxy group positioned neighboring to the triple bond can favor
one regioisomer, but a distal methoxy group lacks such capability. 4,5-Pyrimidyne
was presumably too short-lived and failed to react with azides [20b]. Indolyne and
4,5-benzofuranyne have been successfully applied in cycloaddition with azides
(Scheme 3.12) [22]. Although poor-to-moderate selectivity was observed for 4,5- and
5,6-indolynes due to the less extent of distortion of the ring, excellent regioselectivity
was observed for 6,7-indolyne where the ring was distorted to a greater extent.
77
78
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
OMe
–0.075 natural charge
OMe
N
N
N
2
1
1.010
2
–0.334 natural charge
1
R
0.826
OTf
Internal angle: C1 135°, C2 119°
1.031
2
–0.075 natural charge
N
N
N
2
1
Bpin
1
–0.334 natural charge
0.781
TfO
2
R
0.953
1
Internal angle: C1 133°, C2 122°
0.907
(a)
(b)
Figure 3.5
(NBO).
Regioselectivity rationales: (a) Aryne distortion and (b) natural bond orbital
4,5-Benzofuranyne was distorted slightly more than 4,5-indolyne and therefore the
regioselectivity was consequently better.
N
(a)
N
Only
OMe
N
N
N
N
R
Only
MeO
N
N
N
N
R
(d)
+
R
N
N
N
MeO
N
N
N
N
N
R
1.9 : 1 for R = CH2CO2Et
N
OMe
(b)
N
R
N
N
N
(c)
N
MeO
+
N
N
1.6 : 1 for R = CH2CO2Et
OMe
OMe
N
(e)
N
N
N
R
Only
N
N
N
R
Scheme 3.11 [3+2] Cycloaddition of pyridynes with azides. Source: Saito et al. [20a];
Medina et al.[20b].
This type of heteroarynes will be more systematically discussed in Chapter 9.
Their cycloaddition scope with dipoles other than azides, however, is much scattered and not systematic. Known successful examples include the cycloaddition of
4,5-benzofuranyne with diazo compound, nitrone, azomethine imine, and Sydnone
[22b], as well as the cycloaddition of 2,3-pyridyne with nitrone and azomethine
imine only (diazo compound, Sydnone, and nitrile oxide do not afford desired
products) [20b]. Cycloaddition of 3,4-pyridyne with nitrone has also been reported
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
N N
Bn N
O
N N
N
123°
130°
6.2 : 1
O
O
N N
Bn N
N
R
Bn
2.4 : 1 for R = Me
5 : 1 for R = Boc
N
R
1.6 : 1 for R = Me
1.8 : 1 for R =Boc
N
R
Exclusive
R = Me or Boc
O
N N
N
N
R
Bn
N
N
N
Bn N
N N
Bn
125°
129°
N
129°
N
N
R
N
R
N
Me
N
R
N
Bn
N
R
N
Me
127°
135°
116°
N
Me
Scheme 3.12 [3+2] Cycloaddition of indolynes and benzofuranyne with azides. Source: Im
et al. [22a]; Shah et al. [22b].
[19a]. These reaction scopes will not be mentioned again in the following individual
sections unless necessary.
3.2.1.3 Reactions of Arynes with Nitrile Oxides
Unlike azides or diazo compounds, nitrile oxides are typically unstable and thus not
isolated and used in pure form. Rather, they are generated in situ from either the
corresponding hydroximoyl chlorides under basic conditions, or the nitroalkanes
with a dehydration agent.
The biggest challenge for the [3+2] dipolar cycloaddition of arynes with nitrile
oxides lies in the fact that both reacting partners are unstable and generated in situ.
Therefore, a key factor is to match the rates at which arynes and nitrile oxides are
generated so that neither of them is accumulated to undergo side reactions. In this
aspect, Larock group developed a slow-vs.-slow approach using insoluble CsF as a
promoter, which serves both as a base to transform hydroximoyl chlorides to nitrile
oxides and a desilylation agent to generate aryne [23]. The chlorooximes had to be
added slowly via syringe pump to further control the concentration of nitrile oxides
(Scheme 3.13). Moses and Browne groups used the same precursors but applied
a fast-vs.-fast approach, where soluble tetrabutylammonium fluoride (TBAF) was
used and no syringe pump addition was required [24]. The reaction could be completed in half a minute.
Moses group also reported another 1,3-dipolar cycloaddition variant using arynes
generated from diazotized anthranilic acids (Scheme 3.14) [25]. This is presumably
also a fast-vs.-fast approach, and t-BuONO and K2 CO3 were used to generate arynes
and nitrile oxides, respectively.
79
80
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
R
TMS
Z
R
Cl
+
N
HO
OTf
Z
N
O
Fast: TBAF
Slow: CsF
R
+
Z
Scheme 3.13
[3+2]
N
O
[3+2] Cycloaddition of arynes with in situ–generated nitrile oxides.
R
NH2
+
CO2H
Cl
R
t-BuONO, K2CO3
N
N
HO
O
Scheme 3.14 [3+2] Cycloaddition of arynes with nitrile oxides: another variant. Source:
Spiteri et al. [25].
3.2.1.4 Reactions of Arynes with Nitrile Imines
Nitrile imines are even less stable than nitrile oxides. Their reaction with aryne
also requires a similar precursor and a suitable condition for their generation at a rate
matching that of aryne formation so as to restrain the self-dimerization. This work
was demonstrated using hydrazonyl chlorides as nitrile imine precursors, similar
to that of nitrile oxides [26]. That said, due to the greater instability nature, nitrile
imine cycloaddition had to follow a fast-vs.-fast approach, and either TBAF or large
excess of CsF in combination of 18-C-6 would work (Scheme 3.15).
TMS
+
Z
OTf
R2
NH
N
Cl
R1
R1
Fluoride
R1
Via
Scheme 3.15
Z
N
N
R2
N
N
R2
[3+2] Cycloaddition of arynes with in situ–generated nitrile imines.
3.2.1.5 Reactions of Arynes with Nitrones
Nitrones, also known as imine oxides, are stable and isolable dipoles and have
been widely used to react with various dipolarophiles to synthesize five-membered
heterocycles [27]. The [3+2] cycloaddition of arynes with nitrones provides a direct
and simple route to benzisoxazolines. Even before the systematic investigation
of aryne–nitrone cycloaddition, Danishefsky and coworkers have applied such
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
strategy to the synthesis of cortistatin A [28], where 2-bromophenyl triflate was
treated with n-BuLi to generate aryne (Scheme 3.16).
R1
Br
Z
+
OTf
N
O
Scheme 3.16
R2
R1
n-BuLi
R2
N R3
Z
R3
O
[3+2] Dipolar cycloaddition of aryne with an α, β-unsaturated nitrone.
Systematic studies quickly followed, commencing from isolated nitrones in
a general sense (Scheme 3.17) [29]. Kaliappan group expanded the scope to
sugar-derived nitrones [30], and demonstrated a mild reductive cleavage of the
N—O bond to open the isoxazoline ring (Scheme 3.18). Mo and coworkers reported
the use of N-vinyl-α,β-unsaturated nitrones, whose primary [3+2] cycloadduct with
arynes could undergo a stereospecific 3,3-sigmatropic rearrangement to afford a
benzannulated nine-membered ring (Scheme 3.19) [31]. Subsequent N–O cleavage
under different conditions could afford either pyrrole or polyketide scaffolds.
R1
TMS
+
Z
OTf
O
R2
N
R 1 R2
Fluoride
N R3
Z
R3
O
Scheme 3.17 [3+2] Dipolar cycloaddition of arynes with isolated nitrones. Source: Wu
et al. [29a]; Wu et al. [29b]; Lu et al. [29c].
O
N
TMS
+
Z
OTf
BnO
Scheme 3.18
TMS
Z
OTf
OH
H
N
O
OBn
Fluoride
Z
N
cis
OBn
H
BnO
OBn Zn, AcOH
Z
H
OBn
OBn
BnO
OBn
[3+2] Dipolar cycloaddition of arynes with sugar-derived nitrones.
R4
+ R3
N
R1
Fluoride
[3+2]
O
R2
R4 3′ 1′ O
N
1
R3
R1
R2
3
1′
R3
Z
[3,3] sigmatropic
R4
R2
N O
3′
3
Z
1
R1
Scheme 3.19 [3+2] Dipolar cycloaddition with N-vinyl-α,β-unsaturated nitrones: ring
enlargement by sigmatropic rearrangement. Source: Based on Ma et al. [31].
Despite being stable and isolable, nitrones exhibit high polarity and often cause
difficulty in isolation and purification. Hence, much efforts were devoted to bypass
this isolation and purification process and use in situ–generated nitrones or nitrone
surrogates. Oxaziridines were found to react with arynes to give the same product
as that of nitrones [32]. The reaction could possibly proceed through in situ ring
81
82
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
TMS
Z
OTf
O
N 3
+
R
R2
3
R = tert-alkyl only
R1
Path A
N
R3
N R3
Z
O
R1
R2
R1 R2
Fluoride
R2
O
R3
R1
N
O
R2 R1
Path B
Scheme 3.20
R3 N
O
Cycloaddition of arynes with oxaziridines.
opening of oxaziridines to nitrones, followed by [3+2] cycloaddition with arynes
(Scheme 3.20, path A). However, it is also possible that arynes directly insert into
the C—O bond of the oxaziridines (Scheme 3.20, path B), affording the same
product. In addition, hydroxylamines could react with acetylenedicarboxylates to
form nitrones in situ and this type of nitrones, bearing active methylene units, could
react with arynes preferentially in a [3+2] cycloaddition manner (Scheme 3.21)
[33]. Another interesting way to form nitrones is to react ketoximes with aryne in
an N-arylation fashion, and subsequent cycloaddition with another equivalent of
aryne could take place smoothly (Scheme 3.22) [34]. It is interesting to note that
only ketoximes worked in this way and aldoximes simply underwent O-arylation
with arynes (as seen for OH groups in phenols and aromatic carboxylic acids). It is
not clear why ketoximes and aldoximes behave differently and why isoelectronic
hydrazones behave differently from the oxime counterparts (cf. Scheme 3.7 and
vide infra Section 3.4.2).
CO2R1
TMS
Z
+ R2NHOH
+
OTf
O
R1O2C
CO2R1
N R2
Z
O
CO2R1
Via
R1O2C
Fluoride
N
R2
CO2R1
Scheme 3.21 [3+2] Cycloaddition of arynes with nitrones in situ generated from
hydroxylamines and acetylenedicarboxylates. Source: Based on Li et al. [33].
In the latter report, it has been observed that the afforded cycloadduct dihydrobenzisoxazole 6 could readily undergo thermal rearrangement to a more
stable dihydrobenzoxazole 7. This rearrangement seems intrinsic and can occur
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
TMS
N
+
R1
OTf
OH
Fluoride
R2
Ph
R1 R2
+
N Ph
via
R1/R2 ≠ H
R1
N
O
O
7
Major product at 40–80 °C
6
Major product at 10 °C
R2
R1 R2
3
Ph
N R1
2
O R
40 oC
1′
N Ph
O
2
6
1
7
Path B
[1,3]-sigmatropic
Path A
R1 R2
R1 R2
N
Ph
3
2
O
Ph
N R1
2
O R
N
1′
R1
R2
N
Ph
O
Ph
O
1
Scheme 3.22 [3+2] Cycloaddition of arynes with ketoxime-derived nitrones and
subsequent rearrangement. Source: Based on Yao et al. [34].
at temperature as low as 40 ∘ C, yet it was not mentioned in the previous reports,
where even higher temperature (such as 65 ∘ C [29c]) has been used to facilitate the
cycloaddition. Structurally, nitrones in this report are ketone-derived and bear aryl
groups at the nitrogen. However, it is not clear whether these factors are necessary
or sufficient to trigger this rearrangement. Putting that aside, the rearrangement
was proposed to take place via a radical dissociation-rearrangement-cyclization
pathway (Scheme 3.22, path A), yet theoretically a 1,3-sigmatropic rearrangement
could also explain the same phenomenon (Scheme 3.22, path B). This type of
rearrangements is commonly seen for analogous structures derived from other
aryne cycloadditions, and will be discussed more in Section 3.2.1.7, where another
type of post-transformation of aryne–nitrone cycloadduct will also be mentioned.
3.2.1.6 Reactions of Arynes with Azomethine Imines and Ylides
Azomethine imines are the nitrogen analogue of nitrones but much less stable.
Despite their reactivity with different dipolarophiles [35], azomethine imines
are more often only transient intermediates and not isolated. However, some
azomethine imine with part of the dipole structure incorporated in a ring and with
an EWG to stabilize the negative charge (Scheme 3.23) can be stable and isolable.
O
O
TMS
Z
+
N
OTf
R
Scheme 3.23
Fluoride
N
N
H
N
Z
R
[3+2] Dipolar cycloaddition of arynes with azomethine imines.
83
84
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
Thus, Yamamoto and Larock groups simultaneously reported [3+2] cycloaddition
of arynes with such dipole [7, 36], where the cycloadduct can be obtained in
moderate-to-good yields.
Azomethine ylides are the carbon analogue and even less stable. Using the
aryne activation approach as shown in Scheme 3.22, imine 8 could be successfully
transformed into an azomethine ylide, but this ylide was apparently so short-lived
that it reacted with another molecule of 8 as opposed to aryne (Scheme 3.24) [37].
EWG
Ph N
[3+2] with aryne
TMS
N
+
OTf
Ar
EWG
Fluoride
Ph
Ar
N
EWG
Not observed
Ar
8
EWG
Ar
[3+2] with 8
Ph N
N
EWG
Ar
High yield
Scheme 3.24 Failed [3+2] cycloaddition of arynes with azomethine ylide. Source: Swain
et al. [37a]; Jia et al. [37b].
A successful example of azomethine ylide cycloaddition was indeed reported
(Scheme 3.25) [38] for an isatin imine substrate. This ylide was presumably stabilized both by the strong electron-withdrawing CF3 group and the extra conjugation
into the oxyindole system. The lifetime of the ylide was long enough to react with
arynes, presumably through an extra stabilization of an internal hydrogen bonding,
as proposed.
F3C
CF3
TMS
Z
N
+
OTf
R1
R
O
N
R1
O
N
R2
CF3
H
O
N
R2
Z
1
N
R2
CF3
Via
HN
Fluoride
N
R1
H
O
N
R2
Scheme 3.25 [3+2] Dipolar cycloaddition of arynes with azomethine ylides. Source: Based
on Ryu et al. [38].
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
3.2.1.7 Reactions of Arynes with Pyridinium N-Oxides
Pyridinium N-oxides can be classified as a cyclic version of nitrones, with part of
the dipole structure embedded into a pyridine ring. However, one should keep in
mind that [3+2] cycloaddition with arynes breaks the aromaticity of the pyridine
and forms a rather weak N—O single bond, rendering the intrinsic driving force of
the cycloadducts to undergo a variety of post-transformations to form more stable
products.
Larock and Liu groups sequentially disclosed two comprehensive studies of aryne
cycloaddition with pyridinium N-oxides under different conditions [39]. In
both cases, the reaction involved a first [3+2] dipolar cycloaddition to afford an
aromaticity-broken intermediate 9 (Scheme 3.26). This intermediate can then
undergo either a deprotonation/elimination to cleave the N—O bond to afford
2-arylpyridine 10 (path A), or a 3,5-sigmatropic-like rearrangement to afford 11
(path B) followed by internal rearrangement to finally afford 3-arylpyridine 12.
The exact choice is complicated and depends on the substitution of the pyridine,
the reaction conditions, and even the aryne precursor and the conditions under
which aryne is generated. Thus, Larock’s conditions involving excess aryne with
CsF/MeCN preferred 12, while Liu’s conditions with reversed stoichiometry
involving TBAF/dichloromethane (DCM)-tetrahydrofuran (THF) preferred 10.
5′
TMS
R
+
Z
OTf
Fluoride
R
Path A
H
3
1′ N
N
O
O
1
R
N
Z
HO
10
Z
9
Path B
[3,5] sigmatropic
1
O
H
N
3
1′ H
Z
Z
5′
R
R
11
Scheme 3.26
OH
N
12
[3+2] Dipolar cycloaddition of arynes with pyridinium N-oxides.
Quinolinium N-oxides behave similarly, but are more sensitive to the substitution
and reaction conditions. 2-Unsubstituted quinolinium N-oxides reacted with arynes
under CsF conditions to afford two products 10A and 13 (Scheme 3.27) [40]. Formation of 10A came from elimination (path A) and formation of 13, preferred with
excessive arynes under harsher conditions, presumably arose from an additional
aryne insertion to the N—O single bond at the stage of the cycloadduct 9A (path
C). 2-Substiuted quinolinium N-oxides under KF/18-C-6 conditions could afford
12A preferably (path B) [41]. Acridinium N-oxides reacted smoothly as well and
the cycloadduct 9B underwent a 3,9-sigmatropic-like rearrangement to finally afford
4-aryl acridines 12B (Scheme 3.28).
85
86
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
R
N
10A
Z
HO
Path A
R
R
TMS
Z
Fluoride
+
N
O
N
O
OTf
Path B
H
Path C
N
Z
9A
Z
R
OH
12A
Z
R
Z
N
O
Z
Scheme 3.27
[3+2] Dipolar cycloaddition of arynes with quinolinium N-oxides.
R
R
5′
TMS
Z
13
KF, 18-C-6
+
1′ N
N
O
OTf
7′
9′
3
1O
Z
9B
R
R
5′
[3,9] sigmatropic
1′
N
O
1
3
5′
1′
9′
H
Z
N
HO
1
3
9′
Z
12B
Scheme 3.28
[3+2] Dipolar cycloaddition of arynes with acridinium N-oxides.
The [3+2] cycloadduct of arynes with regioisomeric isoquinolinium N-oxides,
generated from Ag-catalyzed cyclization of 2-alkynylbenzaldoximes, underwent a
different post-transformation [42]. Here, a bicyclic [3.2.2] skeleton 14 was formed
via either a radical dissociation/recombination or an equivalent 1,3-sigmatropic-like
rearrangement (Scheme 3.29). In this case, the 5′ -position belongs to another aromatic system and is not accessible for 3,5-rearrangement as seen in Scheme 3.26.
In contrast, however, the cycloadduct of dihydroisoquinolinium N-oxide, a real
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
nitrone rather than a pyridinium N-oxide analogue, could undergo CsF-promoted
deprotonative elimination to give rise to an imine product 10B (Scheme 3.30) [40].
Z
TMS
Z
+
N
R1
OH
1O
OTf
R2
TBAF
R
AgOTf
+
Z
O
R2
[3+2] Dipolar cycloaddition of arynes with isoquinolinium N-oxides.
+
+
R2
O1
N 1′
5′
R1
3′
TMS
N 1′
radical or
[1,3] sigmatropic
[3+2]
R2
Scheme 3.29
3′
14
Z
N
R1
1
N
–
O
CsF
N
OTf
OH
O +
+ Overreacted products
N
9C
10B
Increasing under
harsher conditions
Major under
mild conditions
CsF
Scheme 3.30 [3+2] Dipolar cycloaddition of aryne with a dihydroisoquinolinium N-oxide
(a nitrone). Source: Based on Okuma et al. [40].
3.2.1.8 Reactions of Arynes with Pyridinium N-Imides
Pyridinium N-imide is isoelectronic to pyridinium N-oxide and can be considered
as an azomethine imine with part of the dipole structure incorporated in a pyridine
ring. Pyridinium N-imide is less stable than the corresponding oxide but more
stable than regular acyclic azomethine imines. If the exocyclic nitrogen is equipped
with an EWG, the pyridinium N-imide can be isolated. An early study in this
regard demonstrated a feasible cycloaddition with subsequent elimination at
the intermediate that afforded a final product resembling 10 (cf. Scheme 3.26,
path A) [43]. This is likely facilitated by the weak N—N bond, as well as the
fact that EWG-equipped nitrogen could serve as a leaving group. An alternative
solution has been recently disclosed [44], where the subsequent event can be
tuned mechanistically by replacing the EWG (at the exocyclic nitrogen) by a tosyl
group. Tosyl group itself could function as a leaving group, and therefore could
strategically switch the mechanism at the stage of 9D to a 1,4-elimination to afford
pyrido[1,2-b]indazoles 15 (Scheme 3.31). This alternative outcome exploited the
tosyl group as a traceless group and provided another mechanistic solution to
87
88
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
the instability of the cycloadduct. Under the same conditions, quinolinium and
isoquinolinium imides behaved similarly, and the latter could be prepared in situ
from the corresponding N ′ -(2-alkynylbenzylidene)-tosylhydrazides in the presence
of a silver catalyst [44b].
R
R
TMS
Z
+
OTf
R
Fluoride
N
N
H
Ts
Ts
N
N
N
N
Z
9D
Z
15
Z
TMS
Z
+
N
R2
OTf
NHTs
Fluoride, Ag salt
R1
N
via R2
NTs
N
R2
N
R1
R1
Scheme 3.31 [3+2] Dipolar cycloaddition of arynes with N-tosylpyridinium and
isoquinolinium imides.
A recent study has also revealed, somewhat strikingly, that the direct cycloadduct
9E could be stable enough to be isolated for quinolinium N-benzoylimides and
would not experience 1,2-elimination to cleave the N—N bond [45]. Scheme 3.32
shows this reaction and the similar one with the N-tosyl variant for a comparison [44b].
TMS
R
+
Z
OTf
TMS
R
+
Z
OTf
KF, 18-C-6
+
N
–
N
H
MeCN, r.t.
Bz
ref 45
CsF
+
N
–
N
R
THF, 70 °C
Ts
ref 44b
Bz
N
N
Z
9E, Isolated in high yields
R
N
N
Z
15A
Scheme 3.32 Divergent outcome from [3+2] dipolar cycloaddition of arynes with
N-benzoyl and N-tosylquinolinium imides. Source: Based on Zhao et al. [44b].
Another interesting event observed during this study was the pyridinium imide
bearing two leaving groups at 3,5-positions [44b]. In this case, the intermediates
9F underwent a 1,5-sigmatropic-like rearrangement to afford intermediates 11A,
which, upon further elimination, afforded 5H-pyrido[3,2-b]indoles 16 in good combined yield (Scheme 3.33).
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
MeO 3′
5′
Br
TMS
+
OTf
Fluoride
N
N
MeO 5′
Ts
N
1′
Br
N
16
Ts
N
Ts OMe
3′ Br
1N
[1,5] sigmatropic
H
5′
N 1′
N
1 Ts
Scheme 3.33
–HBr
H
11A
3′
Ts
N
MeO
5′
1′N
N
Ts 1
9F
Br
MeO
Br Ts
N1
[1,5] sigmatropic MeO 3′
H
N
H 1′
–MeOH
Br
N
[3+2] Dipolar cycloaddition of aryne with a special N-tosylpyridinium imide.
The cycloaddition with pyridynes is also worth special mentioning [46]. While
the parent 3,4-pyridyne reacted with in situ–generated N-tosylisoquinolinium
imides uneventfully to afford product 15B via elimination of tosyl anion, it was
found that 2-chloro-3,4-pyridyne afforded 14A instead via apparent 1,3-sigmatropic
rearrangement (or a radical dissociation/recombination) (Scheme 3.34).
N
R2
N
NTs
N
N
R1
N
R2
N
+
R2
N
N
R1
R1
15B, as mixture of regioisomers
N
N
R2
N
NTs
R1
Ts
Cl
Cl
N
N
R2
14A
R1
Scheme 3.34 Divergent outcome from [3+2] cycloaddition of N-tosylisoquinolinium
imides with different pyridynes.
3.2.1.9 Reactions of Arynes with Pyridinium Ylides
Pyridinium N-ylides are more stable than the acyclic azomethine ylides, particularly
if bearing EWGs to stabilize the carbanion. Such ylides could readily undergo [3+2]
cycloaddition with arynes. The direct cycloadduct in this reaction could undergo a
1,4-elimination if a leaving group is positioned at the ylide carbon [47]. Alternatively,
the cycloadduct could be dehydrogenated by air to furnish pyrido[2,1-a]-isoindoles
as the final product (Scheme 3.35). The latter reaction could be easily performed in
a one-pot fashion, where pyridinium N-ylides were generated from pyridines and
α-haloketones/esters in situ [48].
Another very interesting reaction in this type exploited the dipole nature of
indolizine that electronically resembles an azomethine ylide. Thus, indolizines
successfully react with arynes, followed by a dehydrogenation step to afford
indolizino[3,4,5-ab]isoindoles (Scheme 3.36) [49].
89
90
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
R1
+
R2
EWG
Br
N
R1
EWG = CN
R1
1
R
TMS
Z
– HCN
Fluoride
+
2
R
N
EWG
EWG
R2
Z
H
N
OTf
N
R2 = H
Z
2
R
R1
[O]
N
EWG
Scheme 3.35
N-ylides.
Z
[3+2] Dipolar cycloaddition of arynes with in situ–generated pyridinium
R
TMS
+
Fluoride
R
N
OTf
N
H
[O]
R
N
H
R
N
Cyclic azomethine ylides
Scheme 3.36 [3 + 2] Dipolar cycloaddition of arynes with indolizines. Source: Based on
Shen et al. [49].
3.2.2 [3+2] Dipolar Cycloaddition Reactions of Arynes with Cyclic
1,3-Dipoles
3.2.2.1 Reactions of Arynes with Sydnones
Sydnone is a representative stable and isolable cyclic 1,3-dipole. Structurally, it can
be either viewed as an aromatic system in the form of 1,2,3-oxadiazolium inner
salt, or as an azomethine imine possessing an internal lactone unit. Sydnones
have been widely used in dipolar cycloadditions with various dipolarophiles to
synthesize corresponding indazole derivatives and analogues, and their application
in aryne [3+2] dipolar cycloaddition was advanced as a versatile and efficient way
to synthesize 2H-indazole derivatives [50]. Different from the aforementioned
[3+2] dipolar cycloaddition of arynes with linear 1,3-dipoles, the cycloaddition with
Sydnones afforded a bicyclic [2.2.1] system, which would readily undergo a [4+2]
cycloreversion to re-establish a planar structure along with the extrusion of CO2
(Scheme 3.37).
3.2 1,3-Dipolar Cycloaddition Reactions of Arynes
+
Z
OTf
Fluoride
[3+2]
O
R1
TMS
R2 N
Scheme 3.37
Z
N O
R1
R2 N
R2
N R1
R1
Retro-[4+2]
O
–CO2
N O
N R2
Z
N
O
N O
[3+2] Dipolar cycloaddition of arynes with Sydnones.
This reaction has been expanded in two interesting directions. In one direction,
the scope of Sydnone was extended to a thiazolidine derivative [51]. The product
obtained, after oxidation, could extrude SO2 and form another dipole 17, which
can be exploited in quite a handful of subsequent transformations (Scheme 3.38).
The substrate here functions a dual role: the Sydnone functions as a dipole, and the
thiazolidine functions as a masked secondary dipole precursor.
R
N
N
R2 R
S
1
R2
O
N N
R3
R1
S
O
R3
N
N
2
mCPBA
R R1
O2S
R3
N
N
Heat
or MW
R1
R2
R3
R
N
N
N
N
R
17
R2
R1
R3
N
N
O
N
R4
Scheme 3.38
O
[3+2] Dipolar cycloaddition of arynes with thiazolidine-derived Sydnones.
The other direction was aimed to helicene synthesis by employing 1,2-naphthalyne
and 3,4-phenanthryne as arynes, and densely fused Sydnones derived from at least
an isoquinoline system [52]. An interesting regioselectivity was observed in
favor of the formation of heterohelicenes (as opposed to the zig-zag orientation)
when 3,4-phenanthryne reacted with Sydnones bearing fused aromatic system
positioned in a suitable region (Scheme 3.39). A comprehensive computational
study revealed that a C–H…π interaction (an aromatic C—H bond of the aryne
to the π system of the Sydnone shown in red in Scheme 3.39) during the early
transition state contributed to this observed regioselectivity. It is interesting to
note that the product could also be obtained theoretically from isoquinolinium
imides (cf. Scheme 3.31) and benzo[h]isoquinolinium imides, but no study has
been performed to confirm so.
91
92
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
R
R
R
Fluoride
TMS +
N
N
O
N
N O
OTf
Aromatic region in red
essential for regioselectivity
Scheme 3.39
N
N
+
> 6 : 1 Selectivity for phenanthryne
not much selective for naphthalyne
[3+2] Dipolar cycloaddition of fused arynes with Sydnones.
3.2.2.2 Reactions of Arynes with Münchnones
As another representative cyclic 1,3-dipole, Münchnone is isoelectronic to Sydnone,
and can be viewed either as oxazolium inner salt or as an azomethine ylide with
an internal lactone unit. Münchnones are much less stable than Sydnones, and
only those with an EWG at the 4-position can be stable enough to be isolated. The
cycloaddition of arynes with Münchnones follows that of Sydnones in a [3+2]
cycloaddition/[4+2] cycloreversion pathway (Scheme 3.40). That being said, the
afforded 2H-indole product from Münchnones is much more reactive and will
readily react with another molecule of aryne in a Diels–Alder manner to furnish a
bicyclic [2.2.1] product. Different conditions have been developed and with different
combinations of fluoride sources, solvents, and stoichiometry, one can often obtain
either the 2H-indole or the bicyclic product as the major product [53]. Münchnones
can be prepared from cyclodehydration of amino acid derivatives, and the less stable
ones without EWGs at 4-position can be used in a one-pot fashion without isolation.
R1
TMS
+ R2 N
Z
–
O
+
OTf
O
R3
R1
O
–CO2
Z
R2
1
N R
Z
N R2
R3
Controllable under CsF, MeCN
Z
R3
Z
Preferred under TBAF, THF
O
+
–
R1
Retro-[4+2]
O
Z
R3
R2 N
R2
1
N R
Fluoride
[3+2]
O
R3
Scheme 3.40
[3+2] Dipolar cycloaddition of arynes with Münchnones.
3.3 Other [n+2] Dipolar Cycloaddition Reactions
of Arynes
3.3.1
Cycloaddition with Other Dipoles
Apart from 1,3-dipoles, other dipoles such as 1,5-dipoles and 1,7-dipoles have also
been known to react with arynes to yield corresponding heterocyclic products.
3.3 Other [n+2] Dipolar Cycloaddition Reactions of Arynes
A [4+2] cycloaddition of Au-bearing pyrylium cation with aryne has been reported
[54]. The aurated pyrylium species was generated in situ from Au-catalyzed cyclization of 2-alkynylphenyl ketones. The [4+2] cycloaddition was followed by an
elimination to afford formal O-transpositioned ketones. Whether this [4+2]
cycloaddition should be called a hetero-Diels–Alder reaction or a dipolar variant,
considering the formal charges, is probably in a vague area, yet it remains necessary
to be mentioned (Scheme 3.41).
R1
R1
+
N2
O
+
–
CO2
R2
O
R2
Au cat.
R1
+
+
[4+2]
O
+
R2
R2
R1
[Au]
[Au]
Scheme 3.41
O
[4+2] Cycloaddition of arynes with aurated pyrylium species.
Vinylogous pyridinium N-imide, a pyridinium N-imide bearing an olefin unit
inserted into the N—N bond, has recently been developed as an air-stable 1,5-dipole.
This dipole has been successfully utilized in the [5+2] cycloaddition with arynes to
construct a 1,4-benzodiazepine scaffold [55]. Despite the broken aromaticity, the
primary cycloadduct 18 here cannot undergo any of the processes known for that of
pyridinium oxides/imides (cf. Sections 3.2.1.7 and 3.2.1.8). Instead, it was observed
that the C3 =C4 double bond of the original pyridine moiety quickly reacted with
another equivalent of aryne in a [2+2] cycloaddition fashion (Scheme 3.42). Studies
demonstrated that the subsequent [2+2] cycloaddition was faster than the initial
[5+2] and 18 could be hardly isolated. Vinylogous quinolinium imides followed
the same mechanism. It is worth mentioning that the [2+2] cycloaddition was not
observed in the cycloadducts of N-benzoylquinolinium imides despite a similar
aromaticity-broken structure (cf. Scheme 3.32).
Z
TMS
Z
R1
+
OTf
Fluoride
[5+2]
+
N
R2
N
–
SO2R3
R1
Z Faster [2+2]
N
R2
H
R1
N
N
3
SO2R
18, not isolated
Scheme 3.42
H
R2
N
Z
SO2R3
[5+2]/[2+2] Cycloaddition of arynes with vinylogous pyridinium imides.
93
94
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
3-Oxidopyridinium species is another latent dipole buried in a pyridine scaffold
[56]. This kind of dipole is stable and isolable and has been applied to a variety
of dipolar cycloaddition reactions exhibiting various periselectivity. A systematic
study of its cycloaddition with arynes has been performed and confirmed a [3+2]
cycloaddition mode, where the reaction took place at the C2 ,C6 -positions of the
pyridine [57]. This [3+2] periselectivity (although sometimes called [5+2] in early
literature) can be viewed as involving C2 –N–C6 moiety as a cyclic azomethine ylide,
and afforded a bicyclic [3.2.1] scaffold in moderate-to-good yield (Scheme 3.43).
O
TMS
2
+ R
Z
N
R1
OTf
R2
O
R1
N
Z
R2
O
N
R1
Scheme 3.43
Fluoride
[3+2]
Azomethine ylide
[3+2] Dipolar cycloaddition of arynes with 3-oxidopyridinium species.
The isoelectronic analogue of 3-imidopyridinium species, however, underwent a
totally different pathway. For this substrate, reaction took place at C2 ,N(exocyclic)positions. This can be viewed either as a formal [3+2] cycloaddition (if one counts
only C2 –C3 –N(exocyclic) atoms) or a [7+2] cycloaddition, where the “7” counts the
N(exocyclic)-C3 –C4 –C5 –C6 –N(endocyclic)-C2 atoms in a full conjugation system
carrying 8 electrons in total (cf. Figure 3.3). This [7+2] cycloaddition features an
aromaticity-broken intermediate and, interestingly, this intermediate underwent a
retro-6π electrocyclization to afford a two-substituted indole structure eventually in
low yields (Scheme 3.44).
3
TMS
4
+
OTf
5
Scheme 3.44
1
EWG
7
N6
R
3
N
2
4
2
5
N6 7
R
EWG
N
Fluoride
[7+2]
Retro-6π
N
R
N
H
R
N
1
EWG
EWG
N
OHC
EWG
N
[7+2] Dipolar cycloaddition of arynes with 3-imidopyridinium species.
3-Oxidopyridinium species can also follow this pathway when benzynes bearing
3-methoxy groups were used (Scheme 3.45). For unknown reasons, such benzynes
3.3 Other [n+2] Dipolar Cycloaddition Reactions of Arynes
delivered both the two regioisomeric [3+2] cycloadducts and a benzofuran product that came out of the [7+2] cycloaddition. In contrast, 4-methoxybenzyne only
delivered [3+2] products. What role the 3-methoxy substitution plays in twisting
the periselectivity remains to be elucidated.
–
OMe
TMS
O
+
OTf
N
R
Fluoride
O
R
N
+
O
R
N
3.3.2
O
+
OMe
OMe
[3+2], both regioisomers
Scheme 3.45
OHC
OMe
[7+2]
Dipolar cycloaddition of 3-methoxybenzyne with 3-oxidopyridinium species.
Cycloaddition of Extended Scope of Arynes
As can be seen, most of the recent advances in aryne cycloaddition reactions have
relied on the utilization of the Kobayashi aryne precursor, which can be counted
as one of the most important stepstones in recent aryne chemistry. Despite the
wide application and successful commercialization, Kobayashi aryne precursors
used so far have limited functionality partly due to the necessity to use BuLi during
the preparation. Although a few individual functionalized precursors have been
used, limited availability of functionalized aryne precursors remains a key issue for
further expansion.
In this regard, a recent study has shed light on broadening the scope of functionalized aryne precursors by demonstrating that Ir-catalyzed C–H borylation [58] can
be applied to the assembled Kobayashi precursors [59]. Such last-stage functionalization affords a handful of borylated aryne precursors (Scheme 3.46a), which have
been successfully applied to several dipolar cycloaddition reactions (Scheme 3.46b).
The regioselectivity of the borylation generally installs the boryl group at a distal
position and the tolerance of the boryl group in cycloaddition reactions allows an
orthogonal functionality remaining at the aryne moiety. Needless to mention, the
boryl group can be oxidized by peroxide, aminated via Chan–Lam reaction, iodinated under Cu-mediated conditions, and can undergo Suzuki coupling to form
biaryl units, or Rh-catalyzed conjugate addition to Michael acceptors, thus providing
a versatile handle for manipulation.
Another interesting direction to expand the scope is benzdiynes. In general, the
concept of “benzdiyne” refers to generation of the two “yne” units sequentially, not
simultaneously. The general aspects of 1,2-benzdiyne will be discussed in Chapter
8, and two cases for 1,3- and 1,4-benzdiyne are shown here.
A Kobayashi-type benzdiyne precursor bearing two differentiated silyl groups was
prepared (Scheme 3.47). Activation of the more labile TMS group could trigger the
formation of the first “yne” under controlled reaction time. Subsequent activation
of the less labile t-butyldimethylsilyl (TBS) group over elongated period triggered
the second “yne” formation [60]. Thus, as a proof of concept, two sequential dipolar
95
96
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
Z
TMS
Z
[Ir] cat., B2pin2
Bpin
OTf
Bpin
TMS
Bpin
OTf
Bpin
TMS
OTf
OTf
Bpin
TMS
OTf
TMS
Br
Bpin
Br
Bpin
N
N
OH
N
N
With pyridinium N-oxide
O
Bpin
Me
(b)
TMS
F
Br
Br
N
Bpin
OTf
Me
(a)
F
TMS
OTf
Bpin
OTf
OMe
TMS
N
TMS
With azide
With nitrone
Scheme 3.46 Borylation of aryne precursors: more arynes and more dipolar cycloadducts.
(a) Scope of more aryne precursors and (b) scope of dipolar cycloaddition products.
cycloadditions, or one dipolar cycloaddition with one reaction of another type, have
been successfully applied to the two differentiated “yne” units. The challenges for
the synthetic applications are the moderate overall yield and the moderate regioselectivity (see Scheme 3.10 for that of 3-sillyarynes).
TMS
TfO
Reaction 1
CsF, MeCN, rt 30 min
Reaction 2
CsF, MeCN, rt 18–24 h
TfO
OTf
TBS
1
via
1
2
TBS
1
via
TfO
TBS
86 : 14 regio
N
Bn N
N N
Scheme 3.47
O
N
>98 : 2 regio
O
Bn N
N N
Ph
78 : 22 regio
89 : 11 regio
Sequential cycloaddition of 1,3-benzdiyne from disilylaryl ditriflate.
Another benzdiyne precursor was the benzobis(oxadisilole) precursor (see
Figure 3.4). By controlling the reaction conditions and stoichiometry, activation of
3.4 Formal Cycloaddition Reactions of Arynes
only one oxadisilole could be achieved. Formation of the first “yne” and subsequent
trapping readily took place and the sequence could be repeated to activate and trap
the second “yne” unit (Scheme 3.48) [61]. This precursor is quite versatile and can
offer more diversity of the polyynes. However, preparation and activation of this
precursor is a little step intensive.
O
Si
Si
O
O
Si
1. PhI(OAc)2, TfOH
2. TBAF, Reaction 1
Si
Si
Via
Si
O
1
1. PhI(OAc)2, TfOH
2. TBAF, Reaction 2
2
N
1
Si
Via
O
O
1
Si
Cl
Scheme 3.48 Sequential cycloaddition of 1,4-benzdiyne from benzobis(oxadisilole).
Source: Based on Ma et al. [61].
3.4 Formal Cycloaddition Reactions of Arynes
Formal cycloaddition could refer to as widely as reactions of arynes with amphiphilic
reagents that could result in a ring formation. There are indeed many smartly
designed amphiphilic substrates with tethered nucleophiles and electrophiles,
leading to interesting and useful benzannulated heterocycles [62]. For the scope
of the discussion, we wish to narrow it down to substrates that at least involve π
systems or resemble dipole-like structures. Herein, three cherry-picked systems are
summarized and discussed.
3.4.1 Formal Cycloaddition with N–C–C Systems Forming
Indole/Indoline/Oxyindole Scaffolds
Enamines are nucleophiles, and those with strategically positioned EWGs can act as
amphiphilic reagents.
N-Boc-2-methyleneglycine derivatives stand as an interesting substrate of this
class [63a]. The enamine nitrogen could serve as the nucleophile, and the Michael
acceptor functioned as the electrophile for the aryl anion to back attack
(Scheme 3.49). The reaction afforded indoline products and the enamine substrate exhibited overall reactivity equivalent to an N(δ−)–C=C(δ+) system in a
formal [3+2] cycloaddition reaction.
Somewhat counterintuitively, it was demonstrated that replacing the Boc group
on the enamine nitrogen to an acyl group could shift the polarity of the enamine
system. The nucleophilic site changed from the nitrogen to the enamine carbon
(which functioned as the electrophilic site in the former case). Thus, the formal
[3+2] cycloaddition was changed to a polarity-reversed formal [4+2] cycloaddition
that final afforded isoquinolines after a dehydration (Scheme 3.50) [63].
A more ambiguous example was the reaction of aryne with iminophosphorane 19
(Scheme 3.51), generated in situ from a reaction of 2-azidoacrylates with stoichiometric phosphine [64]. Intermediate 19 could undergo formal [3+2] cycloaddition
97
98
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
Z
R
R
TMS
Fluoride
+
BocHN
OTf
Z
N
Boc
cis
CO2Me
R
Z
Via
Scheme 3.49
derivatives.
N
CO2Me
Boc
Formal [3+2] cycloaddition of arynes with N-Boc-2-methyleneglycine
TMS
R3
OTf
R2
R2
O
+
Z
CO2Me
R1
Fluoride
Z
R1
N
H
N
R3
– H2O
R2
O
R3
R1
Z
N
R2
Z
R2
N
R1
R1
Z
O
N
R3
R3
OH
Scheme 3.50 Formal [4+2] cycloaddition of arynes with N-acylenamines. Source: Gilmore
et al. [63a]; Zhao et al. [63b].
TMS
Z
R
R
Fluoride, PPh3, air
+
OTf
CO2Et
Z
N3
N
H
CO2Et
PPh3, –N2
[O], –POPh3
R
R
Z
OEt
Z
N
CO2Et
PPh3
N
19
R
R
Z
A
Scheme 3.51
N
Ph3P
P O
Ph3
OEt
O
Z
B
N
Ph3P
OEt
O
Formal [3+2] cycloaddition of arynes with 2-azidoacrylates.
3.4 Formal Cycloaddition Reactions of Arynes
with arynes, and subsequent extrusion of phosphine oxide through hydrolysis and
air oxidation/dehydrogenation could afford an indole product. Despite the success
of the reaction, the electronics of 19 remain in the vague area. The arrow-pushing
mechanism A, proposed by the authors, mimics the electron flow of that in
Scheme 3.49 and a similar N(δ−)–C=C(δ+) system as well. However, reaction with
3-methoxybenzyne afforded a regioselectivity opposite to this electron flow. This
regioselectivity could, however, be accounted for by an alternative arrow-push
mechanism B, exhibiting a polarity reversed N(δ+)=C–C(δ−) system. The real
scenario is elusive and a computational study could potentially help to answer the
question.
Apart from the N(δ−)–C=C(δ+) and the N(δ+)=C–C(δ−) systems described
above, a third class, namely α-halo-N-alkoxycarboxyamides, was reported to
undergo formal [3+2] cycloaddition with arynes to afford N-alkoxy oxyindoles in
good yields (Scheme 3.52) [65]. Here, the reactive partner exhibited a conceptually
different N(δ−)–C–C(δ+) system. Unlike the two aforementioned systems that
involve π bonds and are equivalent to four-electron units, this new system does
not have a π bond and is perhaps more suitably considered as a two-electron
unit. Although multiple mechanistic pathways could explain the formation of
the described product, experiment using a chiral α-bromoamide led to complete
erosion of stereochemistry (Scheme 3.53). This evidence is contradictory to the
stepwise mechanism where at least some chiral memory should retain, and
points to an in situ elimination of HBr first to afford a system that looks like a
hetero-trimethylenemethane (hetero-TMM) unit bearing an N(δ−)–C–C(δ+) typed
electron distribution, followed by its reaction with arynes.
+ Br
Z
OTf
R1
O
TMS
R1
N
H
OR2
Fluoride
Z
O
N
OR2
Scheme 3.52 Formal [3+2] cycloaddition of arynes with α-halo-N-alkoxyamides. Source:
Singh et al. [65].
3.4.2
Formal Cycloaddition with Hydrazone-Derived N–N–C Systems
Formal [3+2] cycloaddition of arynes with different hydrazones has been extensively
studied. The mechanism and outcomes are heavily influenced by the hydrazone
substitution and the reaction conditions.
As mentioned before in Section 3.2.1.4, N-monosubstituted hydrazonyl chlorides
can generate nitrile imines by in situ elimination of HCl under basic conditions
(cf. Scheme 3.15). It was later found that N,N-disubstituted hydrazonyl chlorides
could react with arynes to afford very similar products as monosubstituted hydrazonyl chlorides do. Clearly, the disubstituted ones cannot generate nitrile imines and
the reaction has to proceed through a presumable stepwise manner to afford a formal [3+2] cycloadduct 20 (Scheme 3.54) [66a]. This intermediate could subsequently
99
100
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
Me
O
TMS
+ Br
OTf
Me
N
H
Fluoride
OBn
O
N
OBn
Racemic
77 %ee
Stepwise pathway
O
Br
N
OBn
Me
Hetero-TMM pathway
O
Br
Me
N
H
–HBr
OBn
Scheme 3.53
O
O
Me
N
OBn
N
Me
O
Me
OBn
N
OBn
Evidence supporting involvement of a 2-electron hetero-TMM.
eliminate the chloride, and one of the methyl groups was then scavenged by an external nucleophile to afford indazoles.
Me
N
N
Me
TMS
+
Z
OTf
R
Cl
Via
Z
R Cl
Fluoride
Cl
Me
N
N
Me Me
20
Z
R
–Cl
–
Z
R
Nu
N
Z
–NuMe
N
Me
Me
N
N
Me
R
N
N
Me
Scheme 3.54 Formal [3+2] cycloaddition of arynes with N,N-dimethylhydrazonyl
chlorides. Source: Based on Markina et al. [66a].
Without the chloride at the imidoyl position, aldehyde-derived N,N-dialkyl
hydrazones could still react with arynes to afford a similar formal [3+2] adduct 20A
(Scheme 3.55). As there is no chloride to eliminate, a proton shift took place to form a
carbanion, which triggered N–N cleavage to open the newly formed five-membered
ring to afford an imine derivative [66b]. This imine can be manipulated in different
workup procedures to afford different products [66c].
In addition to this pathway, cycloadduct 20A can be trapped by electrophiles such
as Ac2 O. Treatment of the trapped adduct 21, without isolation, with hydrazine
under high temperature could afford indazoles (Scheme 3.56). This reaction is quite
similar to the overall transformation shown in Scheme 3.54 without being necessary
to form the chloride. Although the authors did not mention, the hydrazine workup
theoretically requires an oxidant to give rise to the aromatized structure.
3.4 Formal Cycloaddition Reactions of Arynes
R1
Z
N
R2
[H]
TMS
N
+
Z
OTf
R
1
R2
N
R2
Fluoride
H
Scheme 3.55
R2
Z
Z
N
R2
NH H2O
R2
N
N
R2
R1
1. NCS
2. Heat
NR 2 Being NMe2 or cyclic amines
NBn2 Undergoes debenzylation
O
R2
N
N
R2
Z
2
N
R2
Z
Formal [3+2] cycloaddition of arynes with N,N-dialkylhydrazones.
Z
+
OTf
R
Ac2O
N
N
Me Me
20A
H
R
R
Nu
N Ac
– NuMe
N
Me Me
Scheme 3.56
R H
Me
Fluoride
N
N
Me
Z
TMS
Z
NH
N
2
R2 R
R1
H
via
Z
N
N
2
R2 R
20A
Z
R1
R1
R1
R1 H
NH2
R2
Z
21
R
N Ac
N
Me
N2H4
Heat
[O]
N
N
Me
Z
Formal [3+2] cycloaddition of arynes with N,N-dimethylhydrazones.
Parallel to this work, another report disclosed a similar oxidative strategy to form
indazoles from aryne formal [3+2] cycloaddition. In this case, aldehyde-derived
N-monosubstituted hydrazones were used as the substrate and the reaction was
carried out under aerobatic oxidation conditions with a desired volume of air
serving as the oxidant (Scheme 3.57) [67]. This reaction can be additionally viewed
in comparison with the aforementioned examples, as well as the reaction involving N-tosylhydrazones shown in Scheme 3.7. The oxidation could occur on the
TMS
N
+
Z
OTf
R1
H
N
R1 H
R2
Fluoride
N
Z
N
R2
H
R1
[O]
Z
N
N
R2
Also possible [O]
N
N
Z
R2
R1
Scheme 3.57 Formal [3+2] cycloaddition of arynes with N-monosubstituted hydrazones
under oxidative conditions. Source: Based on Li et al. [67].
101
102
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
cycloadduct to convert it to the final indazole. However, attempts in trapping this
cycloadduct by Ac2 O were unsuccessful, which brings the additional likelihood
that the role of air was perhaps to convert the hydrazones to nitrile imines, followed
by a real [3+2] cycloaddition.
Shown above are several examples, where different substitution patterns could
be exploited in manipulation of the primary cycloadduct in different subsequent
reactions to give rise to different products. The overall events could be complicated
and multiple mechanistic pathways are available for the primary cycloadducts, and
subtle changes in substrate structure and reaction conditions may alter the mechanism and consequently the final outcome. It is worth mentioning that despite the
already-existing complexity, to date, studies still have not covered all substitution
patterns in this series.
3.4.3
Formal Cycloaddition and with Sulfur-Containing Substrates
Sulfur is a soft nucleophile and can extend its valence. Thus, even sulfur atoms in
thioethers and thiocarbonyls remain nucleophilic. Several sulfur-containing substrates have been known to react with arynes in formal [3+2] cycloaddition manner.
Interestingly, despite their reactivity, many substrates of this type may not appear
amphiphilic.
Aryl vinyl sulfides bearing EWGs at the distal vinylic position (i.e. β-(arylthio)
acrylates or analogues) have been found to react with arynes in a [3+2] dipolar cycloaddition manner [68]. The sulfur atom serves as the nucleophile to
generate a primary cycloadduct 22 (Scheme 3.58), which is essentially a sulfur
ylide. Computational studies showed that formation of 22 is actually a concerted
cycloaddition process despite the lack of dipole-like structural feature of the substrate. Subsequent proton shift at the stage of 22 took place via a water-facilitated
protonation–deprotonation process [69]. A final elimination afforded a diaryl sulfide. It is noteworthy that the overall reaction looks identical to an aryne insertion
into the S—C bond of the substrate, and Chapter 4 will focus on aryne insertion
chemistry of this type. However, mechanistically, this reaction does not follow the
typical aryne insertion and has more cycloaddition feature.
TMS
Z
ArS
R
+
OTf
EWG
Fluoride
[3+2]
Ar
S
Z
R
22
Scheme 3.58
EWG
H2O, –OH–
then OH–, –H2O
Ar
S
Z
S
R
EWG
Z
Ar
R
EWG
[3+2] Cycloaddition of arynes with vinyl sulfides.
When a second EWG was present and in the absence of water, 22A underwent
a further arylation with aryne (Scheme 3.59). Subsequent deprotonation triggered a
similar elimination to afford a stilbene product.
Similar to vinyl sulfides, ketene dithioacetals have been known to act as a formal
1,3-dipole, and have been used to construct five-membered carbocycles through
formal [3+2] cycloaddition with electrophiles [70]. A special ketene dithioacetal
3.4 Formal Cycloaddition Reactions of Arynes
TMS
Z
EWG2
ArS
+
EWG1
OTf
Ar
S
Fluoride
22A
Scheme 3.59
EWG2
Z
[3+2]
Ar
S EWG2
Z
Z
S Ar
Z
EWG1
Z
EWG1 H
EWG1
EWG2
Z
H
[3+2] Cycloaddition of arynes with vinyl sulfides: further arylation variant.
substrate derived from ethanedithiol has been studied in aryne cycloaddition. The
reaction presumably took place via the zwitterionic resonance structure of the
ketene dithioacetal, and the ethanedithiol unit allowed for an either subsequent
or simultaneous extrusion of ethylene to afford 2-mercaptobenzothiophenes [71],
which reacted further with aryne in an S-arylation event (Scheme 3.60).
O
TMS
Z
+
Fluoride
R
OTf
R
S
S
[3+2]
S
O
Retro [3+2]
– C2H4
Z
S
R
O
R
O
Z
Z
S
Z
S
S
S
Z
One-step also possible
O
O
R
R
Z
HS
S
Scheme 3.60
S
S
Formal [3+2] cycloaddition of arynes with ketene dithioacetals.
Apart from the thiol ether category, 1,2,5-thiadiazoles represent another class of
formal dipole that could react with arynes. Symmetrical 1,2,5-thiadiazoles were
known long time ago to undergo aryne [3+2] cycloaddition, followed by a subsequent [3+2] cycloreversion to afford benzoisothiazoles with extrusion of a cyanide
[72a]. This chemistry has been recently revisited to incorporate both symmetrical
and unsymmetrical 1,2,5-thiadiazoles [72b]. For the unsymmetrical substrates, it
was found that when R1 and R2 are hydroxyl and amino groups, respectively, the
highest level of discrimination was achieved, and extrusion of cyanic acid occurred
selectively (Scheme 3.61).
R1
R1
R2
N
Z
+
Z
R2
R1
TMS
OTf
N
S
N
S
– R2CN
retro-[3+2]
N
Z
> 20 : 1 selectivity
When R1 = amino, R2 = OH
Fluoride
[3+2]
R2
R2
R1
N
Scheme 3.61
N
S
N
S
Z
– R1CN
retro-[3+2]
Z
N
S
Formal [3+2] cycloaddition of arynes with 1,2,5-thiadiazoles.
Last but not least, electron-deficient thioamides have also been known to react
with a special class of benzyne [73]. This will be mentioned in Chapter 10.
103
104
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
3.5 Summary
Aryne dipolar cycloaddition reactions have received considerable attention. Major
efforts have been devoted to the synthetic applications and reactivity exploration.
Mechanistic studies have also been widely conducted to answer questions or
provide rationale to scientific curiosity. In the past decade, a handful of heterocyclic
scaffolds have been made attainable through aryne dipolar cycloadditions, and
many more will surely come in the future. Yet more importantly, these studies have
brought us not only more methods in the synthetic toolbox, but also more and
deeper understanding of the reactivity of arynes, which, in turn, would promote
the next round of reaction design and mechanistic study. Computational studies,
more (hetero)arynes scaffolds, more dipoles, and perhaps more kinetic studies will
advance the frontline of our understanding in aryne dipolar cycloadditions and
enrich the aryne chemistry in a broader scope of view.
List of Abbreviations
18-C-6
Ac
Ar
Bn
Boc
Bpin
Bz
DCM
EWG
mCPBA
MW
NBO
NCS
Nu
PTC
TBAF
TBS
Tf
THF
TMM
TMS
Ts
18-crown-6
acetyl
aryl
benzyl
t-butoxycarbonyl
pinacolboryl
benzoyl
dichloromethane
electron-withdrawing group
meta-chloroperbenzoic acid
microwave irradiation
natural bond orbital
N-chlorosuccinimide
nucleophile
phase transfer catalyst
tetrabutylammonium fluoride
t-butyldimethylsilyl
trifluoromethanesulfonyl
tetrahydrofuran
trimethylenemethane
trimethylsilyl
p-toluenesulfonyl
References
1 (a) De, N. and Yoo, E.J. (2018). ACS Catal. 8: 48–58. (b) Hashimoto, T. and
Maruoka, K. (2015). Chem. Rev. 115: 5366–5412.
References
2 (a) Dubrovskiy, A.V., Markina, N.A., and Larock, R.C. (2013). Org. Biomol. Chem.
11: 191–218. (b) Wu, C. and Shi, F. (2013). Asian J. Org. Chem. 2: 116–125.
(c) Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112: 3550–3577. (d) Roy,
T. and Biju, A.T. (2018). Chem. Commun. 54: 2580–2594. (e) Bhojgude, S.S.,
Bhunia, A., and Biju, A.T. (2016). Acc. Chem. Res. 49: 1658–1670. (f) Kaicharla,
T. and Biju, A.T. (2014). Transition-metal-free synthesis of benzo-fused five- and
six-membered heterocycles employing arynes. In: Green Synthetic Approaches
for Biologically Relevant Heterocycles (ed. G. Brahmachari), 45–76. Elsevier
Science. (g) Pérez, D., Peña, D., and Guitián, E. (2013). Eur. J. Org. Chem.:
5981–6013. (h) Gampe, C.M. and Carreira, E.M. (2012). Angew. Chem. Int. Ed.
51: 3766–3778. (i) Bhunia, A., Yetra, S.R., and Biju, A.T. (2012). Chem. Soc. Rev.
41: 3140–3152. (j) Okuma, K. (2012). Heterocycles 85: 515–544. (k) Chen, Y. and
Larock, R.C. (2009). Arylation reactions involving the formation of arynes. In:
Modern Arylation Methods (ed. L. Ackermann), 401–473. Weinheim (Germany):
Wiley-VCH. (l) Sanz, R. (2008). Org. Prep. Proced. Int. 40: 215–291. (m) Wenk,
H.H., Winkler, M., and Sander, W. (2003). Angew. Chem. Int. Ed. 42: 502–528.
(n) Pellissier, H. and Santelli, M. (2003). Tetrahedron 9: 701–730.
3 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett. 12: 1211–1214.
4 (a) Huisgen, R. (1984). 1,3-Dipolar cycloadditions – introduction, survey, mechanism. In: 1,3-Dipolar Cycloaddition Chemistry, vol. 1 (ed. A. Padwa), 3–6.
New York: Wiley. (b) Gothelf, K.V. and Jørgensen, K.A. (1998). Chem. Rev. 98:
863–909.
5 (a) Decuypère, E., Plougastel, L., Audisio, D., and Taran, F. (2017). Chem. Commun. 53: 11515–11527. (b) Stewart, F.H.C. (1964). Chem. Rev. 64: 129–147.
(c) Lopchuk, J.L. (2012). Top. Heterocycl. Chem. 29: 381–413. (d) Kawase, M.,
Sakagami, H., and Motohashi, N. (2009). Top. Heterocycl. Chem. 16: 135–152.
(e) Ollis, W.D. and Ramsden, C.A. (1976). Adv. Heterocycl. Chem. 19: 1–122.
(f) Gribble, G. (2002). Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, vol. 59 (eds. A. Padwa and
W.H. Pearson), 681–753. Wiley.
6 Ford, A., Miel, H., Ring, A. et al. (2015). Chem. Rev. 115: 9981–10080.
7 (a) Jin, T. and Yamamoto, Y. (2007). Angew. Chem. Int. Ed. 46: 3323–3325.
(b) Jin, T., Yang, F., and Yamamoto, Y. (2009). Collect. Czech. Chem. Commun.
74: 957–972. (c) Liu, Z., Shi, F., Martinez, P.D.G. et al. (2008). J. Org. Chem. 73:
219–226.
8 (a) Reddy, B.V.S., Reddy, R.R.G., Thummaluru, V.R., and Sridhar, B. (2017).
ChemistrySelect 2: 4290–4293. (b) Cheng, B., Zu, B., Bao, B. et al. (2017). J. Org.
Chem. 82: 8228–8233. (c) Cheng, B., Bao, B., Zu, B. et al. (2017). RSC Adv. 7:
54087–54090. (d) Hari, Y., Sone, R., and Aoyama, T. (2009). Org. Biomol. Chem.
7: 2804–2808.
9 (a) Chen, G., Hu, M., and Peng, Y. (2018). J. Org. Chem. 83: 1591–1597.
(b) Phatake, R.S., Mullapudi, V., Wakchaure, V.C., and Ramana, C.V. (2017).
Org. Lett. 19: 372–375.
10 Wang, C.-D. and Liu, R.-S. (2012). Org. Biomol. Chem. 10: 8948–8952.
105
106
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
11 (a) Li, P., Zhao, J., Wu, C. et al. (2011). Org. Lett. 13: 3340–3343. (b) This reaction
is only applicable to hydrazones derived from aldehydes or non-enolizable
ketones. For those derived from enolizable ketones, a Fischer indole type reaction sequence can take place, see, McAusland, D., Seo, S. et al. (2011). Org. Lett.
13: 3667–−3669.
12 (a) Moses, J.E. and Moorhouse, A.D. (2007). Chem. Soc. Rev. 36: 1249–1262.
(b) Gil, M.V., Arevalo, M.J., and Lopez, O. (2007). Synthesis: 1589–1620.
13 (a) Agard, N.J., Prescher, J.A., and Bertozzi, C.R. (2004). J. Am. Chem. Soc. 126:
15046–15047. (b) Jewett, J.C. and Bertozzi, C.R. (2010). Chem. Soc. Rev. 39:
1272–1279. (c) Müller, M., Maichle-Mossmer, C., and Bettinger, H.F. (2014).
J. Org. Chem. 79: 5478–5483. (d) Gold, B., Batsomboon, P., Dudley, G.B., and
Alabugin, I.V. (2014). J. Org. Chem. 79: 6221–6232.
14 (a) Shi, F., Waldo, J.P., Chen, Y., and Larock, R.C. (2008). Org. Lett. 10:
2409–2412. (b) Campbell-Verduyn, L., Elsinga, P.H., Mirfeizi, L. et al. (2008).
Org. Biomol. Chem. 6: 3461–3463. (c) Chandrasekhar, S., Seenaiah, M., Rao, L.,
and Reddy, C.R. (2008). Tetrahedron 64: 11325–11327.
15 Ankati, H. and Biehl, E. (2009). Tetrahedron Lett. 50: 4677–4682.
16 (a) Lin, Y., Chen, Y., Ma, X. et al. (2011). Tetrahedron 67: 856–859. (b) Chen, X.,
Yu, H., Xu, Z. et al. (2015). J. Org. Chem. 80: 6890–6896. (c) Kovács, S., Csincsi,
Á.I., Nagy, T.Z. et al. (2012). Org. Lett. 14: 2022–2025. (d) Sumida, Y., Kato,
T., and Hosoya, T. (2013). Org. Lett. 15: 2806–2809. (e) Gann, A.W., Amoroso,
J.W., Einck, V.J. et al. (2014). Org. Lett. 16: 2003–2005. (f) Chang, D., Zhu, D.,
and Shi, L. (2015). J. Org. Chem. 80: 5928–5933. (g) Yoshida, S., Morita, T., and
Hosoya, T. (2016). Chem. Lett. 45: 726–728.
17 (a) Subba, R., Basi, V., Praneeth, K., and Yadav, J.S. (2011). Carbohydr. Res. 346:
995–998. (b) Singh, G., Kumar, R., Swett, J., and Zajc, B. (2013). Org. Lett. 15:
4086–4089. (c) Zhang, F. and Moses, J.E. (2009). Org. Lett. 11: 1587–1590.
18 (a) Ikawa, T., Takagi, A., Goto, M. et al. (2013). J. Org. Chem. 78: 2965–2983.
(b) Ikawa, T., Kaneko, H., Masuda, S. et al. (2015). Org. Biomol. Chem. 13:
520–526.
19 (a) Goetz, A.E. and Garg, N.K. (2013). Nat. Chem. 5: 54–60. (b) Goetz, A.E. and
Garg, N.K. (2014). J. Org. Chem. 79: 846–851.
20 (a) Saito, N., Nakamura, K., and Sato, Y. (2014). Heterocycles 88: 929–937.
(b) Medina, J.M., Jackl, M.K., Susick, R.B., and Garg, N.K. (2016). Tetrahedron
72: 3629–3634.
21 Fang, Y. and Larock, R.C. (2012). Tetrahedron 68: 2819–2826.
22 (a) Im, G.-Y.J., Bronner, S.M., Goetz, A.E. et al. (2010). J. Am. Chem. Soc. 132:
17933–17944. (b) Shah, T.K., Medina, J.M., and Garg, N.K. (2016). J. Am. Chem.
Soc. 138: 4948–4954.
23 (a) Dubrovskiy, A.V. and Larock, R.C. (2010). Org. Lett. 12: 1180–1183.
(b) Dubrovskiy, A.V., Jain, P., Shi, F. et al. (2013). ACS Comb. Sci. 15: 193–201.
24 (a) Spiteri, C., Sharma, P., Zhang, F. et al. (2010). Chem. Commun. 46:
1272–1274. (b) Crossley, J.A. and Browne, D.L. (2010). Tetrahedron Lett. 51:
2271–2273.
25 Spiteri, C., Mason, C., Zhang, F. et al. (2010). Org. Biomol. Chem. 8: 2537–2542.
References
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
Spiteri, C., Keeling, S., and Moses, J.E. (2010). Org. Lett. 12: 3368–3371.
Murahashi, S.-I. and Imada, Y. (2019). Chem. Rev. 119: 4684–4716.
Dai, M., Wang, Z., and Danishefsky, S.J. (2008). Tetrahedron Lett. 49: 6613–6616.
(a) Wu, K., Chen, Y., Lin, Y. et al. (2010). Tetrahedron 66: 578–582. (b) Wu,
Q.-C., Li, B.-S., Lin, W.-Q. et al. (2007). Chin. J. Synth. Chem. 15: 292–295.
(c) Lu, C., Dubrovskiy, A.V., and Larock, R.C. (2012). J. Org. Chem. 77:
2279–2284.
Khangarot, R.K. and Kaliapan, K.P. (2012). Eur. J. Org. Chem.: 5844–5854.
Ma, X.-P., Li, L.-G., Zhao, H.-P. et al. (2018). Org. Lett. 20: 4571–4574.
Kivrak, A. and Larock, R.C. (2010). J. Org. Chem. 75: 7381–7387.
Li, P., Wu, C., Zhao, J. et al. (2013). Can. J. Chem. 91: 43–50.
Yao, T., Ren, B., Wang, B., and Zhao, Y. (2017). Org. Lett. 19: 3135–3138.
(a) Nájera, C., Sansano, J.M., and Yus, M. (2015). Org. Biomol. Chem. 13:
8596–8636. (b) Coldham, I. and Hufton, R. (2005). Chem. Rev. 105: 2765–2809.
Shi, F., Mancuso, R., and Larock, R.C. (2009). Tetrahedron Lett. 50: 4067–4070.
(a) Swain, S.P., Shi, Y.-C., Tsay, S.-C. et al. (2015). Angew. Chem. Int. Ed. 54:
9926–9930. (b) Jia, H., Guo, Z., Liu, H. et al. (2018). Chem. Commun. 54:
7050–7053.
Ryu, H., Seo, J., and Ko, H.M. (2018). J. Org. Chem. 83: 14102–14109.
(a) Raminelli, C., Liu, Z., and Larock, R.C. (2006). J. Org. Chem. 71: 4689–4691.
(b) Shaibu, B.S., Kawade, R.K., and Liu, R.-S. (2012). Org. Biomol. Chem. 10:
6834–6839.
Okuma, K., Hirano, K., Shioga, C. et al. (2013). Bull. Chem. Soc. Jpn. 86:
615–619.
Dhiman, A.K., Kumar, R., Kumar, R., and Sharma, U. (2017). J. Org. Chem. 82:
12307–12317.
Ren, H., Luo, Y., Ye, S., and Wu, J. (2011). Org. Lett. 13: 2552–2555.
Yamashita, Y., Hayashi, T., and Masumura, M. (1980). Chem. Lett. 9: 1133–1136.
(a) Zhao, J., Wu, C., Li, P. et al. (2011). J. Org. Chem. 76: 6837–6843. (b) Zhao, J.,
Li, P., Wu, C. et al. (2012). Org. Biomol. Chem. 10: 1922–1930.
Kumar, R., Chaudhary, S., Kumar, R. et al. (2018). J. Org. Chem. 83:
11552–11570.
Jiang, L., Yu, X., Fang, B., and Wu, J. (2012). Org. Biomol. Chem. 10: 8102–8107.
(a) Matsumoto, K., Katsura, H., Uchida, T. et al. (1996). J. Chem. Soc., Perkin
Trans. 1: 2599–2602. (b) Tominaga, Y., Shiroshita, Y., Matsuda, Y., and Hosomi,
A. (1987). Heterocycles 26: 2073–2075.
(a) Xie, C., Zhang, Y., and Xu, P. (2008). Synlett: 3115–3120. (b) Huang, X. and
Zhang, T. (2009). Tetrahedron Lett. 50: 208–211.
Shen, Y.-M., Grampp, G., Leesakul, N. et al. (2007). Eur. J. Org. Chem.:
3718–3726.
(a) Wu, C., Fang, Y., Larock, R.C., and Shi, F. (2010). Org. Lett. 12: 2234–2237.
(b) Fang, Y., Wu, C., Larock, R.C., and Shi, F. (2011). J. Org. Chem. 76:
8840–8851.
Soares, M.I.L., Nunes, C.M., Gomes, C.S.B., and Pinho e Melo, T.M.V.D. (2013).
J. Org. Chem. 78: 628–−637.
107
108
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry
52 Yen-Pon, E., Champagne, P.A., Plougastel, L. et al. (2019). J. Am. Chem. Soc. 141:
1435–1440.
53 (a) Fang, Y., Larock, R.C., and Shi, F. (2014). Asian J. Org. Chem. 3: 55–57.
(b) Lopchuk, J.M. and Gribble, G.W. (2014). Tetrahedron Lett. 55: 2809–2812.
54 Asao, N. and Sato, K. (2006). Org. Lett. 8: 5361–5363.
55 Shin, J., Lee, J., Ko, D. et al. (2017). Org. Lett. 19: 2901–2904.
56 Katritzky, A.R. and Dennis, N. (1989). Chem. Rev. 89: 827–861.
57 Ren, H., Wu, C., Ding, X. et al. (2012). Org. Biomol. Chem. 10: 8975–8984.
58 (a) Preshlock, S.M., Ghaffari, B., Maligres, P.E. et al. (2013). J. Am. Chem. Soc.
135: 7572–7582. (b) Ishiyama, T., Takagi, J., Hartwig, J.F., and Miyaura, N.
(2002). Angew. Chem. Int. Ed. 41: 3056–3058.
59 Demory, E., Devaraj, K., Orthaber, A. et al. (2015). Angew. Chem. Int. Ed. 54:
11765–11769.
60 Ikawa, T., Masuda, S., Takagi, A., and Akai, S. (2016). Chem. Sci. 7: 5206–5211.
61 Ma, X., Chen, Y., Zhang, Y. et al. (2012). Eur. J. Org. Chem.: 1388–1393.
62 For selected examples on formal cycloadditions of arynes with substrates including nucleophilic and electrophilic sites, see:(a)Huang, X. and Zhang, T. (2010).
J. Org. Chem. 75: 506–509. (b) Lu, C., Dubrovskiy, A.V., and Larock, R.C. (2012).
Tetrahedron Lett. 53: 2202–2205. (c) Zhao, J. and Larock, R.C. (2005). Org. Lett.
7: 4273–4275. (d) Zhao, J. and Larock, R.C. (2007). J. Org. Chem. 72: 583–588.
(e) Okuma, K., Nojima, A., Matsunaga, N., and Shioji, K. (2009). Org. Lett. 11:
169–171. (f) Rogness, D.C. and Larock, R.C. (2010). J. Org. Chem. 75: 2289–2295.
(g) Fang, Y., Rogness, D.C., Larock, R.C., and Shi, F. (2012). J. Org. Chem. 77:
6262–6270. (h) Samineni, R., Madapa, J., Srihari, P., and Mehta, G. (2017). Org.
Lett. 19: 3119–3122. (i) Xu, D., Zhao, Y., Song, D. et al. (2017). Org. Lett. 19:
3600–3603. (j) Pandya, V.G. and Mhaske, S.B. (2018). Org. Lett. 20: 1483–1486.
(k) Hu, W., Zhang, C., Huang, J. et al. (2019). Org. Lett. 21: 941–945.
63 (a) Gilmore, C.D., Allan, K.M., and Stoltz, B.M. (2008). J. Am. Chem. Soc. 130:
1558–1559. (b) Zhao, M.-N., Ren, Z.-H., Wang, Y.-Y., and Guan, Z.-H. (2012).
Chem. Commun. 48: 8105–8107.
64 Hong, D., Chen, Z., Li, X., and Wang, Y. (2010). Org. Lett. 12: 4608–4611.
65 Singh, R., Nagesh, K., Yugandhar, D., and Prasanthi, A.V.G. (2018). Org. Lett. 20:
4848–4853.
66 (a) Markina, N.A., Dubrovskiy, A.V., and Larock, R.C. (2012). Org. Biomol.
Chem. 10: 2409–2412. (b) Dubrovskiy, A.V. and Larock, R.C. (2011). Org. Lett.
13: 4136–4139. (c) Dubrovskiy, A.V. and Larock, R.C. (2012). J. Org. Chem. 77:
11232–11256.
67 Li, P., Wu, C., Zhao, J. et al. (2012). J. Org. Chem. 77: 3149–3158.
68 Li, Y., Muck-Lichtenfeld, C., and Studer, A. (2016). Angew. Chem. Int. Ed. 55:
14435–14438.
69 For a similar proton shift via water-facilitated protonation-deprotonation, see,
Xia, Y., Liang, Y. et al. (2007). J. Am. Chem. Soc. 129: 3470–−3471.
70 (a) Dong, J., Pan, L., Xu, X., and Liu, Q. (2014). Chem. Commun. 50:
14797–14800. (b) Fang, Z., Liu, J., Liu, Q., and Bi, X. (2014). Angew. Chem.
Int. Ed. 53: 7209–7213.
References
71 Garg, P. and Singh, A. (2018). Org. Lett. 20: 1320–1323.
72 (a) Bryce, M.R., Dransfield, T.A., Kandeel, K.A., and Vernon, J.M. (1988).
J. Chem. Soc., Perkin Trans. 1: 2141–2144. (b) Chen, Y. and Willis, M.C. (2015).
Org. Lett. 17: 4786–4789.
73 Zhang, J., Page, A.C.S., Palani, V. et al. (2018). Org. Lett. 20: 5550–5553.
109
111
4
Recent Insertion Reactions of Aryne Intermediates
Suguru Yoshida and Takamitsu Hosoya
Tokyo Medical and Dental University (TMDU), Institute of Biomaterials and Bioengineering (IBB), Laboratory
of Chemical Bioscience, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
4.1 Introduction
A wide variety of insertion reactions of aryne intermediates have been reported so
far [1, 2]. Such reactions have enabled the straightforward synthesis of diverse aromatic compounds that were difficult to achieve by the conventional methods. Since
arynes show a remarkably high electrophilic reactivity, due to their significantly low
LUMO level, various reactions involving arynes proceed via nucleophilic addition
of arynophiles to arynes [3]. The resulting carbanions react intramolecularly to
form a new covalent bond at the electrophilic moiety of the attacked arynophiles
via substitution reactions, including protonation (Figure 4.1a) or addition reactions
(Figure 4.1b). A broad range of transformations have been achieved through either
of these stepwise mechanisms. This chapter overviews recently reported diverse
insertion reactions of arynes by mainly categorizing the nucleophilic atoms of the
arynophiles.
4.2 Amination and Related Transformations
4.2.1
Transformations Involving the Formation of C—N and C—H Bonds
The synthesis of aniline derivatives via arynes had been studied more than 50 years
ago. For example, addition reactions of amines 1 to arynes, followed by protonations to afford aniline derivatives 2 (Figure 4.2a). In particular, aniline synthesis
from aryl halides 3 by treatment with sodium amide in liquid ammonia is often
described in basic organic chemistry textbooks as a representative aryne reaction
(Figure 4.2b) [4].
Numerous studies on the aniline synthesis by aryne insertion reactions have been
performed from the viewpoint of substituted aniline synthesis. For example, in 2003,
Larock and coworkers reported the amination of arynes, which were generated from
o-silylaryl triflates (Kobayashi precursors) [5] by treatment with cesium fluoride,
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
112
4 Recent Insertion Reactions of Aryne Intermediates
Insertion of arynes into σ bonds
Insertion of arynes into π bonds
A
A
+
+
A
A
B
B
B
B
A
A
A
A
B
B
B
(a)
(b)
Figure 4.1
Typical reactions of benzyne.
+
R
R
N
H
R
N R′
R′
N
H
1
H 2
R R′
N
H
R′
(a)
Cl
FG
(b)
NH2
NaNH2
liq. NH3
3
FG
OTf
+ H2N Ph
SiMe3
X
(c)
4a
X=H
OMe 4b
Figure 4.2
1a
2′
H
N
CsF
MeCN
25 °C
Ph
H
X
2a 81%
X=H
OMe 2b 84%
Addition reactions of amines to arynes.
B
4.2 Amination and Related Transformations
Me
SiMe3
+ H2N n-Bu
1b
OTf
SiMe3
4c
n-Bu4NF
H
N
Me
THF
–40 °C
SiMe3
2ca
(a)
SiMe3
Me
+
OTf
X
N Ph
H
1c
MeCN
60 °C
X = F 4d
N
H
92%
(11:89)
X
2da–2ga
80% (2da only)
Cl
66% (2ea:2eb = >95:5)
Br
67% (2fa:2fb = 93:7)
I
OTf
Me
+
SiMe3
N
N Ph
H
1c
H
N
4h
O
57% (2ga:2gb = 90:10)
Me
N
Ph
KF
18-crown-6
THF
rt
SiMe3
2cb
Ph
N
X
Me
2db–2gb
Cl 4e
4g
n-Bu
H
+
H
X=F
Me
+
Br 4f
I
(b)
Me
N
Ph
CsF
n-Bu
O
2h
84%
(c)
KF
18-crown-6
OTf
+
SiMe3
SPh 4i
(d)
Figure 4.3
H2N Ph
1d
THF
rt
H
N
Ph
H
SPh 2i
80%
Regioselective amination reactions of arynes.
using various amines (Figure 4.2c) [6]. In particular, meta-methoxyaniline derivatives were obtained by the amination of 3-methoxybenzyne generated from 4b due
to the inductive and steric effects of the methoxy group. A wide range of amines,
including anilines, bulky tert-butyl amine, amines bearing functional groups such
as terminal alkyne moiety and unprotected hydroxy group, and sulfonamides, participated in this N-arylation reaction with arynes.
Several regioselective amination reactions of arynes have been reported, in
which the selectivity depends on the substituent on the arynes (Figure 4.3). In
2011, Akai and coworkers reported the ortho-selective amination of 3-silylarynes
based on the electron-donating effect of the silyl group (Figure 4.3a) [7]. Garg
and coworkers showed meta-selective amination of 3-haloarynes, in which the
meta-selectivity decreased with decreasing electronegativity of the halogen atoms
113
114
4 Recent Insertion Reactions of Aryne Intermediates
(Figure 4.3b) [8]. We also reported the meta-amination of 3-morpholinobenzyne
[9a] and 3-(phenylthio)benzyne [9b], which were generated from the corresponding
precursors 4h and 4i, prepared via 3-(triflyloxy)benzyne [10], as described later
(Figures 4.3c,d). Several examples for regioselective amination of pyridynes and
various ring-fused arynes, including hetarynes, have also been reported [11]. The
regioselectivities in these aryne amination reactions were determined by the effect
of the substituent on the benzyne ring, particularly by the characteristics of the
substituted atom.
Various nitrogen nucleophiles have been used in aryne amination reactions;
for instance, Greaney and coworkers reported in 2011 that hydrazone 5 smoothly
reacted with arynes to furnish N-arylhydrazone 6 through the insertion of arynes
into the N—H bond (Figure 4.4a) [12]. Subsequent rearrangement by treating
N-arylhydrazone 6 with boron trifluoride under Fischer indole synthesis conditions
provided indole 7 in high yield. Addition reaction to arynes by hydrazine derivative
I generated in situ by the reaction between diethyl azodicarboxylate and triphenylphosphine was reported by Cheng et al. in 2017 (Figure 4.4b) [13]. N-Arylation
of amidine 10 with arynes also proceeded efficiently in the presence of sodium
bicarbonate (Figure 4.4c) [14].
Several reactions of arynes with tertiary amines have been reported so far; for
example, in 2013, Biju and coworkers found that treatment of a mixture of o-silylaryl
triflate 4a and N,N-dimethylaniline (12) with potassium fluoride and 18-crown-6
in the presence of ammonium bicarbonate at 60 ∘ C yielded aniline derivative
13 through demethylation in excellent yield (Figure 4.4d, upper scheme) [15].
Diesendruck and coworkers reported the efficient synthesis of ammonium salt 14 in
2016 by the reaction between benzyne and N,N-dimethylaniline (12) at room temperature (Figure 4.4d, lower scheme) [16]. In 2017, we also reported the reaction of
N,N-dimethylaniline (12) with aryne III generated by the hexadehydro-Diels–Alder
(HDDA) reaction of aryne II having a 1,3-diyne moiety, which was generated from
o-iodoaryl triflate 15a by treating it with a silylmethyl Grignard reagent as an
activator to promote the iodine–magnesium exchange. In this case, carboamination
product 16 was obtained through intramolecular arylation of IV in high yield
instead of ammonium salt 17 (Figure 4.4e) [17].
Various types of organonitrogen compounds have been prepared easily by
N-arylation reactions involving arynes. The N-arylation of amino sugars with
arynes was demonstrated by Nilsson and coworkers in 2018, which was achieved
using sugars without protection of hydroxy groups (Figure 4.5a) [18]. Jin and
coworkers reported the N-arylation of N-alkoxyamides with arynes in 2016
(Figure 4.5b) [19]. In the case of the reaction of 2-(trifluoroacetylamino)pyridine
(22) with arynes, N-arylation of the pyridine nitrogen took place (Figure 4.5c) [20].
In two independent studies, Singh and coworkers [21] and our group [22] reported
the N-arylation of N-H sulfoximine 24a with arynes (Figure 4.5d, upper scheme).
We also found that aminosulfinylation of arynes involving migratory N-arylation
proceeded when using diaryl sulfoximine 24b (Figure 4.5d, lower scheme) similar
to the reaction with N-H sulfilimines as described later [22].
4.2 Amination and Related Transformations
SiMe3
Ts
HN
+
4a
OTf
Ts
N
CsF
N
MeCN
rt
5
N
H
(a)
MeCN
reflux
6
7
80%
>90% conversion
CsF
18-crown-6
PPh3
CO2Et
N
N
CO2Et
SiMe3
+
OTf
4a
CO2Et
N
H
N
CO2Et
H
9
77%
MeCN
H 2O
rt
8
(b)
H
4a
10
CsF
Ph
N
N
NaHCO3
rt
OTf
CO2Et
N
PPh3
N
CO2Et
I
Ph
N
N
SiMe3
Ts
N
BF3·OEt2
11
70%
H
(c)
KF
18-crown-6
(NH4)HCO3
SiMe3
+
4a
Me
OTf
Me
N
THF
60 °C
Me
N
12
H
13
95%
Me Me
N
CsF
MeCN
rt
H
14
86%
(d)
OTf
PhNMe2 12
Ph
Ph
Et2O
rt
15a
O
Ph
Ph
O
II
Me
N
Ph
O
NMe2
+
Ph
16 81%
Me3SiCH2MgCl
I
O
OTf
III
O
Ph
Me
Ph Me Me
N
Ph
X
H
O
17 not detected
Me
N Me
O
IV
(e)
Figure 4.4
Aryne amination reactions by various nitrogen nucleophiles.
4.2.2 Transformations Involving the Formation of C—N
and C—Mg Bonds
The aminometalation of arynes was reported by Knochel and coworkers, providing
an efficient preparation method for various arylmagnesium reagents [23]. Based on
this approach, Greaney and coworkers developed an efficient method to synthesize
115
116
4 Recent Insertion Reactions of Aryne Intermediates
HO
SiMe3
+
4a
OTf
OH
HO
O
H 2N
CsF
OMe
OBn
+ HN
SiMe3
O
N
H
O
OMe 4b
H
N
20
Bn
19 69%
H
OBn
N
CsF
OBn
MeCN
rt
O
OMe
OH
(a)
OTf
O
H
N
MeCN
rt
OH
18
OH
H
OMe
O
O
N
H
H
N
Bn
OBn
O
21 76%
(b)
SiMe3
N
4a
HN
OTf
N
CsF
+
CF3
O
N
CF3
H
23 O
88%
MeCN
rt
22
(c)
O
Ph
S
Me 24a
KF
18-crown-6
H
N
THF
rt
OTf
CF3
SiMe3
OMe
4b
O
Ph
S
Me
25
H
65%
OMe
N
O
N
H
S
p-Tol
24b
KF
18-crown-6
H
N
THF
60 °C
MeO
(d)
Figure 4.5
CF3
O
S
26
p-Tol
43%
Various N-arylation reactions involving arynes.
aniline derivative 29 via aminomagnesiation of benzyne generated from o-iodoaryl
sulfonate 15b with isopropylmagnesium chloride and subsequent copper-catalyzed
amination using N-benzoyloxymorpholine (28) (Scheme 4.1) [24].
4.2.3
Transformations Involving the Formation of C—N and C—C Bonds
A wide range of carboamination reactions of arynes have been reported using
various amides or related organonitrogen compounds. In 2002, Hiyama and
coworkers reported the synthesis of benzodiazepine 31 by the reaction of arynes
with urea 30, which proceeded through N-arylation followed by ring expansion of
the resulting carbanion intermediate V (Figure 4.6a) [25]. Larock and coworkers
4.2 Amination and Related Transformations
BzO
I
+ Me
OSO2Ar
15b
i-PrMgCl
Ph
N
H
THF
–78 to 0 °C
1c
N
Me
N
Ph
O 28
cat. CuCl
cat. Phenanthroline
MgCl
THF, rt
Me
N
Ph
N
29
64%
27
Ar = C6H4-4-Cl
Scheme 4.1
O
Transformation via aminomagnesiation of benzyne [24].
reported (in 2005) that N-trifluoroacetylanilide 32 reacted smoothly with arynes
to provide the carboaminated products through the C—N bond insertion to
VI (Figure 4.6b) [26]. Carboamination of N-benzoylanilide (34) with arynes
was reported by Greaney and coworkers in 2010, enabling the preparation of
acridone 37 by further intramolecular N-arylation (Figure 4.6c) [27]. In 2007,
Me
N
SiMe3
+
4a
CsF
O
+
(b)
4a
OTf
Ph
HN
O
32
H
N
CsF
MeCN
rt
CF3
HN
4a
OTf
H
N
Ph
O
O
33
77%
VI
Ph
Ph
35
81%
F
O
36
n-Bu4NPh3SiF2
toluene
50 °C
BF3
2
toluene
80 °C
(c)
Figure 4.6
Ph
N
Ph
toluene
50 °C
HN
V
Ph
CF3
O
Ph 34
O
n-Bu4NPh3SiF2
SiMe3
O
Me
O
31
62%
Carboamination reactions of benzyne with amides.
N Me
N
N
(a)
SiMe3
Me
20 °C
N
Me
30
OTf
Me
N
Ph
N
O
37
92%
CF3
117
118
4 Recent Insertion Reactions of Aryne Intermediates
Me
HN
SiMe3
+
4a
OTf
CsF
MeO
THF
65 °C
38
O
Me
N
SiMe3
+
4a
HN
OTf
NH
n-Bu4NPh3SiF2
Me
Me
toluene
60 °C
O 40
O
(b)
Br
SiMe3
+
4a
(c)
Figure 4.7
OTf
CsF
HN
CN
42
THF
70 °C
OMe
Me
O
Me
O
O
39
61%
(a)
O
Me
N
41
89%
H
N
CN
43
87%
Br
Other carboamination and aminocyanation reactions of benzyne.
Larock and coworkers reported acridone synthesis by the reaction between
arynes and o-(methoxycarbonyl)aniline derivative 38 (Figure 4.7a) [28] based
on the xanthone synthesis, as described later. The insertion reaction of arynes
to the C—N bond of imide 40 was also reported by Stoltz and coworkers in
2016, providing carboaminated product 41 in high yield (Figure 4.7b) [29]. The
aminocyanation of arynes with N-cyanoanilide 42 was also reported by Zeng
and coworkers in 2014 (Figure 4.7c) [30]. In 2008, Stoltz and coworkers reported
that the carboamination of arynes with α-(tert-butoxycarbonylamino)acrylic acid
methyl ester 44 led to indoline derivative 45 (Figure 4.8a), while isoquinolines
were obtained with two C—C bond formations when α-(acylamino)acrylic acid
esters were used [31] as described in Section 4.3.3. Moreover, the reaction of
arynes with N,N-dimethylhydrazone 46 was reported to afford carboaminated
products such as 47 through the addition of an amino group to aryne, followed
by intramolecular cyclization and cleavage of the N—N bond (Figure 4.8b) [32].
In 2010, Wang and coworkers achieved the indole synthesis via the reaction of
arynes with azaylide VII prepared from alkenyl azide 48 and triphenylphosphine
(Figure 4.8c) [33].
4.2.4 Transformations Involving the Formation of C—N and C—S, C—P,
C—Cl, or C—Si Bonds
Several methods for the difunctionalization of arynes involving the formation of
C—N and C—S bonds have been reported. Reaction of N-(trifluoromethylsulfinyl)
anilide 50 with arynes efficiently afforded aminosulfinylated product 51
(Figure 4.9a) [26], as is the case using N-(trifluoroacetyl)anilides (Figure 4.6b).
4.2 Amination and Related Transformations
SiMe3
+
4a
Boc
HN
CO2Me
OTf
Boc
N
n-Bu4NPh3SiF2
THF
23 °C
44
45
61%
(a)
NMe2
N
SiMe3
+
4a
OTf
Ph 47 76%
SiMe3
Ph
Ph
N3
4a
Ph 48
PPh3
N
CO2Et
(c)
Figure 4.8
Ph
VII
H
PPh3
CsF
CO2Et
+
OTf
Me Me
N
NH
Me Me
N
N
Ph
(b)
NH
MeCN, 65 °C
Me Me
N
N
NMe2
N
NMe2
CsF
Ph 46
H Boc
N
CO2Me
CO2Me
MeCN, toluene
50 °C
under air
Ph3P
N
Ph
H
N
CO2Et
Ph
49 81%
H
N
O
CO2Et
OEt
H
Ph
Ph
Other carboamination reactions of benzyne.
Hoye and coworkers reported the sulfonylamination of aryne VIII generated by the
HDDA reaction (Figure 4.9b) [34]. We developed a method for o-thioaniline synthesis by the reaction of arynes with sulfilimines affording the products such as 55
via aminosulfanylation and migratory N-arylation (Figure 4.9c) [35]. Recently, Biju
and coworkers reported the reaction of arynes with N-sulfanylamines, including
56, affording aminosulfanylated products (Figure 4.9d) [36].
Difunctionalization of arynes involving C—N and C—P bond formations was
reported by Zhang and coworkers in 2013 (Figure 4.10a) [37]. The reaction
between arynes and azaylide 60 provided phosphonium salt 61 (Figure 4.10b) [38].
When N-chloroamine 62 was used as the arynophile, chloroamination of arynes
proceeded to afford o-chloroaniline derivative 63 (Figure 4.10c) [39].
Silylamination of arynes produces o-aminoarylsilanes. The pioneering work, in
which these results were presented, was reported by Hiroto Yoshida and coworkers
in 2005 [40]. They used N-silylamines such as 64a containing a bulky silyl group to
prevent the decomposition by the fluoride ion used as the activator for generating
arynes from o-silylaryl triflates (Figure 4.11a). We recently found that treatment
of o-iodoaryl triflate 15c with (trimethylsilyl)methylmagnesium chloride in the
presence of N-silylamine 64b efficiently afforded 3-amino-2-silylaryl triflate 4h
via silylamination of 3-(triflyloxy)aryne intermediate, owing to the mild and soft
119
120
4 Recent Insertion Reactions of Aryne Intermediates
Ph
HN
+
S
O
CF3
50
SiMe3
OTf
4a
H
N
n-Bu4NF
THF, rt
S
O
Ph
CF3
51
80%
(a)
Me3Si
O
N
Me3Si
N Me
SO2-p-Tol
O
CHCl3
90 °C
SO2-p-Tol
+
SiMe3
(c)
OMe
4b
NH
S
p-Tol
p-Tol
54
Me
SiMe3
+
(d)
4a
OTf
Figure 4.9
N
S
56
p-Tol
KF
18-crown-6
H
N
THF
60 °C
S
DME
25 °C
Ph
VIII
NH
p-Tol
p-Tol
MeO
SPh
57
83%
Thioamination reactions of arynes.
Cl
+
OTf
HN
PPh2
O
58
KF
18-crown-6
Cs2CO3
H
N
THF, 80 °C
PPh2
O
59
71%
(a)
SiMe3
+
(b)
4a
OTf
O
+
OTf
(c)
Figure 4.10
NBn
PPh3
CsF
MeCN, 10 °C
60
SiMe3
4a
p-Tol
S
p-Tol
Me
N
p-Tol
CsF
SiMe3
4a
OMe
55
77%
Me
SO2-p-Tol
O
53
85%
52
(b)
OTf
N
Me3Si
Me
N
Cl
62
CsF
Cl
NHBn
PPh3 OTf
61
70%
O
N
MeCN, 60 °C
Cl
63
63%
Phosphinyl-/phosphinoamination and chloroamination reactions of benzyne.
4.3 Transformations Involving Bond Formation with Nucleophilic Carbons
SiMe3
NEt2
SiMe2Ph
+
OTf
4a
(a)
NEt2
THF, 0 °C
SiMe2Ph
65
65%
64a
O
O
OTf
+
OTf
15c
Et2O, 0 °C
64b
F3C
OTf
CF3
66
IX
NMe2
F3C
Me3Si NMe2
64c
Et2O
cyclohexane
25 °C
(c)
Figure 4.11
N
SiMe3
OTf
4h
81%
(1-Ad)2NLi
+
O
N
Me3SiCH2MgCl
N
SiMe3
I
(b)
KF
18-crown-6
SiMe3
CF3
67
63%
Silylamination reactions of arynes.
reactivity of the silylmethyl Grignard reagent (Figure 4.11b) [9a]. The subsequent
3-aminoaryne generation, triggered by fluoride ion in the presence of various
arynophiles, allowed for the synthesis of diverse aniline derivatives. Thus, this
“aryne relay” approach enabled the facile synthesis of anilines in a modular
synthetic manner. In 2018, Daugulis and coworkers also reported the silylamination
of arynes generated from aryl triflates or aryl halides by treatment with lithium
di(1-adamantyl)amide (Figure 4.11c) [41].
4.3 Transformations Involving Bond Formation
with Nucleophilic Carbons
4.3.1
Transformations Involving Carbometalation
The carbometallation of arynes is a fascinating approach for biaryl synthesis under
transition metal-free conditions. In 1985, Hart et al. reported the elegant synthesis
of 1,3-diarylbenzenes 69 from 1,3-dihalo-2-iodobenzenes 68 via sequential selective
carbomagnesiations to consecutively generated arynes, which enabled the facile
preparation of various m-terphenyls with functional groups (Figure 4.12a) [42].
This type of transition-metal-free approach to biaryl synthesis has been intensively
studied by Leroux and coworkers. For example, they reported carbolithiation of
arynes generated from 1,2-dibromobenzene (70) with aryllithium 71 afforded biaryl
72 via bromination of aryllithium intermediate X (Figure 4.12b) [43]. In 2015, the
synthesis of chiral biaryls by atropo-diastereoselective aryne coupling was reported
by Panossian and coworkers based on chiral sulfoxide chemistry (Figure 4.12c) [44].
121
122
4 Recent Insertion Reactions of Aryne Intermediates
X
X
Ar
I
E
1. ArMgX′
X
68
X = Br or Cl
2. Electrophile
69
Ar
Ar
MgX′
(a)
MeO
Li
71
Br
MeO
MeO
OMe
THF
0 °C
Br
70
Br
72
(b)
OMe
+
73
Br
O
n-BuLi
S
Li+
74
Br
76
(d)
Figure 4.12
X
Cl
O
t-Bu
S
O
S
THF
–78 °C to 25 °C
I
Cl
Li
Br
t-BuLi
THF
–78 °C
Cl
75
51%
dr = 79:21
(c)
BH3
PPh2
OMe
t-Bu
t-Bu
I
Li
Br 70
THF
–35 °C
BH3
PPh2
Li
H3B Ph
P
77
60%
XI
Transformations via carbolithiation of arynes.
In 2012, Jugé and coworkers reported the stereoselective synthesis of dibenzophosphole derivative 77 via aryllithium intermediate XI prepared in situ by carbolithiation of benzyne generated from 1,2-dibromobenzene (70) (Figure 4.12d) [45].
4.3.2
Benzocyclobutene Synthesis by [2+2] Cycloaddition
The synthesis of benzocyclobutenes by the [2+2] cycloaddition of arynes with
electron-rich olefins, including vinyl ethers and ketene acetal derivatives, has been
shown as one of the most useful aryne transformations. Although the thermal
[2+2] cycloaddition is forbidden in terms of the Woodward–Hoffmann rules,
nucleophilic C—C bond formation between arynes and alkenes, followed by
cyclization, affords the formal [2+2] cycloadducts [46, 47]. For example, in 1965,
the nucleophilic attack of alkenes 79 or 81 to benzyne followed by intramolecular
C-arylation was reported to afford [2+2] cycloadduct 80 and acylalkylated product
4.3 Transformations Involving Bond Formation with Nucleophilic Carbons
OEt 79
N2
78
CH2Cl2
Reflux
+
O
O
CO2
Me
O
OTf
OEt
Me
O
EtO
I
OTBS
83
OMe
THF
–78 °C
OTBS
OEt
OMe
84
89%
15d
O
OMe
TfO
via Repeated
[2+2] cycloaddition
85
(c)
SiMe3
+
OTf
N
Ts
Bn
O
O
86
CsF
dioxane
100 °C
87
(d)
Figure 4.13
O
OMe
MeO
4a
82
25%
n-BuLi
+
Br
OEt
OEt 81
THF
60 °C
(a)
(b)
80
c. 40%
N Bn
Ts
88
87%
Synthesis of benzocyclobutenes via arynes.
82, respectively (Figure 4.13a) [47a]. Recent remarkable advances in synthetic aryne
chemistry have enabled diverse transformations, including [2+2] cycloadditions
and difunctionalizations. In particular, Suzuki and coworkers extensively studied
synthetic chemistry applying the [2+2] cycloaddition of arynes. In 1995, they
reported an efficient benzocyclobutene synthesis by the [2+2] cycloaddition of
arynes, generated from o-iodoaryl triflates by treatment of butyllithium at –78 ∘ C,
with ketene silyl acetals (Figure 4.13b) [48]. The rapid iodine–lithium exchange
reaction enabled aryne generation at a quite low temperature. Based on this [2+2]
cycloaddition reaction, elegant syntheses of various tricylobutabenzene derivatives
such as 86 were accomplished (Figure 4.13c) [49]. In addition, [2+2] cycloaddition
of arynes with N-benzyl-N-tosylenamide 87 was reported by Hsung and coworkers
in 2009 (Figure 4.13d) [50].
123
124
4 Recent Insertion Reactions of Aryne Intermediates
4.3.3
Acylalkylations and Related Transformations
The acylalkylation of arynes using 1,3-dicarbonyl compounds has attracted the
attention of many synthetic organic chemists because the products are useful
synthetic intermediates. In 2005, Stoltz and coworkers [51] and Hiroto Yoshida
et al. [52] independently reported the acylalkylation of arynes with 1,3-dicarbonyl
compounds (Figures 4.14a,b). These reactions enabled the facile preparation of a
range of benzene-fused macrocyclic compounds 93 by ring expansion (Figure 4.14c)
[52a] and multisubstituted benzenes such as 90b (Figure 4.14d) [51c].
After these pioneering works, various reactions between arynes generated from
o-silylaryl triflates and active methylene or methyne compounds have been reported.
These include acylalkylation reactions of arynes with α-cyanoketones (Figure 4.15a)
[52c], 9-acyl-9H-fluorenes (Figure 4.15b, lower scheme) [52d], and trifluoromethyl
benzyl ketones (Figure 4.15c, upper scheme) [52f] that efficiently afforded
the corresponding ketones, while acylclkylation did not undergo using ethyl
α,α-diphenylacetate (Figure 4.15b, upper scheme). When trifluoromethyl phenethyl
ketone (102) was used, benzocyclobutenol 103 was obtained (Figure 4.15c, lower
scheme) [52f]. Cyclic ketones, such as β-tetralone (104) (Figure 4.16a) [53] and
O
O
SiMe3
+
4a
OTf
CsF
OMe
(a)
O
MeCN
80 °C
Me
89
O
Me
90a
90%
O
+
4a
OTf
OEt
O
O
THF
rt
OEt
91
OEt
92
71%
(b)
OMe
OEt
O
OEt
KF
18-crown-6
O
SiMe3
OMe
O
O
O
OMe
(c)
O
OMe
MeO
SiMe3
+
Me
(d)
4j
Figure 4.14
OTf
OMe
O
Me
CsF
MeO
MeCN
80 °C
Me
89
Acylalkylation reactions of arynes.
O
93e
93d
MeO
O
O
O
O
93c
93b
O
15
O
9
O
93a
O
O
O
OMe
O
Me
90b
90%
19
4.3 Transformations Involving Bond Formation with Nucleophilic Carbons
SiMe3
CN
KF
18-crown-6
CN
+
4a
OTf
O
O
THF
rt
t-Bu
94
t-Bu
95
82%
(a)
Ph
Ph
OEt 96
KF
18-crown-6
O
THF
rt
Ph
O
OEt
97
Not detected
SiMe3
4a
Ph
OTf
i-Pr 98
KF
18-crown-6
O
THF
rt
(b)
O
i-Pr
99
97%
Ph
CF3 100
KF
18-crown-6
O
THF
rt
SiMe3
Ph
O
CF3
101
60%
Bn
OTf
4a
CF3 102
KF
18-crown-6
O
THF
rt
(c)
Figure 4.15
H
Bn
OH
CF3
103
47%
Various acylalkylation reactions of benzyne.
125
126
4 Recent Insertion Reactions of Aryne Intermediates
SiMe3
CsF
+
4a
OTf
THF
105 °C
O
104
Me
O
+
4a
Figure 4.16
H
106
6%
O
O
CsF
Me
OTf
(b)
O
105
63%
(a)
SiMe3
+
O
107
MeCN
80 °C
O
108
75%
Acylalkylation reactions of benzyne with cyclic ketones.
1,3-pentanedione 107 (Figure 4.16b) [54], also participated in the reaction to afford
eight- and seven-membered compounds, respectively. The reaction of benzyl phenyl
ketone (109) (Figure 4.17a) [55] and imidoester 112 (Figure 4.17b, top scheme) [56]
with arynes afforded acyl- and imidoylalkylated products 110 and 113, respectively.
In the reaction between arynes and amidine 114, imidoylalkylated product 115 was
obtained as a major product by using tetrabutylammonium fluoride as an activator
(Figure 4.17b, middle scheme), while N-arylation with arynes proceeded to afford
diarylated product 116 as a major product when cesium fluoride was used as an
activator (Figure 4.17b, bottom scheme) [56].
Acylalkylation of arynes has been useful in constructing fused skeletons; for
example, Okuma et al. reported the synthesis of isocoumarin 118 (Figure 4.18a)
[57a] and 1-naphthol 119 (Figure 4.18b) [57b] via the acylalkylation of arynes
using diketones 117a and 117b, respectively, followed by cyclization. When
2-benzyl-3-hydroxy-1,4-naphthoquinone (120) was used as an arynophile, tetracyclic compound 121 was obtained diastereoselectively (Figure 4.18c) [58]. In
2016, Suzuki and coworkers reported an efficient method for the synthesis of
3-alkoxy-2-naphthol 124 via the reaction of arynes with 1,3,5-tricarbonyl equivalent
122 (Figure 4.19a) [59]. The reaction of arynes with tricarbonyl compound 125
afforded indane derivative 126 via acylalkylation and subsequent intramolecular
cyclization (Figure 4.19b) [60].
Further arylation of the acylalkylated products by arynes at the active methylene
group proceeds depending on the substrates. For example, diarylmethyl sulfone 128a
and diarylacetonitrile 128b were obtained through a second arylation of the acylalkylated products formed from the reaction between arynes and sulfonylacetonitrile 127a and malononitrile (127b), respectively (Figure 4.20a) [61]. The reaction of
α-sulfonyl-substituted ethyl acetate with aryne afforded 130 without further arylation (Figure 4.20b, upper scheme) [62]. Acylalkylation followed by ring formation
with fumaric acid diester 131 yielded naphthol 132 (Figure 4.20b, lower scheme).
4.3 Transformations Involving Bond Formation with Nucleophilic Carbons
Ph
SiMe3
Ph
+
OTf
Ph
O
4a
109
Ph
Ph
KF
18-crown-6
+
O
THF
rt
110 Ph
(a)
H
67%
(20 : 1)
O
111
Ph
Ph
TsN
OEt 112
CsF
MeCN
rt
NTs
OEt
113
83%
TsN
N
H
114
SiMe3
4a
n-Bu4NF
OTf
THF
rt
N
+
TsN
N
Ts N
H
115
61%
116
15%
TsN
N
H
114
CsF
MeCN
rt
(b)
Figure 4.17
N
TsN
115
5%
+
Ts N
N
H
116
85%
Reactions of benzyl phenyl ketone, imidoester, and amidine with benzyne.
In contrast to the reaction of arynes with α-sulfonyl esters, in which no C—S
bonds were formed, C—P bond formation proceeded in the reaction of arynes with
α-phosphinylacetonitrile 133 (Figure 4.21a) [52b]. On the other hand, the reaction
of arynes with β-ketophosphonic acid diester 135 resulted in a selective acylalkylation (Figure 4.21b) [63]. When sulfonium salt 137 was used as an arynophile,
methylthioalkylated product 138 was obtained via nucleophilic addition and
subsequent intramolecular C—S bond formation, where acylalkylation did not
proceed (Figure 4.21c) [64].
127
128
4 Recent Insertion Reactions of Aryne Intermediates
+
4a
Me
O
SiMe3
OTf
Me
O
CF3
Me
CsF
Me
+
4a
OH
O
SiMe3
OTf
Me
O
117b
(b)
CsF
MeCN
reflux
119
80%
Bn
CsF
+
4a
OTf
HO
O
120
MeCN, THF
80 °C
(c)
Figure 4.18
Me
O
O
SiMe3
O
CF3
O
118
68%
117a
(a)
O
O
MeCN
reflux
Bn
OH
O
121
70%
(99:1 dr)
Bn
O
O
O
Synthesis of cyclic compounds by acylalkylation reactions of benzyne.
Isoquinoline synthesis via the reaction between arynes and α-(acylamino)acrylic
acid ester 139 involving nucleophilic C—C bond formation, followed by intramolecular acylation and dehydration, was reported by Stoltz and coworkers in 2008
(Figure 4.22a) [31]. As described in Section 4.2.3, the reaction pathway depended
on the substituent at the nitrogen. Formal formylalkylation of arynes was achieved
using enamine 141 as an arynophile (Figure 4.22b) [65]. In addition, alkynyl ether
143 reacted with arynes to afford o-ethoxyphenylacetylene (144) via C–O insertion
(Scheme 4.2) [66].
CsF
SiMe3
+
OTf
4a
Scheme 4.2
4.3.4
OEt
143
MeCN
rt
OEt
144
51%
Reaction of benzyne with an alkynyl ether [66].
Transformations Involving C—C and C—H Bond Formations
Aryne transformations involving C—C and C—H bond formations have also been
reported. The carbene-catalyzed hydroformylation of arynes with aldehydes was
reported by Biju and Glorius in 2010 (Figure 4.23a) [67]. C-arylations of arynes with
enamide 147 [68] or amides 149a and 149b [69] were also reported (Figures 4.23b,c),
while a diarylation took place to give 151 when the latter amide was employed
4.4 Etherification and Related Transformations
Me Me
SiMe3
O
+
4a
Cs2CO3
18-crown-6
O
O
OTf
O
THF
rt
Me 122
O
Me
Me
O
123
O 86%
O
Me
Cs2CO3
MeOH, THF, rt
Me
Me
OH
O
O
OMe
O
Me
Me
(a)
O
Ph
SiMe3
O
+
4a
OEt
OTf
Me 125
O
K+ O
OEt
O
O
THF
0 °C
HO Me
O
(b)
Figure 4.19
benzyne.
Me
Ph 126
78%
(86:14 dr)
OEt
O
Ph
O
OEt
KF
18-crown-6
O
124
85%
O
Ph
O
Me
Synthesis of multisubstituted cyclic compounds by acylalkylation reactions of
(Figure 4.23c, lower scheme). Coquerel, Rodriguez, et al. reported the arylation
of arynes with α-amido-substituted cyclopentanone (Figure 4.24a), enabling the
synthesis of chiral amide using a catalytic amount of thiourea as an organocatalyst,
albeit in low enantiomeric excess [70]. The arylation was successfully applied to
the chiral ketoester synthesis by Garg and Houk et al. using a chiral amine 155
(Figure 4.24b) [71]. Furthermore, arylation of arynes with amide 158 having a fluoro
group and subsequent removal of the ethoxycarbonyl group efficiently afforded
α-aryl-α-fluororactamide derivative 159 (Figure 4.24c) [72].
4.4 Etherification and Related Transformations
The addition of phenols or carboxylic acids to arynes proceeds smoothly enabling
the O-arylation under transition metal-free conditions as reported by Larock and
coworkers in 2004 (Figure 4.25a and top scheme of Figure 4.25b) [73a]. They found
that oxyacylated product 164 was obtained from the reaction of arynes with aliphatic
129
130
4 Recent Insertion Reactions of Aryne Intermediates
O O
S
p-Tol
127a
CN
KF
18-crown-6
p-Tol
THF
rt
CN
128a
75%
SiMe3
CN
4a
OTf
O
S OH
CN 127b
KF
18-crown-6
THF
rt
CN
H
CN
128b
57%
(a)
O O
S
Ph
O
OEt 129
KF
18-crown-6
Ph
O
S O
THF
rt
OEt
130
85%
SiMe3
4a
(b)
Figure 4.20
group.
O
OTf
KF
18-crown-6
NaH
THF
O O rt
CO2Et
S
Ph
EtO2C
O
OEt
129
131
CO2Et
CO2Et
OH
132
69%
Reactions of benzyne with various compounds having an active methylene
4.4 Etherification and Related Transformations
SiMe3
+
O
OTf
4a
PPh2
THF
rt
133
134
67%
(a)
KF
18-crown-6
+
OTf
4a
(b)
135
O
KF
18-crown-6
Cs2CO3
S Me
Me Br 137
MeCN
rt
Ph
SiMe3
P(OMe)2
O
THF
60 °C
Me
O
O
P
Ph2
O
O
P(OMe)2
SiMe3
CN
KF
18-crown-6
CN
Me
Ph
+
4a
OTf
136
84%
O
S
138
Me 57%
Ph
Ph
Ph
O
O
O
Me
S
Me
S Me
Me
S Me
Me
X
(c)
Figure 4.21
group.
Reactions of benzyne with other compounds having an active methylene
CO2Me
SiMe3
+ O
4a
OTf
NH
Me 139
n-Bu4NPh3SiF2
CO2Me
N
THF
23 °C
O
Me
140
92%
(a)
CO2Et
SiMe3
CsF
CO2Et
+
4a
OTf
(b)
Figure 4.22
Ni-Pr2
141
MeOH
MeCN
rt
CO2Me
CHO
142
82%
Reactions of benzyne with aminoacrylates.
NH
Me
CO2Et
Ni-Pr2
131
132
4 Recent Insertion Reactions of Aryne Intermediates
ClO4
N Mes
cat. S
cat. t-BuOK
KF
18-crown-6
O
SiMe3
O
+
4a
THF
OTf
146
Br 92%
H
Br
145
R
O
N
H
Mes
S
S
O
(a)
NMes
H
O
SiMe3
Me
+
4a
O
OEt
OTf
HN
147
(b)
O
OEt
Me
N
Ph
O 149a
CsF
O
HN
C6H4-4-F
H
148
87%
O
Me
H
N
C6H4-4-F
OEt
Me
N
Ph
O
H
150
90%
NHC6H4-4-Cl
MeCN
rt
Figure 4.23
OEt
OEt
O 149b
CsF
(c)
O
Me
MeCN
C6H4-4-F rt
SiMe3
OTf
OEt
CsF
MeCN
rt
4a
Br
H
CO2Et
CONHC6H4-4-Cl
H
151
86%
Benzyne transformations involving C—C and C—H bond formations.
carboxylic acid 162b (Figure 4.25b, middle scheme) [73c, e],while xanthene 165
was available via further O-arylation with second arynes, followed by cyclization
(Figure 4.25b, bottom scheme) [28, 73e]. Addition of the hydroxy group of phenols
166 and 168 to arynes and subsequent ring closure afforded xanthone (167) [28,
73b] and xanthene 169 [73d], respectively (Figures 4.25c,d).
Oxysulfanylations of aryne intermediates with sulfoxides bearing a nucleophilic
oxygen have also been reported. In 2017, Studer and coworkers found that alkenyl
sulfoxide 170 smoothly reacted with arynes to afford oxysulfanylated products
such as 171 via the S—O bond cleavage (Figure 4.26a) [74]. In 2017, we achieved
the difunctionalization of arynes using diaryl sulfoxides at 110 ∘ C, while the
4.5 Sulfanylation and Related Transformations
O
Me
Me
SiMe3
+
4a
O
OTf
H
N
O
KF
18-crown-6
Ph 152
THF
rt
Me
Me
HO
153
82%
(a)
NHPh
1.
155
SiMe3
Et
O
OTf 4a
NH2
Et
O
CsF, DMF, 30 °C
O
benzene
80 °C
OMe
154
HN
2. 1 M HCl aq.
O
156 OMe
(b)
O
SiMe3
+
4a
OTf
OEt
n-Bu4NF
NHC6H4-4-Br
F
O
158
MeCN
rt
CO2Me
H
157
68%, 92% ee
O
F
OEt
NHAr
NHC6H4-4-Br
H
O
F
O
H
159
83%
(c)
Figure 4.24
α-Phenylation of β-carbonyl amide or ester derivatives with benzyne.
reaction performed at 60 ∘ C resulted in the formation of sulfonium salt 173 [75]
(Figure 4.26b) [76].
Transformations of arynes involving C—O and C—N bond formations have also
been reported. The reaction of arynes with nitrosobenzene (175) led to the formation of carbazole (176) via oxyamination, N—O bond cleavage, ring closure, and
dehydration (Figure 4.27a) [77]. The oxyamination of arynes with N-hydroxyimide
177 afforded N-aryloxindole derivative 178 (Figure 4.27b) [78]. Furthermore, transformations of arynes involving C—O and C—Si bond formations were reported
by Hoye et al., who demonstrated that the intramolecular oxysilylation of aryne
XII having a silyloxy group through an appropriate linker proceeded efficiently
(Figure 4.27c) [79].
4.5 Sulfanylation and Related Transformations
4.5.1
Hydrosulfanylation of Arynes
Several sulfanylation reactions of arynes with various nucleophilic organosulfur
compounds have been reported so far. The efficient synthesis of aryl sulfides by
sulfanylation of arynes generated from o-silylaryl triflates with thiols was reported
by Larock and coworkers in 2006 (Figure 4.28a) [6b]. Thioxantone synthesis
was achieved by the reaction of arynes with benzene thiol 183 having an ester
moiety at the ortho position (Figure 4.28b) [28]. We found that the generation
of 3-fluorobenzyne from 3-fluoro-2-iodophenyl triflate (15e) by treatment of a
silylmethyl Grignard reagent in the presence of 1-dodecanethiol (185) at room
133
134
4 Recent Insertion Reactions of Aryne Intermediates
SiMe3
HO
OTf
4a
O
CsF
+
MeCN
25 °C
160
H
161
92%
(a)
Ph
HO
O 162a
CsF
MeCN
25 °C
HO
SiMe3
4a
Et
O 162b
CsF
THF
125 °C
OTf
HO
Ph
O
H
163
81%
O
OH
Et
O
164
77%
Et
O 162b
CsF
O
DME
125 °C
Et
165
50%
(b)
HO
SiMe3
+
4a
MeO
OTf
O
(c)
O
CsF
THF
65 °C
O
167
75%
166
HO
CsF
Cs2CO3
SiMe3
O
+
(d)
4a
OTf
Ph
O
168
THF
65 °C
Ph
O
Figure 4.25
Addition reactions of phenols or carboxylic acids to benzyne.
169
80%
4.5 Sulfanylation and Related Transformations
SiMe3
+
4a
Ph
OTf
O
S
Ph
CO2Me
O
S
CO2Me
O
MeCN
55 °C
170
CO2Me
CsF
H2 O
171
65%
S Ph
O CO Me
2
O
S
Ph
S
Ph
CO2Me
(a)
KF
18-crown-6
O p-Tol
O
+
THF
60 °C
OTf
+
SiMe3
OMe
p-Tol
O
S
OTf
S p-Tol
OMe
174
8%
172
1,4-dioxane
110 °C
(b)
Figure 4.26
p-Tol
173
63%
p-Tol
KF
18-crown-6
4b
S p-Tol OMe
MeO
O p-Tol
S p-Tol
OMe
174
71%
Oxysulfanylations of arynes.
temperature afforded sulfanylated arene 186, while performing the reaction at
−78 ∘ C provided three-component coupling product 187, which was obtained by
initial formation of a C—O bond through the reaction of aryne with THF used as
a solvent (Figure 4.28c) [80]. Phenylsulfonylation and triflylation of arynes with
sodium sulfinates 188 and 190 were reported by Mhaske and coworkers [81] and
Shibata and coworkers [82], respectively (Figures 4.28d,e).
Phenylsulfanylation of arynes was also achieved efficiently using ethyl phenyl sulfide (192a), from which ethylene was eliminated after the nucleophilic attack of
sulfide to aryne (Figure 4.29a) [83]. In 2017, Peng and coworkers reported sulfonium salt formation by the reaction between arynes and diphenyl sulfide (192b)
(Figure 4.29b) [84].
4.5.2
Transformations Involving C—S and C—C Bond Formations
In 2016, Studer et al. reported the carbosulfanylation of arynes by alkenyl sulfide
195, which afforded o-alkenylaryl sulfide 196 (Figure 4.30a) [85]. The carbosulfanylation of arynes that resulted in the formation of a benzisothiazole skeleton was
reported by Willis and coworkers in 2015, wherein 3,4-dichloro-1,2,5-thiadiazole
(197) was used to react with arynes followed by S—N and C—C bond cleavage
(Figure 4.30b) [86].
135
136
4 Recent Insertion Reactions of Aryne Intermediates
SiMe3
4a
O
N
+
CsF
MeCN, 20 °C
OTf
175
N
(a)
SiMe3
OTf
+
O
Me
(b)
Me3Si
179
(c)
Figure 4.27
OH
N
DME
rt
Me3Si
CDCl3
26 °C
N
KF
18-crown-6
Me
177
O
TBS
O
4.5.3
OH
N
O
176
65%
HO H
O
O
N
O
N
4a
N
H
Me 178
Me
60%
O
O
TBS
180
83%
Me3Si
O TBS
O
XII
Transformations of arynes involving C—O and C—N bond formations.
Other Transformations Involving C—S and C—X Bond Formations
Various transformations of arynes involving C–S and C–Mg, C–S, C–P, C–Si, C–Sn,
or C–Bi have been reported. Sulfanylmagnesiations of arynes were achieved by
treating o-iodoaryl sulfonate-type precursors such as 15b with isopropylmagnesium chloride in the presence of magnesium thiolates or thiols (Figures 4.31a,b)
[23b, 24]. Thianthrene (204) was synthesized by disulfanylation of benzyne with
1,3-benzodithiol-2-imine (203) that was promoted by the liberation of a cyanide
ion (Figure 4.31c) [87]. We found a reaction involving the sulfanylation of arynes
by diphenyl sulfide (192b), followed by a thia-Fries rearrangement to afford
zwitterionic sulfonium salt 205 (Figure 4.31d) [10a]. Disulfanylations of arynes
with disulfides 206a and 206b were reported by Raminelli and coworkers [88]
and Daugulis and coworkers [89], respectively (Figures 4.32a,b). Furthermore,
Hiroto Yoshida et al. reported the sulfanylstannylation of arynes by S-stannyl
sulfides in 2004 (Figure 4.33a) [90]. We recently reported the silylsulfanylation
of 3-(triflyloxy)arynes using S-silyl sulfides, which enabled the facile preparation
4.5 Sulfanylation and Related Transformations
SiMe3
HS
OTf
4a
(a)
MeCN
rt
181
HS
SiMe3
+
S
CsF
+
THF
65 °C
O
4a
S
CsF
MeO
OTf
182
70%
O
184
64%
183
(b)
HS n-C12H25 185
S
Me3SiCH2MgCl
THF
rt
OTf
F
n-C12H25
186
63%
I
F
HS n-C12H25 185
Me3SiCH2MgCl
15e
O
S
THF
–78 °C
F
(c)
SiMe3
+
4a
O
S
Ph
NaO
188
OTf
n-Bu4NF
MeCN
rt
(d)
SiMe3
+
4a
(e)
Figure 4.28
OTf
O
S
NaO
CF3
190
CsF
15-crown-5
t-BuOH
MeCN
40 °C
n-C12H25
187
74%
O O
S
Ph
H
189
95%
O O
S
CF3
H
191
43%
Reactions of arynes with various thiols and sulfinates.
137
138
4 Recent Insertion Reactions of Aryne Intermediates
N2
S
+
78
CO2
S
Et
Ph
192a
ClCH2CH2Cl
reflux
+
(b)
4a
Figure 4.29
OTf
Ph
S
CsF
Ph
H
194
90%
MeCN
rt
192b
+
OTf
CO2Me
195
SiMe3
+
OTf
N
Cl
S Ph
MeCN
80 °C
CO2Me
Figure 4.30
OTf
196
63%
CO2Me
Ph
S
(a)
(b)
Ph
CsF
H 2O
Ph
S
Ph
S
4a
H
Reactions of sulfides with benzyne.
SiMe3
4a
S
Ph
Ph
H
193
96%
(a)
SiMe3
Ph
S
S
N
197
Cl
MeO2C H
CsF
THF
60 °C
S
N
198
76%
Cl
Carbosulfanylation of benzyne.
of o-silylaryl triflate-type 3-sulfanylaryne precursors (Figure 4.33b) [9b]. In 2018,
Daugulis and coworkers achieved the silylsulfanylation of arynes generated by
deprotonation of aryl halides or triflates with lithium di(1-adamantyl)amide
(Figure 4.33c) [41]. Bismuthosulfanylation of arynes was reported by Murafuji and
coworkers in 2011 (Figure 4.34a) [91]. In 2011, Alajarin et al. reported the synthesis
of phosphonium salt 216 by the reaction of arynes with phosphine sulfide 215 via
C—S and C—P bond formations followed by S—P bond cleavage and cyclization
(Figure 4.34b) [92].
Reactions of arynes with various thiocarbonyl compounds have been reported
to afford a range of cyclic sulfides. For example, the synthesis of pyridine-fused
benzothiophene 219 through the reaction of benzyne, generated from o-diazoniumphenyl carboxylate, with N-acetoxythiopyridone (218) was reported by Biehl
and coworkers in 2002 (Figure 4.35a) [93]. In 2016, Hoye and coworkers found
4.5 Sulfanylation and Related Transformations
(a)
MgCl
S
I
i-PrMgCl
+
OSO2Ar
15b
(Ar = 4-Cl-C6H4)
I
S
THF
–78 °C
to 0 °C
199
202
t-Bu
I
201a
83%
MgCl
200a
i-PrMgCl
HS
+
OSO2Ar
15b
(Ar = 4-Cl-C6H4)
S
I2
S
THF
–78 °C
to 0 °C
MgCl
N
S
cat. CuCl
cat. phen
THF
rt
N
BzO
t-Bu
200b
201b
76%
(b)
SiMe3
S
+
4a
HN
KF
18-crown-6
S
MeCN
80 °C
S
S
203
OTf
t-Bu
204
95%
CN
S
S
N
H
(c)
S
S
base
S+Ph2
OTf
(d)
I
OTf 15c
Figure 4.31
+ SPh2
192b
OTf
SiMe3
4a
Et2O, –30 °C
O
Tf
205 76%
OTf
Ph
S
S
206a
+ F3C S S CF
3
206b
SPh
CsF
Ph
MeCN
rt
S
S
SPh
207a
29%
CsF
ClCH2CH2Cl
110 °C
(b)
Figure 4.32
O
S O
CF3
Various transformations of arynes involving C–S and C–X formations.
+
(a)
Me3SiCH2MgCl
O
SiMe3
4a
S+Ph2
Disulfanylations of benzyne with disulfides.
SCF3
SCF3
207b
71%
Ph
Ph
139
140
4 Recent Insertion Reactions of Aryne Intermediates
SiMe3
4a
KF
18-crown-6
+ n-Bu3Sn SPh
OTf
S Ph
S
THF
0 °C
208
Sn(n-Bu)3
209
54%
(a)
OTf
Me3Si SPh
I
(b)
CH2Cl2
rt
210
OTf
15c
Me3Si SPh
210
211
(c)
Figure 4.33
+
p-Tol2Bi–SPh
SiMe3
212
61%
213
SiMe3
S
+ Ph2P
OTf
215
Ph
SPh
CsF
MeCN
rt
OTf
4a
Figure 4.34
Et2O
cyclohexane
0 °C
Sulfanylstannylation and silylsulfanylations of arynes.
SiMe3
(b)
SPh
(1-Ad)2NLi
+
4a
SiMe3
OTf
4i
79%
OTf
(a)
Sn(n-Bu)3
SPh
Me3SiCH2MgCl
+
Ph
Bi(p-Tol)2
214
60%
CsF
S
MeCN
rt
P
Ph2
216
82%
Ph
S
OTf
P
Ph2
Ph
Bismuthosulfanylation and phosphinosulfanylation of benzyne.
that thioamide 221 reacted with arynes generated from triyne 220 by the HDDA
reaction to form a six-membered ring via C—S bond cleavage and C—S bond
formation (Figure 4.35b) [94]. In addition, [2+2] cycloaddition between benzyne
and thioketone 224 was reported by Okuma et al. in 1998 (Figure 4.35c) [95].
4.6 Transformations Involving Bond Formation
with Other Heteroatom Nucleophiles
4.6.1
Transformations Involving C—P Bond Formation
Reactions between arynes and nucleophilic organophosphorus compounds
have also received great attention. Insertion reaction of arynes to P—Li bonds
was achieved by the reaction between lithium phosphide, generated from
4.6 Transformations Involving Bond Formation with Other Heteroatom Nucleophiles
CO2H
S
+
NH2
217
OAc
N
N
acetone
CH2Cl2
reflux
218
(a)
S
i-AmylONO
Me
219
52%
Me
S
Me3Si
Ph
O
S
Me3Si
NMe2 221
N
O
benzene
90 °C
Ph
222
67%
220
Me
Me
Me3Si
H
S
N
O
Me3Si
Me
S
H
O
Me
Me3Si
N
Me
S
N
O
Ph
Ph
Me
Me
Ph
(b)
SiMe3
Ph
I
OTf
(c)
223
Figure 4.35
+
n-Bu4NF
S
t-Bu
Ph
224
MeCN
rt
S
Ph
t-Bu
225
58%
Reactions of arynes with various thiocarbonyl compounds.
phosphine–borane 226, and 1,2-dibromobenzene (70) by Leroux, Jugé, et al. in
2012 (Figure 4.36a) [96]. Addition reactions of organophosphorus compounds to
arynes, including Michaelis–Arbuzov-type reactions, were reported independently
by our group [97] and Mhaske’s group et al. [98] in 2013 (Figures 4.36b,c). In 2016,
Chen et al. reported the P-arylation of arynes using phosphonic acid diester 232
(Figure 4.36d) [99].
The stannylphosphination of arynes generated from o-iodoaryl sulfonates
triggered by the turbo-Grignard reagent was reported by Studer et al. in 2016
(Figure 4.37a) [100]. In addition to the silylamination and silylsulfanylation
reactions, Daugulis and coworkers reported the silylphosphination of arynes
(Figure 4.37b) [41]. In 2018, Miura, Hirano, et al. reported an efficient synthesis of
1,2-diphosphinobenzene derivatives such as 236 by treatment of o-silylaryl triflates
with tetrabutylammonium difluorotriphenylsilicate (TBAT) as an activator in the
presence of diphosphine 235 (Figure 4.37c) [101].
141
142
4 Recent Insertion Reactions of Aryne Intermediates
Br
BH3
H PPh2
226
n-BuLi
Br 70
THF
–78 °C
THF
–78 °C
+
4a
OTf
OMe
P(Ni-Pr2)2
228
n-Bu4NF·3H2O
THF
0 °C
(b)
SiMe3
CsF
+
4a
OTf
230
SiMe3
+
(d)
Figure 4.36
4.6.2
PPh2
PPh2
Br
Li
O
P(Ni-Pr2)2
H
229
89%
O
P(OEt)2
P(OEt)3
MeCN
rt
(c)
4a
BH2
227
75%
(a)
SiMe3
BH2
OTf
O
H P(OEt)2
232
H
231
96%
O
P(OEt)2
CsF
Cs2CO3
MeCN
25 °C
231
85%
H
Reactions of benzyne with organophosphorus compounds.
Transformations Involving C—B, C—I, or C—Cl Bond Formations
The borylzincation of arynes was reported by Uchiyama and coworkers in
2013, where the key to the success of the reaction was the formation of
o-borylatedarylzincate XIII via the reaction of arynes with borylzincate intermediate generated from diboron 237, dimethyl zinc, and magnesium tert-butoxide
(Figure 4.38a) [102]. Diiodination of arynes was reported by Guitián, Pérez, and
coworkers in 2012 (Figure 4.38b) [103]. Hiroto Yoshida, Kunai, and coworkers
succeeded in the chloroacylation of arynes using acid chloride 240 as an arynophile
(Figure 4.39a) [104a]. This reaction was extended to the chloroarylation of arynes
using cyanuric chloride derivative 242 (Figure 4.39b) [104b].
4.7 Conclusions
This chapter has summarized recent insertion reactions and related transformations
of arynes. A wide range of arynophiles have become available with the increase in
the number of precursors and generating conditions of arynes, greatly expanding the
4.7 Conclusions
I
OSO2Ar
15b
(Ar = 4-Cl–C6H4)
1. i-PrMgCl·LiCl
Et2O, –78 °C
PPh2
2. Me3Sn–PPh2 233
–78 °C to rt
SnMe3
234a
90%
(a)
OTf
PPh2
(1-Ad)2NLi
+
Me3Si PPh2
Et2O
0 °C
233
211
SiMe3
234b
67%
(b)
SiMe3
+
4a
OTf
PPh2
PPh2
n-Bu4NPh3SiF2
MS4A
S8
DCE
60 °C
DCE
60 °C
235
S
PPh2
PPh2
S
236
79%
(c)
Figure 4.37
I
(a)
73
Br
Stannylphosphination, silylphosphination, and diphosphination of arynes.
B(pin)
+
B(pin)
237
SiMe3
OTf
(b)
Figure 4.38
Dioxane
120 °C
Br
1,4-dioxane
75 °C
I
I2
MeCN
rt
B(pin)
B(pin)
CsF
+
4a
Me2Zn
Mg(Ot-Bu)2
239
81%
I
Borylzincation and diiodination of benzyne.
238
84%
XIII
ZnR2
143
144
4 Recent Insertion Reactions of Aryne Intermediates
SiMe3
+
4a
OTf
Cl
CsF
Cl
240
O
OMe
MeCN
rt
OMe
O
(a)
241
70%
Cl
SiMe3
+
4a
OTf
N
N
KF
18-crown-6
N
Cl
N
Cl 242
Cl
THF
0 °C
N
N
Cl
Cl
243
58%
(b)
Figure 4.39
Chloroacylation and chloroarylation of benzyne.
range of synthesizable compounds. Efficient insertion reactions, including difunctionalizations of arynes, enable the facile preparation of multisubstituted benzenes,
which are often difficult to synthesize by the conventional methods. Thus, continuous efforts to further expand the utility of synthetic aryne chemistry would allow
the expeditious development of compounds that could be useful in a broad range of
research fields, such as materials science and pharmaceutical chemistry.
References
1 Hoffmann, R.W. (ed.) (1967). Dehydrobenzene and Cycloalkynes. New York:
Academic Press.
2 For some recent reviews on arynes, see:(a)Tadross, P.M. and Stoltz, B.M.
(2012). Chem. Rev. 112: 3550. (b) Dubrovskiy, A.V., Markina, N.A., and Larock,
R.C. (2013). Org. Biomol. Chem. 11: 191. (c) Yoshida, S. and Hosoya, T. (2015).
Chem. Lett. 44: 1450. (d) Goetz, A.E., Shah, T.K., and Garg, N.K. (2015). Chem.
Commun. 51: 34. (e) García-López, J.-A. and Greaney, M.F. (2016). Chem. Soc.
Rev. 45: 6766. (f) Shi, J., Li, Y., and Li, Y. (2017). Chem. Soc. Rev. 46: 1707. (g)
Idiris, F.I.M. and Jones, C.R. (2017). Org. Biomol. Chem. 15: 9044. (h) Roy, T.
and Biju, A.T. (2018). Chem. Commun. 54: 2580. (i) Yoshida, S. (2018). Bull.
Chem. Soc. Jpn. 91: 1293. (j) Matsuzawa, T., Yoshida, S., and Hosoya, T. (2018).
Tetrahedron Lett. 59: 4197. (k) Takikawa, H., Nishii, A., Sakai, T., and Suzuki,
K. (2018). Chem. Soc. Rev. 47: 8030.
3 (a) Kessar, S.V. (1992). Chap. 2.3: Nucleophilic coupling with arynes. In: Comprehensive Organic Synthesis: Additions to and Substitutions at C—C π-Bonds,
vol. 4 (eds. B.M. Trost, M.F. Semmelhack and I. Fleming), 483–516. Pergamon.
References
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(b) Hoffman, R., Imamura, A., and Hehre, W.J. (1968). J. Am. Chem. Soc. 90:
1499.
(a) Wotiz, J.H. and Huba, F. (1959). J. Org. Chem. 24: 595. (b) de Graaff, G.B.R.,
den Hertog, H.J., and Melger, W.C. (1965). Tetrahedron Lett. 6: 963.
Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett. 12: 1211.
(a) Liu, Z. and Larock, R.C. (2003). Org. Lett. 5: 4673. (b) Liu, Z. and Larock,
R.C. (2006). J. Org. Chem. 71: 3198.
Ikawa, T., Nishiyama, T., Shigeta, T. et al. (2011). Angew. Chem. Int. Ed. 50:
5674.
Medina, J.M., Mackey, J.L., Garg, N.K., and Houk, K.N. (2014). J. Am. Chem.
Soc. 136: 15798.
(a) Yoshida, S., Nakamura, Y., Uchida, K. et al. (2016). Org. Lett. 18: 6212. (b)
Nakamura, Y., Miyata, Y., Uchida, K. et al. (2019). Org. Lett. 21: 5252.
(a) Yoshida, S., Uchida, K., Igawa, K. et al. (2014). Chem. Commun. 50: 15059.
(b) Ikawa, T., Kaneko, H., Masuda, S. et al. (2015). Org. Biomol. Chem. 13:
520. (c) Shi, J., Qiu, D., Wang, J. et al. (2015). J. Am. Chem. Soc. 137: 5670. (d)
Uchida, K., Yoshida, S., and Hosoya, T. (2016). Synthesis 48: 4099.
(a) Hamura, T., Ibusuki, Y., Sato, K. et al. (2003). Org. Lett. 5: 3551. (b)
Bronner, S.M., Bahnck, K.B., and Garg, N.K. (2009). Org. Lett. 11: 1007. (c)
Cheong, P.H.-Y., Paton, R.S., Bronner, S.M. et al. (2010). J. Am. Chem. Soc. 132:
1267. (d) Im, G.-Y.J., Bronner, S.M., Goetz, A.E. et al. (2010). J. Am. Chem. Soc.
132: 17933. (e) Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). J. Am. Chem.
Soc. 133: 3832. (f) Goetz, A.E., Bronner, S.M., Cisneros, J.D. et al. (2012).
Angew. Chem. Int. Ed. 51: 2758. (g) Goetz, A.E. and Garg, N.K. (2013). Nat.
Chem. 5: 54.
McAusland, D., Seo, S., Pintori, D.G. et al. (2011). Org. Lett. 13: 3667.
Cheng, B., Bao, B., Chen, Y. et al. (2017). Org. Chem. Front. 4: 1636.
Yao, T. (2015). Tetrahedron Lett. 56: 4623.
Bhojgude, S.S., Kaicharla, T., and Biju, A.T. (2013). Org. Lett. 15: 5452.
Hirsch, M., Dhara, S., and Diesendruck, C.E. (2016). Org. Lett. 18: 980.
Yoshida, S., Shimizu, K., Uchida, K. et al. (2017). Chem. Eur. J. 23: 15332.
Pal, K.B., Mahanti, M., and Nilsson, U.J. (2018). Org. Lett. 20: 616.
Zhang, L., Geng, Y., and Jin, Z. (2016). J. Org. Chem. 81: 3542.
Cheng, B., Wei, J., Zu, B. et al. (2017). J. Org. Chem. 82: 9410.
Aithagani, S.K., Dara, S., Munagala, G. et al. (2015). Org. Lett. 17: 5547.
Yoshida, S., Nakajima, H., Uchida, K. et al. (2017). Chem. Lett. 46: 77.
(a) Sapountzis, I., Lin, W., Fischer, M., and Knochel, P. (2004). Angew. Chem.
Int. Ed. 43: 4364. (b) Lin, W., Sapountzis, I., and Knochel, P. (2005). Angew.
Chem. Int. Ed. 44: 4258. (c) Lin, W., Ilgen, F., and Knochel, P. (2006). Tetrahedron Lett. 47: 1941.
García-López, J.-A., Çetin, M., and Greaney, M.F. (2015). Angew. Chem. Int. Ed.
54: 2156.
Yoshida, H., Shirakawa, E., Honda, Y., and Hiyama, T. (2002). Angew. Chem.
Int. Ed. 41: 3247.
Liu, Z. and Larock, R.C. (2005). J. Am. Chem. Soc. 127: 13112.
145
146
4 Recent Insertion Reactions of Aryne Intermediates
27 Pintori, D.G. and Greaney, M.F. (2010). Org. Lett. 12: 168.
28 Zhao, J. and Larock, R.C. (2007). J. Org. Chem. 72: 583.
29 Wright, A.C., Haley, C.K., Lapointe, G., and Stoltz, B.M. (2016). Org. Lett. 18:
2793.
30 Rao, B. and Zeng, X. (2014). Org. Lett. 16: 314.
31 Gilmore, C.D., Allan, K.M., and Stoltz, B.M. (2008). J. Am. Chem. Soc. 130:
1558.
32 Dubrovskiy, A.V. and Larock, R.C. (2012). J. Org. Chem. 77: 11232.
33 Hong, D., Chen, Z., Lin, X., and Wang, Y. (2010). Org. Lett. 12: 4608.
34 Wang, Y., Zheng, L., and Hoye, T.R. (2018). Org. Lett. 20: 7145.
35 Yoshida, S., Yano, T., Misawa, Y. et al. (2015). J. Am. Chem. Soc. 137: 14071.
36 Gaykar, R.N., Bhattacharjee, S., and Biju, A.T. (2019). Org. Lett. 21: 737.
37 Shen, C., Yang, G., and Zhang, W. (2013). Org. Lett. 15: 5722.
38 Lopez-Leonardo, C., Raja, R., López-Ortiz, F. et al. (2014). Eur. J. Org. Chem.:
1084.
39 (a) Hendrick, C.E., McDonald, S.L., and Wang, Q. (2013). Org. Lett. 15: 3444.
(b) Hendrick, C.E. and Wang, Q. (2014). J. Org. Chem. 80: 1059.
40 Yoshida, H., Minabe, T., Ohshita, J., and Kunai, A. (2005). Chem. Commun.:
3454.
41 Mesgar, M., Nguyen-Le, J., and Daugulis, O. (2018). J. Am. Chem. Soc. 140:
13703.
42 Hart, H., Harada, K., and Du, C.J.F. (1985). J. Org. Chem. 50: 3104.
43 Diemer, V., Begaud, M., Leroux, F.R., and Colobert, F. (2011). Eur. J. Org.
Chem.: 341.
44 Berthelot-Bréhier, A., Panossian, A., Colobert, F., and Leroux, F.R. (2015). Org.
Chem. Front. 2: 634.
45 Diemer, V., Berthelot, A., Bayardon, J. et al. (2012). J. Org. Chem. 77: 6117.
46 Hayes, D.M. and Hoffmann, R. (1972). J. Phys. Chem. 76: 656.
47 (a) Wasserman, H.H. and Solodar, J. (1965). J. Am. Chem. Soc. 87: 4002. (b)
Stevens, R.V. and Bisacchi, G.S. (1982). J. Org. Chem. 47: 2396.
48 (a) Hosoya, T., Hasegawa, T., Kuriyama, Y. et al. (1995). Synlett: 177. (b)
Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K. (1995). Tetrahedron
Lett. 36: 3377.
49 (a) Hamura, T., Ibusuki, Y., Uekusa, H. et al. (2006). J. Am. Chem. Soc. 128:
3534. (b) Hamura, T., Ibusuki, Y., Uekusa, H. et al. (2006). J. Am. Chem. Soc.
128: 10032. (c) Shinozaki, S., Hamura, T., Ibusuki, Y. et al. (2010). Angew.
Chem. Int. Ed. 49: 3026.
50 Feltenberger, J.B., Hayashi, R., Tang, Y. et al. (2009). Org. Lett. 11: 3666.
51 (a) Tambar, U.K. and Stoltz, B.M. (2005). J. Am. Chem. Soc. 127: 5340. (b)
Tadross, P.M., Virgil, S.C., and Stoltz, B.M. (2010). Org. Lett. 12: 1612. (c)
Tambar, U.K., Ebner, D.C., and Stoltz, B.M. (2006). J. Am. Chem. Soc. 128:
11752. (d) Tadross, P.M., Gilmore, C.D., Bugga, P. et al. (2010). Org. Lett. 12:
1224.
52 (a) Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Chem. Commun.: 3292. (b) Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005).
References
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
Chem. Lett. 34: 1538. (c) Yoshida, H., Watanabe, M., Ohshita, J., and Kinai, A.
(2005). Tetrahedron Lett. 46: 6729. (d) Yoshida, H., Kishida, T., Watanabe, M.,
and Ohshita, J. (2008). Chem. Commun.: 5963. (e) Yoshida, H., Morishita, T.,
and Ohshita, J. (2010). Chem. Lett. 39: 508. (f) Yoshida, H., Ito, Y., Yoshikawa,
Y. et al. (2011). Chem. Commun. 47: 8664.
Rao, B., Tang, J., Wei, Y., and Zeng, X. (2016). Chem. Asian J. 11: 991.
Samineni, R., Srihari, P., and Mehta, G. (2016). Org. Lett. 18: 2832.
Rao, B., Tang, J., and Zeng, X. (2016). Org. Lett. 18: 1678.
Kranthikumar, R., Chegondi, R., and Chandrasekhar, S. (2016). J. Org. Chem.
81: 2451.
(a) Okuma, K., Hirano, K., Tanabe, Y. et al. (2014). Chem. Lett. 43: 492. (b)
Okuma, K., Itoyama, R., Sou, A. et al. (2012). Chem. Commun. 48: 11145.
Kumar, A.S., Thirupathi, G., Reddy, G.S., and Ramachary, D.B. (2019). Chem.
Eur. J. 25: 1177.
Takikawa, H., Nishii, A., and Suzuki, K. (2016). Synthesis 48: 3331.
Hu, W., Zhang, C., Huang, J. et al. (2019). Org. Lett. 21: 941.
Yoshida, H., Watanabe, M., Morishita, T. et al. (2007). Chem. Commun.: 1505.
Huang, X. and Xue, J. (2007). J. Org. Chem. 72: 3965.
Liu, Y.-L., Liang, Y., Pi, S.-F., and Li, J.-H. (2009). J. Org. Chem. 74: 5691.
Ahire, M.M., Thoke, M.B., and Mhaske, S.B. (2018). Org. Lett. 20: 848.
Li, R., Wang, X., Wei, Z. et al. (2013). Org. Lett. 15: 4366.
Ła̧czkowski, K.Z., García, D., Peña, D. et al. (2011). Org. Lett. 13: 960.
Biju, A.T. and Glorius, F. (2010). Angew. Chem. Int. Ed. 49: 9761.
Ramtohul, Y.K. and Chartrand, A. (2007). Org. Lett. 9: 1029.
Dhokale, R.A., Thakare, P.R., and Mhaske, S.B. (2012). Org. Lett. 14: 3994.
Mohanan, K., Coquerel, Y., and Rodriguez, J. (2012). Org. Lett. 14: 4686.
Picazo, E., Anthony, S.M., Giroud, M. et al. (2018). J. Am. Chem. Soc. 140:
7605.
Gupta, E., Kant, R., and Mohanan, K. (2017). Org. Lett. 19: 6016.
(a) Liu, Z. and Larock, R.C. (2004). Org. Lett. 6: 99. (b) Zhao, J. and Larock,
R.C. (2005). Org. Lett. 7: 4273. (c) Dubrovskiy, A.V. and Larock, R.C. (2010).
Org. Lett. 12: 3117. (d) Lu, C., Dubrovskiy, A.V., and Larock, R.C. (2012).
Tetrahedron Lett. 53: 2202. (e) Dubrovskiy, A.V. and Larock, R.C. (2013). Tetrahedron 69: 2789.
Li, Y. and Studer, A. (2017). Org. Lett. 19: 666.
Li, X., Sun, Y., Huang, X. et al. (2017). Org. Lett. 19: 838.
Matsuzawa, T., Uchida, K., Yoshida, S., and Hosoya, T. (2017). Org. Lett. 19:
5521.
Chakrabarty, S., Chatterjee, I., Tebben, L., and Studer, A. (2013). Angew. Chem.
Int. Ed. 52: 2968.
Chen, Z. and Wang, Q. (2015). Org. Lett. 17: 6130.
Hoye, T.R., Baire, B., Niu, D. et al. (2012). Nature 490: 208.
Yoshida, S., Nagai, A., Uchida, K., and Hosoya, T. (2017). Chem. Lett. 46: 733.
Pandya, V.G. and Mhaske, S.B. (2014). Org. Lett. 16: 3836.
147
148
4 Recent Insertion Reactions of Aryne Intermediates
82 Sumii, Y., Sugita, Y., Tokunaga, E., and Shibata, N. (2018). Chemistry Open 7:
204.
83 Nakayama, J., Fujita, T., and Hoshino, M. (1983). Chem. Lett. 12: 249.
84 Zhang, L., Li, X., Sun, Y. et al. (2017). Org. Biomol. Chem. 15: 7181.
85 Li, Y., Mück-Lichtenfeld, C., and Studer, A. (2016). Angew. Chem. Int. Ed. 55:
14435.
86 Chen, Y. and Willis, M.C. (2015). Org. Lett. 17: 4786.
87 Pawliczek, M., Garve, L.K.B., and Werz, D.B. (2015). Chem. Commun. 51: 9165.
88 Toledo, F.T., Marques, H., Comasseto, J.V., and Raminelli, C. (2007). Tetrahedron Lett. 48: 8125.
89 Mesgar, M. and Daugulis, O. (2017). Org. Lett. 19: 4247.
90 Yoshida, H., Terayama, T., Ohshita, J., and Kunai, A. (2004). Chem. Commun.:
1980.
91 Chen, J., Murafuji, T., and Tsunashima, R. (2011). Organometallics 30: 4532.
92 Alajarin, M., Lopez-Leonardo, C., Raja, R., and Orenes, R.-A. (2011). Org. Lett.
13: 5668.
93 Rao, U.N. and Biehl, E. (2002). J. Org. Chem. 67: 3409.
94 Palani, V., Chen, J., and Hoye, T.R. (2016). Org. Lett. 18: 6312.
95 Okuma, K., Shiki, K., and Shioji, K. (1998). Chem. Lett. 27: 79.
96 Bayardon, J., Laureano, H., Diemer, V. et al. (2012). J. Org. Chem. 77: 5759.
97 Yoshida, S. and Hosoya, T. (2013). Chem. Lett. 42: 583.
98 Dhokale, R.A. and Mhaske, S.B. (2013). Org. Lett. 15: 2218.
99 Chen, Q., Yan, X., Du, Z. et al. (2016). J. Org. Chem. 81: 276.
100 Li, Y., Chakrabarty, S., Mück-Lichtenfeld, C., and Studer, A. (2016). Angew.
Chem. Int. Ed. 55: 802.
101 Okugawa, Y., Hayashi, Y., Kawauchi, S. et al. (2018). Org. Lett. 20: 3670.
102 Nagashima, Y., Takita, R., Yoshida, K. et al. (2013). J. Am. Chem. Soc. 135:
18730.
103 Rodríguez-Lojo, D., Cobas, A., Peña, D. et al. (2012). Org. Lett. 14: 1363.
104 (a) Yoshida, H., Mimura, Y., Ohshita, J., and Kunai, A. (2007). Chem. Commun.: 2405. (b) Yoshida, H., Mimura, Y., and Ohshita, J. (2009). Chem. Lett. 38:
1132.
149
5
Multicomponent Reactions Involving Arynes and Related
Chemistry
Hiroto Yoshida
Hiroshima University, Graduate School of Advanced Science and Engineering, Higashi-Hiroshima 739-8526,
Japan
5.1 Introduction
Multicomponent reactions enable three or more starting materials to be put together
generally in one chemical step in one pot; a wide range of organic molecules become
readily accessible, as compared with conventional two-component, multistep reactions, with higher molecular diversity, structural complexity, and synthetic
convenience, verifying their outstanding significance in chemical synthesis [1].
Arynes, one of the most representative reactive intermediates in organic chemistry
[2], have been demonstrated to serve as a useful and reliable component in multicomponent reactions, thus leading to direct formation of multisubstituted arenes
and benzo-annulated structures in a selective manner, despite their highly reactive
and transient characters. In particular, this field has experienced remarkable
progress in the last 15 years, triggered mainly by the use of a combination of
2-(trimethylsilyl)aryl triflates with a fluoride ion for generating arynes (Kobayashi’s
method) [3]. With Kobayashi’s method, arynes can be generated at a moderate
temperature and pace under neutral conditions, being compatible with a wide
variety of functionalized reagents, thus expanding considerably reaction patterns
and accessible products in the aryne-based multicomponent reactions. This chapter
aims to summarize the recent advance in the transition metal-free multicomponent
reactions of arynes based upon their highly electrophilic character, focusing on
those reported during the last five years; the previous results published before 2013
have been thoroughly collected in Chapter 4.9 of Ref. [4]’s book and Chapter 3 of
Ref. [4]’s book and review articles [2, 4]. Because the concept of “multicomponent
reaction” covers vast scale of examples, this chapter will not include transition
metal-catalyzed reactions and reactions via hexadehydro Diels–Alder (HDDA)
route, which will be individually discussed in Chapters 6 and 10.
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
150
5 Multicomponent Reactions Involving Arynes and Related Chemistry
5.2 Classification of Multicomponent Reactions
The multicomponent reactions of arynes, discussed in this chapter, are mainly triggered by addition of neutral nucleophiles, and can basically be classified into three
categories depending on reaction modes (Scheme 5.1).
1) An initially formed zwitterion is directly trapped by an electrophile (El) to afford
1,2-disubstituted arenes. The reaction often includes cyclization depending
upon the structures of nucleophile/electrophile, resulting in the formation of
benzo-annulated heterocycles.
2) An initially formed zwitterion first interacts with a pronucleophile (X–Nu′ ); a
generated nucleophile (Nu′– ) then reacts with an electrophilic site (Nu+ ) to afford
products.
3) A formal [2+2] cycloaddition between an aryne and a nucleophilic–electrophilic
double bond (Nu=El) provides a benzocyclobutene species. It then undergoes
4π-electrocyclization (ring-opening) to give an ortho-quinoid intermediate,
which is finally trapped by a third component.
Nu
El
(1)
El
Nu
Nu
X
Nu’
Nu
Nu′
(2)
X = H, halogen
Nu
El
Nu
X
Nu
Nu
(3)
El
Scheme 5.1
El
El
Classification of multicomponent reactions involving arynes.
5.3 Carbon Nucleophile–Based Multicomponent
Reactions
5.3.1
Isocyanide
Since Yoshida first developed the three-component reaction of arynes, isocyanides,
and aldehydes [5], that produced benzo-annulated O-heterocycles, isocyanides
have continued to be convenient and useful nucleophiles for multicomponent
reactions of arynes. A zwitterion (1) is a common intermediate, and Biju reported
that this intermediate could be trapped by atmospheric pressure of CO2 to provide
5.3 Carbon Nucleophile–Based Multicomponent Reactions
phthalimide derivatives 3 (Scheme 5.2) [6]. As shown in Scheme 5.2, CO2 reacts
with zwitterion 1 to afford a tentative product (2), which is facilely converted into
3 by fluoride ion–induced rearrangement. A similar three-component synthesis
of phthalimides was later disclosed by Wang and Ji (Scheme 5.3) [7]; various
arylisocyanides smoothly gave the respective products under their conditions
(KF/18-crown-6 in THF), while the reaction with alkylisocyanides became sluggish,
being in sharp contrast to Biju’s results (conditions: CsF in MeCN).
O
TMS
+ R2NC
R1
OTf
+ CO2
1 atm
CsF
NR2
R1
MeCN, 30 °C
3 O
38–87%
2
R = alkyl, aryl
R1
O
R2NC
NR2
F
R1
NR2
R1
O
1
CO2
NR2
NR2
R1
R1
O
O
F–
O
2 O
Scheme 5.2 Three-component reaction of arynes, isocyanides, and CO2 . Source: Based on
Kaicharla et al. [6].
O
TMS
+ R2NC
R1
OTf
+ CO2
1 atm
R2 = aryl, benzyl
KF, 18-crown-6
R1
NR2
THF, 40 °C
3 O
30–71%
Scheme 5.3 Three-component reaction of arynes, isocyanides, and CO2 . Source: Based on
Fang et al. [7].
Biju also demonstrated that water could serve as a pronucleophile for capturing
zwitterion 1, resulting in the direct formation of diverse amides (4) (Scheme 5.4)
151
152
5 Multicomponent Reactions Involving Arynes and Related Chemistry
[6]. The proposed reaction pathway was confirmed by the deuterium incorporation
reaction using D2 O (Scheme 5.5), and Pirali applied this system to the synthesis of
α-aroylamino amides (5) using α-isocyanoacetamides as a nucleophile (Scheme 5.6)
[8]. The synthetic utility of the reaction was exemplified by the total synthesis of
proglumide 6, a cholecystokinin antagonist used in the treatment of stomach ulcers.
O
TMS
+ R2NC
R1
KF, 18-crown-6
+ H2O
NHR2
R1
THF, 30 °C
OTf
H
4
26–92%
R2 = alkyl, aryl
NR2
NR2
H2O
R1
OH–
R1
H
1
Scheme 5.4 Three-component reaction of arynes, isocyanides, and H2 O. Source: Based on
Kaicharla et al. [6].
O
TMS
+ t-BuNC
KF, 18-crown-6
+ D2O
THF, 30 °C
84%
OTf
Scheme 5.5
D
ND t-Bu
83% D
84% D
Deuterium incorporation reaction using D2 O.
R1
2 3
+
NR R
CN
OTf
+ H2O
THF, 60 °C
O
N
H
R1
H
5
52–76%
THF, 60 °C
68%
+
NPr2
CN
O
O
CO2H
1. H2O, KF, 18-crown-6
CO2Bn
TMS
NR2R3
KF, 18-crown-6
R2, R3 = alkyl, benzyl
R4 = alkyl, benzyl
OTf
R4
O
R4
TMS
O
N
H
2. H2, Pd/C, MeOH
95%
H
NPr2
O
6
Scheme 5.6 Three-component reaction of arynes, α-isocyanoacetamides, and H2 O. Source:
Based on Serafini et al. [8].
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
5.3.2
Active Methylene Compounds
Insertion reaction of arynes into a C(methylene)—C(EWG) bond of active methylene compounds was well established by Stoltz [9] and Yoshida [10], and the insertion followed by formal [4+2] cycloaddition by use of methyl 3-phenylpropiolates
was reported by Shu and Wu (Scheme 5.7) [11]. Various multisubstituted naphthalenes (7 and 8) were straightforwardly accessible by the three-component reaction with aroylacetonitriles or diaroylmethanes; the aroyl group at the α position of
8, in the latter case, was lacking via elimination (ArCO2 – )–aromatization process as
described in Scheme 5.8.
CN
Ar2
R1
CO2Me
Ar1
TMS
R1
+
OTf
Ar1
7 (EWG = CN)
51–82%
CO2Me
O
EWG
CsF, Cs2CO3
+
MeCN, 80 °C
Ar2
Ar2
R
1
CO2Me
Ar1
8 (EWG = C(O)Ar1)
48–84%
Scheme 5.7 Three-component reaction of arynes, active methylene compounds, and
electron-deficient alkynes. Source: Based on Shu et al. [11].
The same group also developed formal [2+2+2] cycloaddition of arynes, active
methylene compounds, and acetylene dicarboxylates, which gave multisubstituted
naphthalenes (9) (Scheme 5.9) [12]. The difference in the reaction modes between
this and the above may be attributable to the different electrophilicity of alkynoates
employed, and an acetylene dicarboxylate first accepts nucleophilic attack by an
anion of an active methylene compound to forma 1,4-dipole (10), which then
undergoes formal [4+2] cycloaddition with an aryne to afford the final product
(Scheme 5.10).
5.4 Nitrogen Nucleophile–Based Multicomponent
Reactions
5.4.1
Amine
Aziridines bearing a carbonyl substituent at the 2-position were found to be added to
arynes to generate zwitterion 11, which were convertible into α-fluoro-β-amino acid
derivatives (12) through ring opening with a fluoride (Scheme 5.11) [13]. A proton
153
154
5 Multicomponent Reactions Involving Arynes and Related Chemistry
+
O
EWG
Ar1
EWG
EWG = C(O)Ar1
EWG = CN
O
CO2Me
CO2Me
Ar1
Ar2
Ar2
Ar1
CN
Ar2
HO
O
Ar 2
O–
CO2Me
CO2Me
Ar1
Ar1
Ar1
7
O–
Ar 2
O
CO2Me
Ar1
– Ar1CO2–
8
Scheme 5.8 Reaction pathways for three-component reaction of arynes, active methylene
compounds, and electron-deficient alkynes.
TMS
R1
+
OTf
O
R2
R2
CO2Me
EWG
CsF
+
MeCN, 80 °C
CO2Me
R2 = alkyl, aryl
EWG = C(O)R, CO2R, CN
EWG
R1
CO2Me
CO2Me
9
52–89%
Scheme 5.9 Three-component reaction of arynes, active methylene compounds, and
acetylene dicarboxylate. Source: Based on Shu et al. [12].
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
CO2Me
R2
O
CO2Me
EWG
R2
–O
EWG
O
R2
EWG
9
CO2Me
CO2Me
CO2Me
CO2Me
10
Scheme 5.10 A reaction pathway for three-component reaction of arynes, active
methylene compounds, and acetylene dicarboxylate.
source, H2 O, which captures the aryl anion moiety in 11, is necessary for the reaction
to proceed, and thus the use of hydrated TBAF as a fluoride source is the key to the
successful transformation.
TMS
R1
+
OTf
R3
N
O
TBAF•3H2O
R2
THF, rt
R3
N
R1
F
O
R2
H
12
53–92%
R2 = alkoxy, alkyl
R3 = alkyl, benzyl
F–
R3
N
R1
O
R2
11
R3
H2O
N
R1
H
O
R2
Scheme 5.11 Four-component reaction of arynes, aziridines, H2 O, and a fluoride. Source:
Based on Tang et al. [13].
Biju reported that aziridine-derived zwitterion 11 could also be transformed into
ring-opened three-component products (13 and 14) using carboxylic acids or phenols as pronucleophiles (Scheme 5.12) [14]. The reaction was applicable to azetidines
to produce γ-amino alcohol derivatives, and furthermore, the use of water in combination with trifluoroacetic acid led to a similar three-component reaction, where in
situ–generated trifluoroacetate ion acts as an actual nucleophile toward aziridinium
cation (Scheme 5.13) [15].
Aziridines with an electron-withdrawing functionality (CN or CO2 R) were found
to undergo unique three-component reaction with arynes and aldehydes (or isatins)
to provide amino epoxides (16) in a stereoselective manner (Scheme 5.14) [16]. An
initially formed zwitterion (11) is not directly trapped by an aldehyde, but is converted into an aziridinium ylide (15) via proton transfer, which is finally trapped by
an aldehyde to give epoxide 16.
155
156
5 Multicomponent Reactions Involving Arynes and Related Chemistry
R3
N
R1
OTf
13
26–88%
KF, 18-crown-6
n
R2
+
R4
H
R4
HO
R3
+
N
O
O
n
R1
O
TMS
R2
or
THF, –10 °C to rt
R3
N
HO Ar
n = 1, 2
R2 = aryl, CO2Et
R3 = alkyl, benzyl
R4 = alkyl, aryl
R2
O
R1
Ar
H
14
57–60%
Scheme 5.12 Three-component reaction of arynes, aziridines, and carboxylic
acids/phenols. Source: Based on Roy et al. [14].
TMS
R1
R3
+
N
OTf
+
R2
R3
N
CF3CO2H
KF, 18-crown-6
H2O
R2
OH
R1
THF, –10 to 30 °C
H
2
48–91%
R = aryl, CH2OH
R3 = alkyl, benzyl
H2O
hydrolysis
CF3CO2–
R3
N
R2
R1
R3
CF3CO2H
N
R1
R3
N
R2
R2
OC(O)CF3
R1
H
H
Scheme 5.13 Three-component reaction of arynes, aziridines, and trifluoroacetic acid.
Source: Based on Roy et al. [15].
TMS
R1
R2
+ N
OTf
EWG
+
O
R3
R1
KF, 18-crown-6
H
R2
N
O
GWE
16
55–75%
EWG = CN, CO2R
R2 = alkyl, benzyl
R3 = alkyl, aryl
O
R2
R2
N
R1
H
11
EWG
N
R1
H
R3
THF, 30 °C
EWG
R3
O
R2
H
R1
N
R3
EWG
15
Scheme 5.14 Three-component reaction of arynes, aziridines, and aldehydes. Source:
Based on Roy et al. [16].
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
Three-component reaction with cyclic amines accompanied by their ring opening
was also achieved by using DABCO, where various thiols served as an effective
pronucleophile for capturing zwitterion 17 (Scheme 5.15) [17]. A variety of
N-alkyl-N′ -aryl piperazines (18) were straightforwardly accessible in good yields,
and structurally related quinuclidine could participate in the reaction.
TMS
R1
N
+
OTf
+
R2SH
N
N
CsF
MeCN, 100 °C
SR2
N
R1
H
18
45–93%
R2 = alkyl, aryl
R2S–
N
N
R2SH
N
N
R1
R1
H
17
SPh
N
N
H 98%
Scheme 5.15 Three-component reaction of arynes, DABCO, and thiols. Source: Based on
Min et al. [17].
Biju disclosed that zwitterion 19 arising from nucleophilic attack of N,N-dialkylanilines were readily coupled with aldehydes or activated ketones (isatins or trifluoroacetophenone) to afford 21 (Scheme 5.16) [18]. The reaction proceeds through
intramolecular migration of an aryl group from nitrogen to oxygen in intermediate
20, being similar to the process of the Smiles rearrangement.
A similar three-component reaction was found to also take place by employing
an atmospheric pressure of CO2 for trapping the zwitterion (19) [19]; the aryl
migration from nitrogen to oxygen likewise occurs to provide aryl benzoates (22)
insofar as the aryl group possesses an electron-withdrawing substituent at the
para-position (Scheme 5.17). In marked contrast, the reaction with electron-rich and
-neutral N,N-dialkylanilines experienced alkyl migration, furnishing solely alkyl
benzoates (23).
Okuma extended the above methodology to direct synthesis of nine- and
ten-membered dibenzo-N,O-heterocycles (24 and 25) through the SN Ar pathway by
use of N-methylindoline or N-methyltetrahydroquinoline as a nitrogen nucleophile
and aldehydes as an electrophile (Scheme 5.18) [20].
Recently, Kim reported that an atmospheric pressure of sulfuryl fluoride serves
as a good electrophile in the reaction with arynes and secondary amines, resulting
157
158
5 Multicomponent Reactions Involving Arynes and Related Chemistry
R2
TMS
R1
N
+
O
+
R′
Ar
OTf
R2
N
R2
KF, 18-crown-6
R′′
R1
THF
R2
O
Ar
R’ R”
R2 = alkyl
21
SNAr
O
R2 R 2
N
R′
R1
R2 R2
N
R′′
R1
Ar
Ar
O–
R’
19
Aldehyde
Trifluoroacetophenone
Isatin
R2
N
R1
R2
Me
N
Me
O
Ar
O
R1
O
Ar
R’
Me
N
Me
O
Ph
NR′
R′′
R′ = alkyl, aryl
26–87%
R”
20
R′ = Me, Bn
R′′ = H, F, Br
55–74%
CF3
62%
Scheme 5.16 Three-component reaction of arynes, anilines, and carbonyl compounds.
Source: Based on Bhojgude et al. [18].
NMe2
R1
O
O
R2
TMS
R1
OTf
+
Me2
N
CO2 (1 atm)
KF, 18-crown-6
THF
NMe2
R2
R1
22
R2 = 4-CO2Et, 4-CF3, 4-CN,...
58–75%
R2
O–
O
via
R2
Me2
N
19
Scheme 5.17
NMe
R2
R1
R1
O
O
Me
23
R2 = H, 4-Me, 4-F, 3-Br, 2-CO2Et...
56–94%
Three-component reaction of arynes, anilines, and CO2.
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
Me
N
O
Ar
24
52–69%
N
Me
TMS
O
+
OTf
Ar
+
or
H
CsF, 18-crown-6
THF, Reflux
Me
N
N
Me
O
Ar
25
36–59%
Scheme 5.18 Three-component reaction of arynes, N-heterocycles, and aldehydes. Source:
Based on Okuma et al. [20].
in the formation of 2-amino-substituted arenesulfonyl fluorides (26) in good yields
(Scheme 5.19) [21]. A variety of dialkyl-, alkylaryl-, and diarylamines were convertible into the respective products, and furthermore, the reaction was applicable to
other nucleophiles, including tert-butylisocyanide and triphenylphosphine.
TMS
R1
+ R2R3NH +
OTf
SO2F2
1 atm
KF, 18-crown-6
THF, –10 °C
NR2R3
R1
SO2F
26
35–90%
R2, R3 = alkyl, aryl
O
t-BuNC
NHt-Bu
SO2F
67%
PPh3
PPh3
OTf–
SO2F
75%
Scheme 5.19 Three-component reaction using arynes and sulfuryl fluoride. Source: Based
on Kwon et al. [21].
5.4.2
Imine
A multicomponent reaction by use of imines as nucleophiles was first developed
by Yoshida [22], where an initially formed zwitterion (27) was captured by CO2
to give benzoxazinone derivatives. In 2017, Tian reported that 27 could smoothly
react with such pronucleophiles as chloroform, acetonitrile, and methyl propiolate,
affording a variety of functionalized tertiary amines (28) (Scheme 5.20) [23].
N-Aryl-2,2,2-trichloroethanamine is the common molecular structure obtained
with chloroform; however, it further undergoes elimination of HCl, when the
aryl moiety contains an electron-withdrawing group, leading to the formation of
N-aryl-2,2-dichloroethenamine 29 (Scheme 5.21).
159
160
5 Multicomponent Reactions Involving Arynes and Related Chemistry
TMS
R1
+
OTf
R3
N
NR3
R2
+
R3
N
CsF
H–Nu
R1
MeCN, 65 °C
H
28
R2
R1
H–Nu
Acetonitrile
R3
R2
N
R1
H
CCl3
Me
N
H
R2, R3 = alkyl, aryl
51–85%
Nu
R3
N
R2
H
Nu–
R1
27
Chloroform
R2
Methyl propiolate
Me
N
Cy
CH2CN
H
59%
Cy
C CCO2Me
54%
Scheme 5.20 Three-component reaction of arynes, imines, and pronucleophiles. Source:
Based on Xu et al. [23].
TMS
OTf
+
R
NMe
CsF
R
MeCN, 65 °C
+
HCCl3
Scheme 5.21
R
Me
N
H
CCl3
Me
N
–HCl
CCl2
H
29
R = 4-CF3, 4-CN, 4-SO2Me,
4-NO2, 3-NO2
40–64%
Three-component reaction of arynes, imines, and chloroform.
A quite similar three-component reaction with oxazoline and chloroform
was developed by Peng (Scheme 5.22) [24], and moreover, Tian and Yu first
demonstrated that carbon tetrachloride could act as a pronucleophile for the
three-component reaction with arynes and imines (or N-heteroarenes, see Section
5.4.3) [25]. In the latter reaction, the aryl anion moiety of zwitterion 27 attacks the
chlorine atom of carbon tetrachloride to give product 30 accompanied by Ar—Cl
bond-forming process (Scheme 5.23).
In contrast to the results above, imines having a –CH2 CO2 Me substituent on
the nitrogen atom were reported to generate readily azomethine ylides (32) from
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
R3
R3
TMS
R1
+
N
OTf
KF, 18-crown-6
O
HCCl3, 60 °C
R1
R2
H
R2 = alkyl, aryl
R3 = alkyl, aryl, benzyl
Scheme 5.22
O
N
R2
CCl3
16–85%
>67:33 dr
Three-component reaction of arynes, oxazolines, and chloroform.
NR3
TMS
R1
+
+
R2
OTf
R3
N
CsF
CCl4
MeCN, 65 °C
R1
R2, R3 = alkyl, aryl
R3
N
R2
Cl–CCl3
R1
Scheme 5.23
CCl3
Cl
30
40–95%
R3
N
R2
Cl
CCl3–
R1
27
R2
Three-component reaction of arynes, imines, and carbon tetrachloride.
initially formed zwitterions (31) upon treatment with arynes via proton transfer, and
the resulting azomethine ylides (32) were transformable to multisubstituted pyrrolidines (33) stereoselectively by [3+2] cycloaddition with electron-deficient alkenes,
including methyl vinyl ketone, acrylonitrile, and dimethyl maleate (Scheme 5.24)
[26].
TMS
N
+
OTf
R3
R1
R1 = H, Me, OMe, F
N
R1
CO2Me +
R2
CsF
MeCN, 25 °C
R1
R2 = C(O)Me, R3 = H
R2 = CN, R3 = H
R2 = R3 = CO2Me
N
Ph
33
73–88%
[3+2]
N
CO2Me
R1
31
R3
R2
R2
CO2Me
R3
CO2Me
H
32
Scheme 5.24 Three-component reaction of arynes, imines, and electron-deficient alkenes.
Source: Based on Swain et al. [26].
161
162
5 Multicomponent Reactions Involving Arynes and Related Chemistry
R
N
+
•
NR
34
RN • NR
Scheme 5.25
NR
NR
35
•
NR
36
NR
Reaction of arynes with carbodiimides.
Carbodiimides, having cumulative C=N double bonds, were found to be converted into benzoazetine derivatives (35) by formal [2+2] cycloaddition with arynes
probably through zwitterionic intermediates (34) (Scheme 5.25), as were the cases
with imines [27]. The resulting nitrogen four-membered ring then underwent
4π-electrocyclic ring opening to give aza-ortho-quinone methides (36), which were
demonstrated to serve as key intermediates in multicomponent reactions with
pronucleophiles. In 2014, Zhang disclosed that 36 could be trapped by terminal
alkynes to provide alkynylimine derivatives (38) with dual incorporation of arynes
(Scheme 5.26) [28]. The formation of 38 can be rationally explained by N-arylation
of the aniline moiety in primarily generated 37, arising from the capture of 36 with
terminal alkynes. The reaction was also applicable to bromo- and iodoalkynes to
give similar products, although the reaction pathway is unclear.
NR2
R3
TMS
R1
KF, 18-crown-6
+ R2N • NR2 +
R1
THF, rt
OTf
R3
NR2
H
2
R = alkyl
R3 = alkyl, aryl, Bz
R1
38
65–95%
N-arylation
R3
•
NR
NR2
2
R1
R1
NR2
H
37
NR2
36
R3
Ni-Pr
R3
R3
Ni-Pr
X
X
X = Br, I
58–71%
Scheme 5.26 Three-component reaction of arynes, carbodiimides, and alkynes. Source:
Based on Zhou et al. [28].
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions
Water and alcohols were effective pronucleophiles for trapping the carbodiimidederived aza-ortho-quinone methide (36), resulting in the direct formation of amides
(39) and imidates (40), respectively (Scheme 5.27) [29]; two molar amounts of arynes
were incorporated into the final products also in this case.
NHR2
O
R1
NR2
H2O
H
TMS
R1
OTf
+
R2
N •
NR2
CsF
MeCN, 80 °C
•
R1
39
35–77%
NR2
R1
NR2
NR2
36
R2 = alkyl
OR3
R1
R3OH
NR2
H
R3 = alkyl
R1
40
64–81%
Scheme 5.27 Three-component reaction of arynes, carbodiimides, and H2 O/alcohols.
Source: Based on Li et al. [29].
5.4.3
N-Heteroarene
Biju developed a three-component reaction with quinolines and aldehydes that produced various six-membered N,O-heterocycles (42) straightforwardly (Scheme 5.28)
[30], after his pioneering work on the three-component reaction using isoquinolines as N-heteroarene nucleophiles [31]. As was the case with an isoquinoline,
nucleophilic attack of a quinoline to an aryne triggers the reaction; an intermediary
formed zwitterion (41) is then trapped by an aldehyde to give 42. Under Biju’s
conditions (KF/18-crown-6 in THF, −10 ∘ C to rt), the diastereoselectivity was high
on the whole, and cis-isomers were generated preferentially. In addition, such
ketones as benzophenone, p-benzoquinone, and ethyl benzoylformate could also
participate in the reaction. Around the same time, Lei and Hu also reported the
reaction by use of quinolines and aldehydes [32], although the diastereoselectivity
was much lower than that of Biju’s results under their conditions (CsF in THF,
60 ∘ C).
Zwitterions (43 and 41) derived from isoquinolines or quinolines were demonstrated to be transformed into dearomatized trichloro-substituted products (44 and
163
164
5 Multicomponent Reactions Involving Arynes and Related Chemistry
Biju’s conditions
R1
TMS
+
OTf
+
N
O
R2
N
KF, 18-crown-6
H
H
THF, –10 °C to rt
O
H
R2
R1
42
47–96%
c >10:1 dr
R2 = alkyl, aryl
N
R1
41
Lei and Hu’s conditions
TMS
R1
+
OTf
+
N
O
R2
N
CsF
H
THF, 60 °C
H
O
H
R2
R1
R2
= alkyl, aryl
42
35–87%
cis:trans = c.1.2:1
Scheme 5.28 Three-component Reaction of arynes, quinolines, and aldehydes. Source:
Based on Bhunia et al. [30].
45) by employing chloroform as a pronucleophile (Scheme 5.29) [33]. Dichloro- and
dibromomethane could also act as a pronucleophile for capturing 43, and furthermore, the reaction with carbon tetrachloride proceeded in a similar fashion to that
with imines (see Section 5.4.2) to afford products 46 with concurrent construction
of the Ar—Cl bond (Scheme 5.30) [25]. It should be noted that acridine acted as a
nucleophile in the latter case, where an aryne and carbon tetrachloride were added
in 1,4-manner rather than usual 1,2-manner.
Dai and He disclosed that dialkoxyphosphites could be involved as a pronucleophile in the three-component reaction with quinolines or isoquinolines, giving rise
to dearomatized phosphonylated N-heterocycles (47) in good yields (Scheme 5.31)
[34]. Monophosphonylation took place exclusively with 1,10-phenanthrene, and
acridine underwent 1,4-addition to provide 48 and 49.
5.4.4
Diazene
Multicomponent access to cinnoline derivatives by the use of arynes, tosylhydrazine,
and α-bromoketones was reported by Wu [35]. A variety of α-bromoacetophenones
were convertible into the respective cinnolines (50) in a straightforward manner,
5.5 Oxygen Nucleophile–Based Multicomponent Reactions
R2
N
R2
N
CHCl3
R1
R1
R2 = H, aryl, NO2
MeO, halogen
R2
N
CCl3
H
44
70–97%
43
TMS
R1
CsF, MeCN, 70 °C
OTf
R2
R2
R2
N
R2 = H, Me, NO2
alkoxy, halogen
CH2X2
CHCl3
N
N
R1
R1
41
CCl3
H
45
40–95%
N
H
CHX2
X = Br, 52%, X = Cl, 50%
Scheme 5.29 Three-component reaction of arynes, N-heteroaromatics, and
pronucleophiles. Source: Based on Tan et al. [33].
and the actual nucleophile in the reaction is diazene generated in situ from tosylhydrazine (Scheme 5.32).
5.4.5
Nitrite
The highly electrophilic character of arynes allows even sodium nitrite to act as a
nucleophile, leading to a new method for nitrating an aromatic ring [36]. This concept was further extended to the three-component reaction; aromatic aldehydes were
suitable electrophiles in the reaction to produce 2-nitrobenzhydrols (51), although
the yields still remained moderate (Scheme 5.33).
5.5 Oxygen Nucleophile–Based Multicomponent
Reactions
5.5.1
Dimethylformamide
Since Miyabe [37] and Yoshida [38] developed the multicomponent reactions for
synthesizing benzo-annulated O-heterocycles, with a DMF-derived ortho-quinone
165
166
5 Multicomponent Reactions Involving Arynes and Related Chemistry
TMS
R2
R2
+
CsF
+ CCl4
OTf
N
MeCN, 65 °C
N
CCl3
Cl
46
57–82%
R2 = H, Me, Br
CCl3
N
N
Cl
77%
Scheme 5.30 Three-component reaction of arynes, N-heteroaromatics, and carbon
tetrachloride. Source: Based on Li et al. [25].
R2
TMS
R
+
R1
2
OTf
+
N
O
H P(OR3)2
KF, 18-crown-6
THF, rt
N
R1
H
O
47
55–90%
R2 = H, Me, MeO, halogen
R3 = alkyl, benzyl
N
P(OR3)2
N
N
O
P(OMe)2
N
(MeO)2 P
N
N
H
O H
48
70%
49
55%
Scheme 5.31 Three-component reaction of arynes, N-heteroaromatics, and dialkoxy
phosphites. Source: Based on Liu et al. [34].
5.5 Oxygen Nucleophile–Based Multicomponent Reactions
TMS
+ TsNHNH2 +
R1
OTf
O
Ar
Ar
CsF
Br
R1
MeCN, 90 °C
N
N
50
35–70%
–H2O
Br
H
Ar
R1
O
HN
Scheme 5.32
R1
NH
N
N
Three-component reaction of arynes, diazene, and 𝛼-bromoketones.
TMS
+ NaNO2 +
1
R
OTf
Scheme 5.33
OH
Ar
NO2
O
Ar
R1
KF, 18-crown-6
H
OH
THF, 0 °C
Ar
51
26–60%
Three-component reaction of arynes, sodium nitrite, and aldehydes.
methide, arising from formal [2+2] cycloaddition with arynes, this reactive intermediate has continued to be the key scaffold for the development of new multicomponent reactions. Similar to the above pioneering works, the ortho-quinone methide
(52) was found to undergo facilely [4+2] cycloaddition with acetylene dicarboxylates
to provide dimethylamino-4H-chromenes (53) in good yields (Scheme 5.34) [39].
CO2R2
TMS
CsF
+ DMF +
R1
OTf
CO2R2
O
R
1
CO2R2
25 °C
CO2R2
NMe2
53
59–85%
R2 = alkyl
CO2R2
[4 + 2]
CO2R2
O
R1
O
R1
NMe2
52
NMe2
Scheme 5.34 Three-component reaction of arynes, DMF, and acetylene dicarboxylates.
Source: Based on Yoshioka et al. [39].
Li reported that N,S-keteneacetals could serve as efficient dienophiles for trapping ortho-quinone methide 52 to afford diverse 2-aryliminochromenes (54) in high
167
168
5 Multicomponent Reactions Involving Arynes and Related Chemistry
yields (Scheme 5.35) [40]. An intermediary generated [4+2] cycloadduct from 52
and an N,S-keteneacetal is transformed into the final product via elimination of
dimethylamine and methyl mercaptan. A related three-component reaction with in
situ–generated sulfonyl allenes from 2-bromoallyl sulfones, which directly produced
3-(arylsulfonyl)-2H-chromene-2-ols (55), was disclosed by Gogoi (Scheme 5.36) [41].
TMS
O
+ DMF +
R1
R2
OTf
O
SMe
NHAr
NAr
R1
KF
R2
90 °C
54
62–96%
2
R = aryl, NHAr, NHBn
O
– MeSH
– Me2NH
O
O
SMe
R2
1
R
O
NHAr
R1
R2
NMe2
52
SMe
NHAr
NMe2 O
Scheme 5.35 Three-component reaction of arynes, DMF, and N,S-keteneacetals. Source:
Based on Wen et al. [40].
SO2Ar
TMS
+ DMF +
R1
Br
CsF
rt
OTf
O
R1
OH
Me
SO2Ar
55
54–67%
H2O
ArO2S
•
O
R1
O
SO2Ar
R1
52
– Me2NH
NMe2
O
O
R1
R1
SO2Ar
NMe2
Isomerization
SO2Ar
NMe2
Scheme 5.36 Three-component reaction of arynes, DMF, and sulfonyl allenes. Source:
Based on Sharma and Gogoi [41].
The ortho-quinone methide (52) was convertible into 2-aroylbenzofurans (57)
by formal [4+1] cycloaddition followed by elimination of dimethylamine from
5.5 Oxygen Nucleophile–Based Multicomponent Reactions
intermediary formed five-membered ring 56 (Scheme 5.37). Acetophenone-derived
sulfonium salts (A) [42] and α-bromoacetophenones (B) [43] were utilized as C1
source for the three-component reaction, and sulfoniumylides were proposed to be
actual trapping agents in the former case.
A
O
SMe2
Ar
TMS
Br–
CsF, rt
O
R1
66–87%
R1
OTf
+
DMF
O
R1
52
NMe2
B
O
O
Ar
Ar
57
Br
KF, 18-crown-6, K2CO3, 60 °C
54–81%
O
X
R1
– Me2NH
R1
O
52
NMe2 Ar
O
Ar
O
NMe2
X = +SMe, Br
Scheme 5.37
Three-component [4+1] cycloaddition using arynes and DMF.
Jiang reported that treatment of arynes with diaryliodonium salts in DMF gave
ortho-formyl diaryl ethers (58) (Scheme 5.38) [44]. para-Anisyl moiety in unsymmetrical diaryliodonium salts (Ar–I+ –p-anisyl X– ) was found to act as “dummy
group,” leading to the selective installation of an Ar moiety into the final product;
ortho-quinone methide52 is the key intermediate also in the reaction, whose
nucleophilic carbonyl oxygen reacts with an electrophilic diaryliodonium salt to
give 58.
Gogoi disclosed that the nucleophilic carbonyl oxygen of ortho-quinone methide
52 could also be coupled with allyl bromides to give allyl ortho-formylaryl ethers (59)
after hydrolytic work-up (Scheme 5.39) [41].
Lu and Wang developed a unique three-component reaction using aroyl cyanides,
in which ortho-quinone methide 52 was inserted into the ArCO—CN bond to provide α-amino-α-aryl carbonitriles (61) in a straightforward manner [45]. As shown
in Scheme 5.40, the nucleophilic carbonyl oxygen of 52 attacks the carbonyl carbon
of an aroyl cyanide to give intermediate 60, whose cyano group then migrates to the
iminium carbon to form 61.
5.5.2
Sulfoxide
In 2014, Chen and Xiao first demonstrated that a S=O bond of DMSO underwent formal [2+2] cycloaddition with arynes to generate S,O-containing
169
170
5 Multicomponent Reactions Involving Arynes and Related Chemistry
TMS
+ DMF +
R1
Ar
OTf
KF
I
Ar’
OTf–
60 °C
O
R1
Ar
CHO
58
56–96%
H2O
Ar
O
R1
52
I
Ar’
OTf–
O
R1
NMe2
Ar
NMe2
Scheme 5.38 Three-component reaction of arynes, DMF, and diaryliodonium salts. Source:
Based on Liu et al. [44].
TMS
+ DMF +
R1
CsF
Br
R
OTf
2
rt
O
R2
R1
CHO
59
52–78%
R2 = CO2R, Me, Br, CH2Br
Scheme 5.39 Three-component reaction of arynes, DMF, and allyl bromides. Source:
Based on Sharma and Gogoi [41].
Ar
O
TMS
+ DMF +
R1
OTf
O
Ar
CsF
60 °C
CN
O
R1
NMe2
CN
61
29–88%
O
O
R1
O
CN
R1
52
Scheme 5.40
Ar
NMe2
60
O–
Ar
CN
NMe2
Three-component reaction of arynes, DMF, and aroyl cyanides.
four-membered ring 62, which was converted into the respective ortho-quinoid
species (63) (Scheme 5.41) [46]. In the presence of activated alkyl bromides such as
α-bromoketones, α-bromoesters, and a benzyl bromide, ortho-quinoid species 63
was smoothly alkylated at the oxygen atom to afford product 64 through concurrent
demethylation at the sulfur atom.
5.5 Oxygen Nucleophile–Based Multicomponent Reactions
TMS
R
+ DMSO
1
+
R
2
Br
50 °C
OTf
R
1
SMe
64
31–79%
R2 = C(O)R, CO2R, Bn
R1
62
O
S Me
Me
– MeBr
O
R1
R2
O
KF, 18-crown-6
R2
R2
O
Br
R1
Me
S
63 Me
S
Me
Br–
Me
Scheme 5.41 Three-component reaction of arynes, DMSO, and alkyl bromides. Source:
Based on Liu et al. [46].
The DMSO-derived ortho-quinoid species (63) was also found to be captured with
acetylene dicarboxylates to provide maleate derivatives 65 with high stereoselectivity (Scheme 5.42) [47]. The reaction proceeds through conjugate addition of the
nucleophilic carbonyl oxygen to a carbon–carbon triple bond of an acetylene dicarboxylate, accompanied by the demethylation.
CO2R2
2
+ DMSO
R1
R O2C
CO2R2
TMS
OTf
O
KF
+
50 °C
R1
SMe
65
59–81%
CO2R2
R2 = alkyl
CO2R2
O
R1
S
63
R2O2C
R2O2C
CO2R2
O
Me
Me
R1
S
Me
Me
Scheme 5.42 Three-component reaction of arynes, DMSO, and acetylene dicarboxylates.
Source: Based on Hazarika et al. [47].
171
172
5 Multicomponent Reactions Involving Arynes and Related Chemistry
A unique 1,2,3-trifunctionalization of an aromatic ring was developed by Li [48];
treatment of aryl allyl sulfoxides with arynes and carbon electrophiles (activated
alkyl bromides and di-tert-butyl dicarbonate) led to consecutive construction of
Ar1 —O, Ar2 —S, and Ar3 —C bonds, giving 69 in good yields (Scheme 5.43). As were
the cases with DMSO, formal [2+2] cycloaddition between an aryl allyl sulfoxide
and an aryne triggers the reaction to form S,O-four-membered ring 66, which
is converted into 67 via S to O allyl migration. Oxonium Claisen rearrangement
followed by ring-opening then gives 68, which is finally trapped by a carbon
electrophile to provide trifunctionalized product 69.
TMS
+
R1
Ar
OTf
O
S
+
R2 Br
or
CsF
MeCN
Boc2O
3
2
OR2 (or OBoc)
R1
SAr
69
40–87%
1
R2 = allyl, Bn, CH2CO2Et
O
S
Ar
66
R1
R1
67
O
S
Ar
R1
O
S
Ar
O–
R1
68
SAr
Scheme 5.43 Three-component reaction of arynes, aryl allyl sulfoxides, and carbon
electrophiles.
5.5.3
Cyclic Ether
Such a cyclic ether as THF could serve as a good nucleophile toward arynes, and
the resulting zwitterions (70) were found to react facilely with alcohol to offer
three-component reaction products (71) (Scheme 5.44) [49]. Other cyclic ethers
with different ring size could also participate in the reaction; however, the yields
became much lower than those obtained with THF.
Qi and Jiang developed a four-component reaction of cyclic ethers, arynes, CO2 ,
and amines, that provided a variety of functionalized carbamates (74) (Scheme 5.45)
[50]. In stark contrast to other multicomponent reactions, attachment of a triflyloxy
group (OTf) at the adjacent position to the aryne triple bond was indispensable for
the reaction to proceed, which may be due to the enhanced aryne electrophilicity
induced by the OTf substituent. It should be noted that tetrabutylammonium iodide
(TBAI), instead of commonly used fluoride, was the best promoter for the reaction.
5.5 Oxygen Nucleophile–Based Multicomponent Reactions
TMS
+ O
R1
n
R2 = alkyl, Bn
n
n
R1
OR2
H
71
n = 2, 32–73%
n = 1, 29% (R1 = H, R2 = Bn)
n = 3, 46% (R1 = H, R2 = Bn)
60 °C
OTf
O
O
KF, 18-crown-6
+ R2 –OH
R2 –OH
n
O
R1
R1
–OR2
H
70
Scheme 5.44 Three-component reaction of arynes, cyclic ethers, and alcohols. Source:
Based on Thangaraj et al. [49].
The regioselective formation of zwitterion 72, where THF attacks the meta position
to the OTf group, commences the reaction. The resulting zwitterion (72) then undergoes protonation and ring opening with in situ–generated carbamate (73) from CO2
and an amine.
OTf
OTf
TMS
1
R
+
O
+ R2R3 –NH + CO2
rt
1 atm
OTf
H
TBAI
R
O
O
R2 = H, alkyl
R3 = alkyl, Bn
NR2R3
O
1
74
45–85%
R2R3 –NH + CO2
+
R2R3 –NCO2– R2R3–NH2
73
OTf
R1
–
+
O
R2R3–NCO2–
OTf
H
R1
+
O
72
Scheme 5.45 Four-component reaction of arynes, cyclic ethers, amines, and CO2 . Source:
Based on Xiong et al. [50].
5.5.4
Trifluoromethoxide
A trifluoromethoxide anion, generated efficiently from trifluoromethyl benzoate and a fluoride, was reported to be added across arynes, and the resulting
ortho-(trifluoromethoxy)aryl anion could be trapped by a Br+ equivalent (PhC≡Br,
C6 F13 Br, and C6 F5 Br) to afford trifluoromethoxylation–bromination products (75)
(Scheme 5.46) [51]. Iodine and chlorine could also be installed by use of C6 F5 I or
173
174
5 Multicomponent Reactions Involving Arynes and Related Chemistry
CCl4 as an electrophile, respectively, and furthermore, this protocol was extended
to other prefluoroalkoxylation–bromination reactions.
TMS
+
R1
OTf
O
Ph
ORf
+ R2–X
KF
cis-DCy-18-crown-6
ORf
R1
EtOAc, rt
X
75
39–87%
Rf = CF3, C2F5, C3F7, C4F9, CF(CF3)2
X = Br (R2 = PhC=C, C6F13, C6F5)
X = Cl (R2 = CCl3)
X = I (R2 = C6F5)
Scheme 5.46 Three-component reaction using arynes and perfluoroalkoxides. Source:
Based on Zhou et al. [51].
5.6 Phosphorus Nucleophile–Based Multicomponent
Reactions
In 2013, Hosoya disclosed that the phosphorus atom of methyl N,N,N ′ ,N ′ -tetraisopropylphosphorodiamidite [(i-Pr2 N)2 POMe] could act as a good nucleophile
toward arynes [52]; the generated zwitterion (76) was then captured by an atmospheric pressure of CO2 to give methyl esters (77) via methyl group migration
(Scheme 5.47).
TMS
+
R1
OMe
OTf
P(Ni-Pr2)2
+ CO2
1 atm
Bu4
N+[Ph
3SiF2
O
P(Ni-Pr2)2
]–
R1
OMe
THF, rt
O
77
90–96%
i-Pr2N
OMe
P(Ni-Pr2)2
R1
P
R1
Ni-Pr2
O Me
O–
76
Scheme 5.47
CO2
O
Three-component reaction of arynes, phosphorodiamidite, and CO2.
A three-component reaction with phosphines and activated ketones such as trifluoroacetophenones, α-ketoesters, and isatins was reported by Biju (Scheme 5.48) [53].
The reaction proceeds via the initial formation of zwitterion 78 from a phosphine and
an aryne, which is intercepted by an ketone in a formal [3+2] cycloaddition fashion
5.6 Phosphorus Nucleophile–Based Multicomponent Reactions
TMS
+ PR23 +
R1
OTf
O
R
KF, 18-crown-6
EWG
O
R2 = alkyl, aryl
R
2
R2 R 2
P R
O
R1
THF, 30 °C
R EWG
79
44–87%
O
CF3 R
O
CO2R
R2
2
P R
2
R
O
R1
NR
R
78
Ph Ph
As Ph
AsPh3
O
Ph CF3
59%
Scheme 5.48 Three-component reaction of arynes, phosphines, and ketones. Source:
Based on Bhunia et al. [53].
to afford a benzoxaphosphole derivative (79). Triaryl- and trialkylphosphine, and
even triphenylarsine, could be used as a nucleophilic trigger.
A quite similar three-component reaction also took place by use of aldehydes as an
electrophile, and a variety of benzoxaphosphole derivatives (80) were directly available from triaryl- and trialkylphosphines (Scheme 5.49) [54]. In contrast to the above
results, the reaction with triphenylarsine led to the sole formation of arsonium triflate.
2
TMS
+ PR23 +
R1
OTf
O
R3
KF, 18-crown-6
H
THF, –10 °C to rt
R1
R2 R
2
P R
O
R3
80
59–93%
R2
= alkyl, aryl
R3 = alkyl, alkenyl, aryl
Ph Ph
As Ph–
OTf
OH
AsPh3
Cl
52%
Scheme 5.49 Three-component reaction of arynes, phosphines, and aldehydes. Source:
Based on Bhunia et al. [54].
175
176
5 Multicomponent Reactions Involving Arynes and Related Chemistry
5.7 Sulfur Nucleophile–Based Multicomponent
Reactions
Tan and Xu reported that such cyclic thioethers with four- to six-membered ring as
thietane, tetrahydrothiophene, and thiane readily formed zwitterions (81) by treating with arynes, which were finally transformable into the three-component products (82) via ring-opening capture with pronucleophiles (Scheme 5.50) [55]. A wide
variety of carbon-, nitrogen-, oxygen-, and sulfur-centered pronucleophiles with pK a
range (∼13–19) efficiently served as a ring-opening agent: the representative ones,
which furnished high yields of the products (82), were bis(phenylsulfonyl)methane
(C), 2-benzoxazolinone (N), 2-naphthol (O), and ethyl 2-mercaptoacetate (S).
TMS
+
R1
OTf
S
n
+ H Nu
KF, 18-crown-6
THF, 0 °C
n = 1–3
n
S
S
Nu
n
R1
H
82
30–98%
n
S
H Nu
R1
R1
–Nu
H
81
Nu
S
H
Nu = PhO2S
C
O
N
SO2Ph
98%
O
O
96%
86%
EtO2C
S
85%
Scheme 5.50 Three-component reaction of arynes, cyclic thioethers, and pronucleophiles.
Source: Based on Zheng et al. [55].
The ring-opening three-component reaction by use of cyclic thioethers was
also applicable to a fluoride ion, leading to the direct formation of fluorinated
alkyl aryl sulfides (83). A proton source for trapping the aryl anion moiety of an
intermediary-generated zwitterion (81) was necessary for the smooth reaction: Tan
and Xu utilized 2,3-dimethylindole (Scheme 5.51) [56], and He utilized H2 O for
this purpose (Scheme 5.52) [57]. Under the latter reaction conditions, He disclosed
that chlorine, bromine, and thiocyanate were incorporated into the ring-opened
products (84) in the presence of KCl, KBr, or KSCN (Scheme 5.53). Moreover,
trimethylsilyl cyanide, azide, and chloride were demonstrated to serve as a good
ring-opening agent in the three-component reaction (Scheme 5.54).
5.8 Halogen Nucleophile–Based Multicomponent Reactions
TMS
+
R1
OTf
S
n
KF, 18-crown-6
+
n
F
H
83
23–83%
N
H
n
S
THF, 0 °C
N
H
n = 1–3
S
R1
n
S
R1
R
1
–F
H
81
Scheme 5.51 Four-component reaction of arynes, cyclic thioethers, a proton source, and a
fluoride. Source: Based on Fan et al. [56].
TMS
+
R1
OTf
S
n
+
KF, 18-crown-6
H2O
S
CH2Cl2, rt
n = 1–3
F
n
R1
H
83
28–78%
Scheme 5.52 Four-component reaction of arynes, cyclic thioethers, H2 O, and a fluoride.
Source: Based on Jian et al. [57].
TMS
+ S
+ H2O + KX
KF, 18-crown-6
S
CH2Cl2, rt
H
OTf
84
58–90%
X = Cl, Br, SCN
Scheme 5.53
salts.
Four-component Reaction of arynes, cyclic thioethers, H2 O, and potassium
TMS
R1
+ S
n
+ H2O + TMSX
n = 1–3
S
KF, 18-crown-6
OTf
Scheme 5.54
compounds.
X
X = CN, N3, Cl
THF, rt
R1
n
X
H
49–94%
Four-component reaction of arynes, cyclic thioethers, H2 O, and trimethylsilyl
5.8 Halogen Nucleophile–Based Multicomponent
Reactions
Although a fluoride ion has rarely been utilized as a nucleophile toward arynes,
probably owing to “hard (F– )”–“soft (aryne)” mismatch, Hu reported that this
could be involved in the three-component reaction with I+ equivalent, C4 F9 I, in
the presence of a catalytic amount of diphenyliodonium triflate, affording various
177
178
5 Multicomponent Reactions Involving Arynes and Related Chemistry
ortho-fluoroaryl iodides (86) (Scheme 5.55) [58]. The reaction proceeds through
nucleophilic attack of a fluoride ion (from CsF and/or an in situ–generated complex
[85]), and subsequent reaction with C4 F9 I provides 86.
CsF
cat. Ph2I+OTf –
TMS
R1
+
C 4 F9 I
F
R1
MeCN, rt
OTf
86
50–88%
[(Ph2I)m •Fn]m–n
I
85
Scheme 5.55 Three-component reaction of arynes, a fluoride, and I+ equivalent. Source:
Based on Zeng et al. [58].
A four-component reaction with a chloride ion (from KCl), an atmospheric pressure of CO2 , and alkyl chlorides, where diverse alkyl ortho-chlorobenzoates (87)
were straightforwardly produced, was reported by Jiang (Scheme 5.56) [59]. A chloride ion first attacks an aryne to give an ortho-chloroaryl anion, which is sequentially
trapped by CO2 and an alkyl chloride to lead to the final product (87).
Cl
TMS
R1
+ KCl + R2
Cl + CO2
1 atm
OTf
KF, 18-crown-6
R1
O
R2
46 °C
O
87
34–88%
R2 = CH2Cl, (CH2)2Cl, aryl
R2
Cl
Cl
Cl
CO2
R1
R1
O–
O
Scheme 5.56 Four-component reaction of arynes, a chloride, alkyl chlorides, and CO2 .
Source: Based on Jiang et al. [59].
X
TMS
1
+ KX
R
OTf
+
O
R2
X = I, Br, Cl
R2 = alkyl, aryl
KF, 18-crown-6
H
THF, 25 °C
R1
OH
R2
88
24–79%
Scheme 5.57 Three-component reaction of arynes, potassium salts, and aldehydes.
Source: Based on Bhattacharjee et al. [60].
Biju reported that the use of KI allowed a three-component iodination to
occur with aldehydes, giving a variety of ortho-iodobenzhydrol derivatives 88
(Scheme 5.57) [60]. An isatin could also serve as an electrophile in the reaction, and
5.10 Conclusive Remarks
furthermore, the use of KBr or KCl instead of KI resulted in the three-component
bromination or chlorination.
5.9 Miscellaneous
Treatment of a borylzincate species (89), generated in situ from bis
(pinacolato)diboron, Me2 Zn, and Mg(Ot-Bu)2 , with 2-bromoaryl iodides resulted
in the formation of arynes, which further accepted nucleophilic attack by 89 to
provide 2-borylarylzincate species (90) (Scheme 5.58) [61]. The resulting zincates
(90) were finally transformed into three-component allylboration products (91) via
capturing with allyl bromide.
I
R1
+ B(pin) B(pin) +
Br
Me2Zn, Mg(Ot-Bu)2
R1
Dioxane, 120 °C
Br
B(pin)
91
51–84%
Br
R1
+
ZnMe2
Me2Zn B(pin)
89
R1
90
B(pin)
Scheme 5.58 Three-component reaction of arynes, borylzincate, and allyl bromide.
Source: Based on Nagashima et al. [61].
Yoshida and Hosoya developed a three-component reaction of triflyloxy
(OTf)-substituted benzocyclobutenones, organolithium reagents, and arynophiles
such as furans, pyrrole, and aniline (Scheme 5.59) [62]. The reaction is triggered
by nucleophilic addition of an organolithium reagent to the carbonyl moiety of a
benzocyclobutenone. The resulting benzocyclobutenoxide intermediate (92) then
undergoes carbon–carbon bond cleavage/elimination of the OTf moiety to give
an aryne, which is converted into the final product (93) by the reaction with an
arynophile.
5.10 Conclusive Remarks
This chapter depicted that a wide array of multicomponent reactions involving
arynes have now become feasible depending upon their highly electrophilic
character, and that this field has witnessed remarkable progress during the last five
years. Various combinations of nucleophiles and electrophiles/pronucleophiles are
utilizable for the multicomponent reactions under Kobayashi’s conditions, which
leads to convenient and direct access to diverse benzo-annulated structures and
179
180
5 Multicomponent Reactions Involving Arynes and Related Chemistry
OTf
O
R1
+ R2 –Li
+ Arynophile
Toluene, –78 °C to rt
O
R1
R2
93
40–94%
R2 = alkyl, aryl
Arynophile
OTf
OTf
O–
R2
R1
O
R1
O
R1
R2
R2
92
Pyrrole
Furan
Aniline
Ph
NMe2Ph
N
O
O
O
Me
83%
O
Ph
82%
–OTf
Ph
77%
Scheme 5.59 Three-component reaction using triflyloxy-substituted
benzocyclobutenones, and organolithium reagents. Source: Based on Uchida et al. [62].
multisubstituted arenes. In view of the highly reactive yet controllable features of
their strained triple bond, which would enable unique bond cleavage/construction,
development of new multicomponent reactions involving arynes continues to be an
important subject in synthetic organic chemistry.
References
1 (a) Zhu, J., Wang, Q., and Wang, M.-X. (eds.) (2015). Multicomponent Reactions
in Organic Synthesis. Weinheim: Wiley-VCH. (b) Brauch, S., van Berkel, S.S.,
and Westermann, B. (2013). Chem. Soc. Rev. 42: 4948. (c) Zarganes-Tzitzikas, T.,
Chandgude, A.L., and Dömling, A. (2015). Chem. Rec. 15: 981.
2 (a) Chen, Y. and Larock, R.C. (2009). Arylation reactions involving the formation of arynes. In: Modern Arylation Methods (ed. L. Ackermann), 401–473.
Weinheim: Wiley. (b) Pellissier, H. and Santelli, M. (2003). Tetrahedron 59: 701.
(c) Dyke, A.M., Hester, A.J., and Lloyd-Jones, G.C. (2006). Synthesis: 4093. (d)
Sanz, R. (2008). Org. Prep. Proced. Int. 40: 215. (e) Kitamura, T. (2010). Aust. J.
Chem. 63: 987. (f) Yoshida, H., Ohshita, J., and Kunai, A. (2010). Bull. Chem.
Soc. Jpn. 83: 199. (g) Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112:
3550. (h) Bhunia, A., Yetra, S.R., and Biju, A.T. (2012). Chem. Soc. Rev. 41:
3140. (i) Yoshida, H. and Takaki, K. (2012). Synlett 23: 1725. (j) Dubrovskiy,
A.V., Markina, N.A., and Larock, R.C. (2013). Org. Biomol. Chem. 11: 191. (k)
García-López, J.-A. and Greaney, M.F. (2016). Chem. Soc. Rev. 45: 6766.
References
3 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett.: 1211.
4 (a) Yoshida, H. (2014). Nucleophilic coupling with arynes. In: Comprehensive Organic Synthesis, vol. 4 (eds. P. Knochel and G.A. Molander), 517–579.
Amsterdam: Elsevier. (b) Yoshida, H. (2015). Aryne-Based Multicomponent
Reactions. In: Multicomponent Reactions in Organic Synthesis (eds. J. Zhu, Q.
Wang and M.-X. Wang), 39–71. Weinheim: Wiley-VCH. (c) Yoshida, H. and
Takaki, K. (2012). Heterocycles 85: 1333. (d) Miyabe, H. (2015). Molecules 20:
12558. (e) Bhojgude, S.S., Bhunia, A., and Biju, A.T. (2016). Acc. Chem. Res. 49:
1658.
5 Yoshida, H., Fukushima, H., Ohshita, J., and Kunai, A. (2004). Angew. Chem.
Int. Ed. 43: 3935.
6 Kaicharla, T., Thangaraj, M., and Biju, A.T. (2014). Org. Lett. 16: 1728.
7 Fang, Y., Wang, S.-Y., and Ji, S.-J. (2015). Tetrahedron 71: 2768.
8 Serafini, M., Griglio, A., Viarengo, S. et al. (2017). Org. Biomol. Chem. 15: 6604.
9 Tambar, U.K. and Stoltz, B.M. (2005). J. Am. Chem. Soc. 127: 5340.
10 (a) Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Chem. Commun.: 3292. (b) Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005).
Tetrahedron Lett. 46: 6729. (c) Yoshida, H., Watanabe, M., Morishita, T. et al.
(2007). Chem. Commun.: 1505.
11 Shu, W.-M., Liu, S., He, J.-X. et al. (2018). J. Org. Chem. 83: 9156.
12 Shu, W.-M., Zheng, K.-L., Ma, J.-R., and Wu, A.-X. (2016). Org. Lett. 18: 3762.
13 Tang, C.-Y., Wang, G., Yang, X.-Y. et al. (2014). Tetrahedron Lett. 55: 6447.
14 Roy, T., Bhojgude, S.S., Kaicharla, T. et al. (2016). Org. Chem. Front. 3: 71.
15 Roy, T., Baviskar, D.R., and Biju, A.T. (2015). J. Org. Chem. 80: 11131.
16 Roy, T., Thangaraj, M., Gonnade, R.G., and Biju, A.T. (2016). Chem. Commun.
52: 9044.
17 Min, G., Seo, J., and Ko, H.M. (2018). J. Org. Chem. 83: 8417.
18 Bhojgude, S.S., Baviskar, D.R., Gonnade, R.G., and Biju, A.T. (2015). Org. Lett.
17: 6270.
19 Bhojgude, S.S., Roy, T., Gonnade, R.G., and Biju, A.T. (2016). Org. Lett. 18: 5424.
20 Okuma, K., Kinoshita, H., Nagahora, N., and Shioji, K. (2016). Eur. J. Org.
Chem.: 2264.
21 Kwon, J. and Kim, B.M. (2019). Org. Lett. 21: 428.
22 Yoshida, H., Fukushima, H., Ohshita, J., and Kunai, A. (2006). J. Am. Chem. Soc.
128: 11040.
23 Xu, J.-K., Li, S.-J., Wang, H.-Y. et al. (2017). Chem. Commun. 53: 1708.
24 Huang, X., Zhao, W., Chen, D.-L. et al. (2019). Chem. Commun. 55: 2070.
25 Li, S.-J., Wang, Y., Xu, J.-K. et al. (2018). Org. Lett. 20: 4545.
26 Swain, S.P., Shih, Y.-C., Tsay, S.-C. et al. (2015). Angew. Chem. Int. Ed. 54: 9926.
27 (a) Aly, A.A., Mohamed, N.K., Hassan, A.A., and Mourad, A.-F.E. (1999). Tetrahedron 55: 1111. (b) Singal, K.K. and Kaur, J. (2001). Synth. Commun. 31: 2809.
(c) Yoshida, H., Kuriki, H., Fujii, S. et al. (2017). Asian J. Org. Chem. 6: 973.
28 Zhou, Y., Chi, Y., Zhao, F. et al. (2014). Chem. Eur. J. 20: 2463.
29 Li, R., Tang, H., Fu, H. et al. (2014). J. Org. Chem. 79: 1344.
30 Bhunia, A., Porwal, D., Gonnade, R.G., and Biju, A.T. (2013). Org. Lett. 15: 4620.
181
182
5 Multicomponent Reactions Involving Arynes and Related Chemistry
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
Bhunia, A., Roy, T., Pachfule, P. et al. (2013). Angew. Chem. Int. Ed. 52: 10040.
Liu, P., Lei, M., and Hu, L. (2013). Tetrahedron 69: 10405.
Tan, J., Liu, B., and Su, S. (2018). Org. Chem. Front. 5: 3093.
Liu, K., Liu, L.-L., Gu, C.-Z. et al. (2016). RSC Adv. 6: 33606.
Shu, W.-M., Ma, J.-R., Zheng, K.-L., and Wu, A.-X. (2016). Org. Lett. 18: 196.
Dhokale, R.A. and Mhaske, S.B. (2016). Org. Lett. 18: 3010.
Yoshioka, E., Kohtani, S., and Miyabe, H. (2011). Angew. Chem. Int. Ed. 50:
6638.
Yoshida, H., Ito, Y., and Ohshita, J. (2011). Chem. Commun. 47: 8512.
Yoshioka, E., Tamenaga, H., and Miyabe, H. (2014). Tetrahedron Lett. 55: 1402.
Wen, L.-R., Man, N.-N., Yuan, W.-K., and Li, M. (2016). J. Org. Chem. 81: 5942.
Sharma, A. and Gogoi, P. (2019). Org. Biomol. Chem. 17: 333.
Gouthami, P., Chavan, L.N., Chegondi, R., and Chandrasekhar, S. (2018). J. Org.
Chem. 83: 3325.
Neog, K., Das, B., and Gogoi, P. (2018). Org. Biomol. Chem. 16: 3138.
Liu, F., Yang, H., Hu, X., and Jiang, G. (2014). Org. Lett. 16: 6408.
Zhou, C., Wang, J., Jin, J. et al. (2014). Eur. J. Org. Chem.: 1832.
Liu, F.-L., Chen, J.-R., Zou, Y.-Q. et al. (2014). Org. Lett. 16: 3768.
Hazarika, H., Neog, K., Sharma, A. et al. (2019). J. Org. Chem. 84: 5846.
Li, Y., Qiu, D., Gu, R. et al. (2016). J. Am. Chem. Soc. 138: 10814.
Thangaraj, M., Bhojgude, S.S., Mane, M.V., and Biju, A.T. (2016). Chem.
Commun. 52: 1665.
Xiong, W., Qi, C., Cheng, R. et al. (2018). Chem. Commun. 54: 5835.
Zhou, M., Ni, C., Zeng, Y., and Hu, J. (2018). J. Am. Chem. Soc. 140: 6801.
Yoshida, S. and Hosoya, T. (2013). Chem. Lett. 42: 583.
Bhunia, A., Roy, T., Gonnade, R.G., and Biju, A.T. (2014). Org. Lett. 16: 5132.
Bhunia, A., Kaicharla, T., Porwal, D. et al. (2014). Chem. Commun. 50: 11389.
Zheng, T., Tan, J., Fan, R. et al. (2018). Chem. Commun. 54: 1303.
Fan, R., Liu, B., Zheng, T. et al. (2018). Chem. Commun. 54: 7081.
Jian, H., Wang, Q., Wang, W.-H. et al. (2018). Tetrahedron 74: 2876.
Zeng, Y., Li, G., and Hu, J. (2015). Angew. Chem. Int. Ed. 54: 10773.
Jiang, H., Zhang, Y., Xiong, W. et al. (2019). Org. Lett. 21: 345.
Bhattacharjee, S., Guin, A., Gaykar, R.N., and Biju, A.T. (2019). Org. Lett. 21:
4383.
Nagashima, Y., Takita, R., Yoshida, K. et al. (2013). J. Am. Chem. Soc. 135:
18730.
Uchida, K., Yoshida, S., and Hosoya, T. (2017). Org. Lett. 19: 1184.
183
6
Transition-Metal-Catalyzed Reactions Involving Arynes and
Related Chemistry
Kanniyappan Parthasarathy 1 , Jayachandran Jayakumar 2 , Masilamani
Jeganmohan 3 , and Chien-Hong Cheng 2
1
University of Madras, Department of Organic Chemistry, Guindy Campus, Chennai, Tamil Nadu 600025,
India
2
National Tsing Hua University, Department of Chemistry, No. 101, Section 2, Guangfu Road, East District,
Hsinchu 30013, Taiwan
3
Indian Institute of Technology Madras, Department of Chemistry, Chennai, Tamil Nadu 600036, India
6.1 Introduction
Aryne (or) benzyne is one of the most versatile organic electrophilic species and it
has received great attention in structural aspects as well as a reactive carbon–carbon
π-component in the metal-catalyzed organic reaction [1]. In general, an aryne is an
extremely reactive species and it must be generated in situ. The high reactivity of
aryne is due to the less energy gap between the highest occupied molecular orbital
(HOMO) and the lowest unoccupied molecular orbital (LUMO) as compared with
alkynes. Thus, an aryne is always called the superior electrophile in the synthetic
community. Several methods are known to generate benzynes, including strongly
basic conditions, reducing metals, thermally/photochemically driven, and fluoride
sources (mild condition). Among them, a mild method for the in situ generation of
an aryne at ambient temperatures from ortho-silyl aryltriflates 1 (Kobayashi precursor) has received considerable interest in the past two decades [2]. The aryne generation from ortho-(trimethylsilyl)phenyl triflate 1 can be controlled by varying the concentration of fluoride ion in the solution. Usually, CsF, KF, tetra-n-butylammonium
fluoride, and AgF are commonly used as fluoride ion sources. From the mechanism
point of view, the aryne generation takes place via 1,2-elimination of ortho-silyl aryltriflates by fluoride (F− sources). As a result, Kobayashi’s aryne precursor has found
numerous applications in transition-metal-catalyzed reactions. The benzyne can be
transformed into a wide range of new organic molecules by involving cyclo and
cocyclotrimerization, annulations (via C–H and N–H activation), multicomponent
coupling reactions, etc. (Scheme 6.1: see journey map). In this chapter, we have organized the metal-catalyzed reaction types according to the journey of metal-catalyzed
(Pd, Pt, Rh, Ni, Cu, Ag, and Au) benzyne chemistry, including new breakthroughs,
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
184
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
substrate scopes, reaction selectivity, mechanism, limitations as well as applications
toward natural products and bioactive molecules.
A Journey of Metal-Catalyzed Aryne Chemistry (1995-2019)
OH
Br
HMDS
85 °C, 2 h
OSiMe3
1) n-BuLi, THF
2) Ether
Br
3) Tf2O
Brook rearrangement
OTf
1
SiMe3
Kobayashi aryne precursor
F– sources from
CsF, or
KF/18-crown-6, or
TBAF, solvents
–
+
Cumulene-type
Zwitterion structure
Metal-catalyst
with
various organic π-components
and
organometallic reagents
Aryne (or)
benzyne
Cyclotrimerization and cocyclization
annulation (via C–H and N–H activation)
cycloaddition
multi-component coupling reactions of arynes
applications
Scheme 6.1
Aryne generation and general metal-catalyzed reactions.
6.2 Metal-Catalyzed Cyclotrimerization
and Cocyclization of Arynes
6.2.1 Palladium-Catalyzed Cyclotrimerization and Cocyclization
with Arynes
Palladium (Pd) serves as a unique catalyst for various metal-catalyzed organic transformations. These transformations often achieved good reactivity and high functional group tolerance, and provided the expected products in excellent stereo- and
regioselectivity [3]. These factors can be finetuned by varying the ligand, base, solvent, temperature as well as additives. In general, palladium-catalyzed reaction goes
in Pd(0), Pd(II), and Pd(IV) oxidation states. In particular, Pd(0) and Pd(II) oxidation states are majorly involved in aryne reactions to make multiple C—C and C—X
bonds in one pot. It is important to mention that most of palladium-catalyzed aryne
reaction begins with a Pd(0) oxidation state. When Pd(II)-complex is used, the Pd(II)
complex reduces into Pd(0) in the first step of the catalytic cycle with the aid of phosphine ligands or bases or solvents in most of the reactions. The Pd(0) and Pd(II)
complexes are effectively utilized in benzyne-based reactions and also deliver various valuable new products in organic synthesis.
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
In general, benzyne easily undergoes trimerization with the help of a metal-giving
cyclotrimerization product in good-to-excellent yields under mild reaction
conditions. The cocyclization can also be done with one benzyne and two
other carbon–carbon π-components or two benzynes with one carbon–carbon
π-component in a highly selective manner (Scheme 6.2). By employing this strategy,
symmetrical as well as unsymmetrical fused polycyclic aromatic compounds can be
prepared in good-to-excellent yields.
SiMe3
OTf
SiMe3
Fluoride
sources
M
OTf
Same
M
Cyclotrimerization
reactant
Different
M = metal catalyst
R
R
R
R
Cocyclization
Scheme 6.2
Cyclotrimerization and cocyclization employing arynes.
In 1998, palladium-catalyzed cyclotrimerization of arynes was observed
(Scheme 6.3) [4]. When 2-trimethylsilylphenyl triflate (1) was treated with
CsF in the presence of a Pd(PPh3 )4 (3 mol%) in CH3 CN, a triphenylene 2 was
obtained in 83% yield. It is noteworthy that, in the absence of a Pd catalyst, the
triphenylene was not detected. The starting material 1 was recovered when the 1
was treated with [Pd(PPh3 )4 ] in the absence of fluoride source. This observation
indicates that both Pd and fluoride ion are vital for the product formation. Better
regioselectivity was observed for the unsymmetrical ortho-methoxy-substituted
aryne precursor 1a. In the reaction, a mixture of 1,5,12- and 1,5,9- trimethoxytriphenylenes (2a and 2a′ , respectively) was observed in 93 : 7 ratio in 81% combined
yield. Meanwhile, the phosphine-free Pd2 (dba)3 catalyst was also effective for the
reaction. The cyclotrimerization of unsymmetrical benzyne precursor 1b provides
a mixture of strained polycyclic hydrocarbons 2b and 2b′ in 60% yield with a 2.7 : 1
ratio, respectively.
A year later, the same group demonstrated the catalyst-controlled synthesis of
phenanthrenes and naphthalenes via cocyclization of arynes with electron-deficient
alkynes (hexafluoro-2-butyne and dimethyl acetylenedicarboxylate [DMAD]). In
the reaction, cocyclization products such as two benzynes and one alkyne,
phenanthrene derivatives (4), were observed as a major product in the presence of
Pd(PPh3 )4 . The phosphine-free Pd2 (dba)3 complex provided cocyclization of one
benzyne and two alkynes product, naphthalene derivatives (5), as a major product
in good yields. Notably, the reaction of benzyne with other alkynes (3-hexyne and
diphenylacetylene) afforded lower yields as well as selectivity in the formation of
phenanthrenes and naphthalenes in the presence of both catalysts (Scheme 6.4) [5].
185
186
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
SiMe3
Pd(PPh3)4
OTf
CsF, CH3CN
83% yield
2
1
MeO
OMe
OMe
SiMe3
MeO
OMe
Pd(PPh3)4
+
CsF, CH3CN
81%
OTf
MeO
2a
1a
SiMe3
OTf
2a′
MeO
93
:
7
Pd2(dba)3
+
CsF, CH3CN, rt
60%
1b
2b′
2b
2.7
:
1
Scheme 6.3 Palladium-catalyzed [2+2+2] cocyclotrimerization of arynes. Source: Peña
et al. [4a]; Peña et al. [4b]; Peña et al. [4c].
Later on, Yamamoto and coworkers observed a selective synthesis of phenanthrene
derivatives in good yields in the presence of Pd(OAc)2 /P(o-tol)3 /CsF system in
CH3 CN at 60 ∘ C for four hours.
SiMe3
R
R
R
R
+
R
R
4
R
Minor
Pd2(dba)3
R
5
OTf
R1
R1
3
R
R
+
Pd(PPh3)4
R
CsF, rt
R
Major
R
Minor
R1
5 mol% / 5 mol%
Pd(OAc)2/ P(o-tol)3
CsF, CH3CN, 60 °C
5 R
4
3
SiMe3
1
1
+
CsF, rt
Major
+
OTf
R1
4
Scheme 6.4 Palladium-catalyzed [2+2+2] cycloaddition of arynes with alkynes. Source:
Peña et al. [5a]; Peña et al. [5b].
In 2012, Pena and coworkers synthesized a novel hexaphenyl-substituted
[16]cloverphene derivative by a Pd-catalyzed [2+2+2] cycloaddition of polycyclic
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
aryne precursors (Scheme 6.5). In this reaction, the polycyclic aryne was slowly
generated by using a mixture of dichloromethane/MeCN (1 : 6 ratio) at 40 ∘ C with
CsF [6]. Under the slow generation, benzyne undergoes cyclotrimerization in
the presence of 10 mol% of [Pd(PPh3 )4 ] to give cloverphene 2c in 22% yield as a
yellow solid. The prepared cloverphenes are well characterized by 1 H NMR, 13 C
NMR, and MALDI mass spectrum, in which the 1 H NMR spectrum showed a
singlet and a doublet in a deshielded zone at 𝛿 = 8.71 and 8.30 ppm. In 13 C NMR
spectrum, eight CH carbon and seven C aromatic signals were observed. In the
HRMS, the molecular ion peak was observed with a mass of m/z 1284.4. Further,
tetrabenzoheptaphenes 4a were prepared by the cocyclotrimerization of bisarynes
with DMAD under similar reaction conditions.
Ph
Ph
Ph
TMS
OTf
Ph
[Pd(PPh3)4], CsF
CH2Cl2/MeCN, 40 °C
Ph
1c
Ph
Ph
Ph
2c
22% yield Ph
Ph
via
Substituted [16]cloverphene(5.5.5)
Ph
CO2Me
CO2Me
Ph
TMS
OTf
Ph
[Pd(PPh3)4], CsF
MeO2C
CO2Me
Ph
4a
59% yield
Ph
Ph
Tetrabenzoheptaphene
Scheme 6.5 Synthesis of cloverphenes and tetrabenzoheptaphene by using Pd-catalyzed
cyclotrimerization and cocyclotrimerization strategy .
In the meantime, Yamamoto’s group reported the [2+2+2] cycloaddition of benzynes with allylic chlorides (2 : 1), benzynes with alkynes (2 : 1), and benzynes
with allylic chlorides and alkynes (1 : 1 : 1) in the presence of a palladium catalyst
(Scheme 6.6) [7].
Cheng and coworkers reported a palladium-catalyzed [2+2+2] cocyclotrimerization of benzynes with a bicyclic alkene providing norbornane anellated
9,10-dihydrophenanthrene derivatives [8a]. The reaction of 1 with 7 was carried
187
188
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
SiMe3
Cl
+
Me
Pd2(dba)3/dppf
CsF, CH3CN
OTf
6
1
4
R
SiMe3
R
CsF, CH3CN
OTf
1
+ R
Cl
R
OTf
1
4
3
SiMe3
R
Pd(OAc)2/P(o-tolyl)3
+ R
3
Me
Pd2(dba)3/dppf
CH3CN + THF, CsF
6
R
5
R
Scheme 6.6 Palladium-catalyzed reaction of arynes with allylic chlorides or alkynes.
Source: Radhakrishnan et al. [7a]; Yoshikawa et al. [7b]; Yoshikawa et al. [7c].
out in the absence of metal catalyst. In the reaction, only [2+2] cycloaddition product was observed in quantitative yield [8b, c]. The palladium catalyst
is necessary to achieve [2+2+2] cocyclotrimerization product. Similarly, the
bicyclic alkene 7 undergoes [2+2+2] cocyclotrimerization with arynes in the
presence of PdCl2 (PPh3 )2 in CH3 CN at ambient temperature yielding annulated
9,10-dihydrophenanthrenes 8 in good-to-excellent yields (Scheme 6.7). The oxaand azabicyclic alkenes also nicely participated in the reaction. Interestingly, the
observed product readily undergoes deoxyaromatization in the presence of BF3 ⋅OEt2
in DCM solvent yielding polycyclic aromatic compounds in good-to-excellent yields.
Further, when cycloaddition product 8 was refluxed in toluene for 24 hours in the
presence of diethyl acetylenedicarboxylate, the corresponding cycloadduct product
7a and the substituted phenanthrene 4 were obtained in high yields (Scheme 6.7).
In this transformation, the cycloaddition product 8 undergoes retro Diels–Alder
reaction readily generating isobenzo[c]furan, which rapidly reacts with diethyl
acetylenedicarboxylate giving product 7a.
In 2003, a Pd(0)-catalyzed synthesis of benzo[b]fluorenones through partially
intramolecular [2+2+2] cycloaddition of benzodiynes 9 with benzyne precursor 1
was reported (Scheme 6.8) [9]. This transformation proceeds via the coordination
of the alkynes 9 with a palladium metal followed by oxidative cyclization giving a
five-membered palladacycle 8-A. Coordinative insertion of benzyne with the palladacycle 8-A followed by reductive elimination provides the desired cycloaddition
product 10 and regenerates the active palladium(0) species for the next catalytic
cycle.
Mori’s group reported a new Pd-catalyzed [2+2+2] cocyclization of substituted
diynes with arynes giving naphthalene skeletons in good-to-excellent yields [10].
The cycloaddition product was used as a key intermediate for the total synthesis of
Taiwanins C and E (Scheme 6.9).
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
PdCl2(PPh3)2
+ R1
1
R1
CsF,MeCN
rt, 8 h
SiMe3
R
R
O
O
OTf
7
H
H
8
R
R
R
O
BF3.OEt2,
R1
DCM, rt, 1 h
8
R1
2
R
Me
R
Me
Me
Me
O
O
EtO2C
CO2Et
CO2Et
Toluene, reflux, 24 h
Me
8a
Me
Scheme 6.7
+
CO2Et
7a
4
69%
98%
Me
Me
Pd-catalyzed cocyclotrimerization of benzynes with a bicyclic alkene.
R1
O
O
O
SiMe3
R1
+
R2
Pd-Ln
CsF, CH3CN
OTf
9
R1
Pd2(dba)3
R2
10
1
R2
8-A
Scheme 6.8 Pd-catalyzed [2+2+2] cycloaddition of benzodiynes with arynes. Source:
Based on Peña et al. [9].
R
O
R
O
O
11
O
O
+
O
OTf
O
SiMe3
1d
O
Pd2(dba)3, P(o-tol)3
O
O
CsF, CH3CN, rt, 4 h
61%
O
Me
N
OMe
R=
OH
H
O
O
9 steps
O
O
O
O
Taiwanin C
10 steps
O
O
12b
Scheme 6.9
O
O
O
O
12
12
O
O
Taiwanin E
12a
Pd-catalyzed [2+2+2] cocyclization of substituted diynes with arynes.
189
190
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Very recently, Li’s group observed a palladium-catalyzed [2+2+2] cocyclotrimerization of benzynes with allenes (Scheme 6.10) [11]. In the reaction, the internal
double bond of allene 13 reacted with two same moieties of benzynes giving product 4.
R
OTf
1
CO2Et
Pd cat, P(o-tol)3
+
CO2Et
R
SiMe3
CsF, CH3CN
4
13
Scheme 6.10
et al. [11].
Pd-catalyzed cocyclotrimerization of benzynes with allenes. Source: Liu
The selective syntheses of 9,10-dihydrophenanthrenes (15) as well as orthoolefinated biphenyls (16) were achieved through cotrimerization of arynes with
electron-deficient alkenes (14). The phosphine ligand plays a crucial role for the
selectivity. A palladacycloheptadiene intermediate 11-A was proposed as a key
intermediate for the reaction. The bulkier P(o-tolyl)3 phosphine ligand favors
the β-H elimination to give ortho-olefinated biphenyls, whereas the PPh3 ligand
favors the reductive elimination to form 9,10-dihydrophenanthrenes (Scheme 6.11).
Notably, electron-rich alkenes (e.g. ethyl vinyl ether) did not undergo cotrimerization reaction. Further, the cotrimerization of disubstituted alkenes with arynes
was very efficient with a nickel catalyst as compared with a palladium catalyst. For
example, when the dimethyl fumarate (14a) was treated with aryne in the presence
OTf
1 +
EWG
P(o-tolyl)3
EWG
PPh3
SiMe3
R
Pd(dba)3/CsF
R
16
R
EWG
14
R
15
CH3CN:toluene (1 : 1)
60 °C, 16 h
(E/Z)
EWG
β-H elimination
Reductive elimination
Pd-Ln
R
11-A
R
key palladacycloheptadiene
OTf
R1
+
1
SiMe3 R1
14a
R1 = CO2Me
Ni(COD)2/PPh3
CsF
CH3CN:toluene (1 : 1)
60 °C, 16 h
MeO2C
CO2Me
15a
61% yield
Scheme 6.11 Palladium-catalyzed coupling of alkenes with arynes. Source: Based on
Quintana et al. [12].
R
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
of a Ni(cod)2 /PPh3 , trans-dihydrophenanthrene 15a was observed in good yield
without the formation of biaryls 16 (Scheme 6.11) [12].
A new Pd-mediated aryne generation was achieved via simultaneous δ-carbon
elimination and decarboxylation from methyl 2-bromobenzoates 17 [13]. It
undergoes Pd-mediated [2+2+2] cycloaddition to give triphenylenes in moderate yields (Scheme 6.12). Notably, methyl 2-chlorobenzoates and dimethyl
2-bromoterephthalate failed to give trimerization products under similar reaction
conditions.
Pd(OAc)2/PPh3
K2CO3, TABC
CO2Me
17
CO2Me
DMF, 110 °C
Br
Pd
–CH3PdBr
Pd-cat
–CO2
[2+2+2]
2
Br
57%
OMe
MeO
CO2Me
17a
CO2Me
+
conditions
Br
MeO
MeO
Above
2d 42%
MeO2C
16a 18%
OMe
OMe
Scheme 6.12 Pd-catalyzed [2+2+2] cycloaddition of arynes from methyl
2-bromobenzoates.
Greaney and his coworkers explored the synthesis of triphenylenes (2) by using
benzoic acids (18) as alternative aryne precursors (Scheme 6.13). The reaction
R
O
Pd(OAc)2/Cu(OAc)2
CO2H K HPO , TBAB
2
4
R
18
para
4A° MS
Sulfolane, 150 °C
H
R
O
Pd
Pd
–CO2
R
Pd-cat
[2+2+2]
R
Benzyne
C–H Activation
R′
R′
CO2H
18a
meta
H
R′ = Me (35%)
R′ = F (12%)
R′ = CF3 (19%)
R′
2
R′
Ph
CO2H
+
Ph
18
Above
conditions
2
R = H (47%)
R = Me (34%)
R = tBu (33%)
R = F (35%)
R = OMe (18%)
Pd(OAc)2/Cu(OAc)2
1,10-Phenanthroline
K2HPO4, TBAB
4A° MS
Sulfolane, Δ
Ph
Ph
Ph
Ph
(or)
Ph
4 48%
(Acid in excess)
Ph
5 69%
(Alkyne in excess)
Scheme 6.13 Pd-catalyzed [2+2+2] cycloaddition of arynes from benzoic acids as an
aryne precursor. Source: Based on Cant et al. [14].
R
191
192
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
is believed to proceed via a Pd-mediated ortho C—H bond activation followed
by decarboxylation to give a palladium-coordinated aryne species. It undergoes
[2+2+2] cycloaddition with benzynes providing triphenylenes. The [2+2+2]
cycloaddition reaction of para- and meta-substituted benzoic acids (18) produced
triphenylenes as single isomers in moderate yields. The cocyclization was also
achieved with alkynes leading to phenanthrene (4) and naphthalene (5) derivatives.
For example, the excess amount of benzoic acid reacted with diphenylacetylene
(1 equiv) selectively producing phenanthrene in 48% yield (Scheme 6.13) [14],
whereas an excess amount of alkyne provides naphthalene derivative (5) at a
slightly lower temperature of 120 ∘ C.
Further, the new strategy for the synthesis of triphenylenes by trimerization of
arynes was reported by Greaney and his coworker [15]. In this reaction, benzyne
was generated by ortho-halo (or) triflate arylboronates (Scheme 6.14). The Pd(dba)2
catalyst, DPEphos ligand, and potassium tert-butoxide base in toluene as a solvent
at 100 ∘ C are the optimized reaction conditions for the cycloaddition reaction.
Notably, the starting material 2-bromophenylboronic ester (19) is easily prepared
from haloarenes within two steps. In the reaction, a series of Pd(0) and Ni(0)
benzyne complexes were prepared from (2-bromophenyl)boronic esters with the
aid of t BuOK base.
Me
O
B
R
19
R
Me
Me
Me
O
Br/OTf
Scheme 6.14
5 mol%/ 5 mol%
Pd(dba)2/DPEphos
tBuOK (1.1 equiv)
Toluene, 100 °C, 16 h
R
Pd
[2+2+2]
R
2
33–75% yield R
Pd-catalyzed trimerization of (2-bromophenyl)boronic esters via arynes.
Argade and coworker reported an efficient method for the synthesis of highly
substituted naphthalenes by a palladium/NHC-promoted [2+2+2] cocyclization of
arynes with unsymmetrical conjugated dienes (20) [16]. To achieve the synthetic target, the authors studied systematic optimization of [2+2+2] cycloaddition reaction
of arynes with unsymmetrical conjugated dienes. The optimization studies clearly
revealed that the Pd2 (dba)3 (15 mol%), IMes⋅HCl (30 mol%), and CsF (3 equiv) in
CH3 CN reflux for 24 hours are the ideal condition for the cycloaddition reaction.
Other metal complexes such as Ni(cod)2 , Pd(PPh3 )4, Pd(OAc)2 , and PdCl2 (PPh3 )2
failed to give the product. Particularly, one of the naphthalene derivatives was used
as a key intermediate for the synthesis of anti-HIV natural products justicidin B (12d)
and retrojusticidin B (12e) in three steps (Scheme 6.15).
In 2017, Houk and his coworkers prepared a novel class of indole-based conjugated
trimers by a palladium-catalyzed [2+2+2] cycloaddition strategy (Scheme 6.16). The
prepared indole-based trimer molecule has potential application in optoelectronic
materials [17]. This reaction proceeds via a palladium-catalyzed cyclotrimerization
of substituted indole-based arynes by the [2+2+2] cycloaddition strategy. In this
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
O
R
OMe
Ar
TMS
+
Pd(dba)2 (15 mol%)
IMes.HCl (30 mol%)
R
CsF (3 equiv)
20 H
MeCN, reflux, 24 h
O
Oxidative
(a) Rearrangement
addition
(b) Reductive elimination
CO2Me
CO2Me
R
(b)
CO2Me (a)
CO2Me
Pd
R
L
Pd
Ph
H
Ph
L
R
OTf
1
R
R
MeO
CO2Me
O
O
62% Ph
CO2Me
CO2Me
MeO
MeO
CO2Me
66% Ar
CO2Me
R
5
CO2Me
Ar
[OH2]
R
CO2Me
R
CO2Me
Ph
CO2Me
MeO
MeO
64% Ph
CO2Me
Me3SiOK
THF, rt, 5h
O
Justicidin B
MeO
O
MeO
O
12d
O
O
Scheme 6.15
BH3·SMe2
MeO
THF, rt, 2 h MeO
76%
Retrojusticidin B
OH
CO2Me
87%
NaH, LiBH4
1,4-dioxane
O
MeO
O
Reflux, 28 h
MeO
(67% + 28% 12d)
12e
O
O
O
O
Cocyclization of arynes with conjugated dienes by Pd/NHC ligand.
strategy, three carbon–carbon bonds were constructed in one pot. In addition,
computational studies showed that most of the indole-based trimers are out of
planarity to improve the steric interactions.
6.2.2
Ni-Catalyzed Cyclotrimerization and Cocyclization with Benzynes
In 2005, Cheng and Hsieh reported a Ni-catalyzed [2+2+2] cocyclotrimerization of
diyenes with arynes giving naphthalenes containing five to seven-membered rings
[18]. The cocyclotrimerization reaction shows excellent functional group tolerance
and leads to the expected products in moderate-to-good yields. The reaction of
hex-5-ynenitrile with arynes under standard conditions gave a phenanthrene (4)
and naphthalene (21) derivative in 56 : 11 ratios, respectively, in a combined 67%
yield (Scheme 6.17). The cycloaddition reaction proceeds via oxidative cyclization of
C≡C bonds of diynes with a Ni(0)-center providing intermediate (17-II). Next, aryne
inserted into the complex (17-II) affords a seven-membered nickelacycle intermediate (17-III). It easily undergoes reductive elimination, affords naphthalene
derivative, and regenerates the Ni(0) catalyst.
In 2004, Cheng and his coworkers reported a nickel-catalyzed [2+2+2] cocyclotrimerization of allenes (22) with arynes (1) leading to 10-methylene-9,10-dihydrophenanthrenes (23) in moderate-to-good yields [19]. In this method, the
193
194
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
TMS
OTf
N
Me
Me
N
Me
N
Pd2(dba)3
CsF/ BINAP
NMe
+
MeCN, 50 °C
NMe
1e
2e
2e′
MeN
MeN
93%, (1 : 2)
NMe
NMe
OTf
N
Me
TMS
Me
N
Pd(PPh3)4
CsF
+
MeCN, 50 °C
1f
N
Me
MeN
2f′
MeN
2f
80%, (1 : 3)
Pd(PPh3)4
CsF
N
Me
OTf
MeCN, 50 °C
MeN
N
Me
N
Me
+
TMS
1g
Scheme 6.16
precursors.
NMe
2g 9%, (1 : 1)
MeN
NMe
2g′
Palladium-catalyzed cyclotrimerization of substituted indole-based aryne
internal double bond of the allene is selectively reacted with aryne providing
9,10-dihydrophenathrenes (Scheme 6.18). However, the mixture of regioisomers
was formed with 1,1-disubstituted allenes. The proposed mechanism starts with
coordinative oxidative cyclization of an aryne and allene with a Ni(0) to form a
five-membered nickelacycle (18-I). Next, the insertion of another molecule of aryne
into the Ni—C bond affords a seven-membered nickelacycle (18-II). It further
undergoes reductive elimination, provides the expected product, and regenerates
the Ni(0) catalyst.
In 2008, Cheng and coworker developed a Ni-catalyzed [2+2+2] cycloaddition reaction of ortho-dihaloarenes (24) as an aryne precursor with alkynes
or bis-alkynes or nitriles to give substituted naphthalene and phenanthridine
derivatives (Scheme 6.19) [20]. It should be noted that the Pd(PPh3 )4 , Pd(dba)2 ,
PdCl2 (PPh3 )2 , and CoI2 (dppe) complexes were ineffective for this reaction. The
Ni/Zn combination proved the expected octaphenylanthracene (5A) in 64% yield
by the reaction of 1,2,4,5-tetraiodobenzene (24a) with 4 equiv of diphenyl acetylene
(3). The propargylic ether (11) was also underwent cycloaddition with arynes under
similar reaction condition affording dihydrofuronaphthales (20) in good yields.
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
TMS
+
R
R1
[NiBr2(dppe)] (5 mol%)
Zn (15 mol%)
R2
CsF (2 equiv)
MeCN, 80 °C
X
OTf
1
R1
11
X = O, R1, R2 = H, 71%
N
X = CH2, R1, R2 = H, 89%
X = NTs, R1, R2 = H, 74%
X = C(CN)2, R1, R2 = H, 87%
X
R1
R
X
21 R2
15 examples, 37–89% yield
3
+
N
67%
4
56 : 11
R2
4A
Ni(II)
Zn
P
P
X
X
P
Ni
Ni(0)
X
P
17-III
P
P
Ni
X
P
Ni
17-II
Scheme 6.17
X
P
17-I
Ni-catalyzed cocyclotrimerization of arynes with diynes.
Further, phenanthridines (25) were prepared in good yields via cycloaddition of two
molecules of diiodobenzenes with acetonitrile as a π-component in the presence
NiBr2 (dppe) and zinc.
In 2010, Sato and Iwayama developed an efficient methodology for the synthesis
of highly substituted isoquinolines through a Ni(0)-catalyzed [2+2+2] cycloaddition of 3,4-pyridynes with 2 equiv of arynes under the mild reaction conditions
(Scheme 6.20) [21]. It has been found that the 2-butyn-1,4-diol as well as substituted
1,3-diynes were also compatible for the reaction. It was found that the propargylic
oxygen of an alkyne is crucial for the reactivity as well as the selectivity of the
reaction. The reaction proceeds via oxidative cyclization of alkynes having propargylic oxygen substituent with a nickel species providing a nickelacyclopentadiene
intermediate (20-II) in a highly stereoselective manner. Next, the insertion of
3,4-pyridyne into the Ni—C bond of 20-II affords seven-membered nickelacycle
intermediate 20-III or 20-III′ . Subsequent reductive elimination of 20-III or 20-III′
gives isoquinoline product (26) in a highly stereoselective manner and regenerates
a Ni(0)-catalyst for the next catalytic cycle.
195
196
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
TMS
+
R
OTf
R1
NiBr2(dppe)/ Zn
•
CsF, MeCN, 80 °C
22
1
R 23
R
12 examples, 46–69% yield
R1
R1
R = t-Bu, 61%
R = n-Bu, 64%
R = Cy, 67%
Me
R = t-Bu, 61%
R = n-Bu, 64%
R = Cy, 67%
Me
Me
Me
R1
R1
NiBr2(dppe)
Zn
+
Ni(0)Ln
L
L Ni
L Ni
L
18-II
Scheme 6.18
R1
R1
18-I
Ni-Catalyzed cocyclotrimerization of arynes with allenes.
There are few reports on the [2+2+2] cycloaddition of unactivated alkenes
with aryne moieties. In 2009, Sato and his coworkers reported a Ni(0)-catalyzed
[2+2+2] cycloaddition reaction of two arynes with alkenes to afford unexpected
9,10-dihydrophenanthrene derivatives in good yields. In the reaction, a trace
amount of diene, functionalized with a biaryl ring at one of the double bonds,
was also observed (Scheme 6.21) [22]. However, the reaction of substituted
dienes with unsubstituted arynes provided the expected products in moderate
yields.
In 2011, Candito and Lautens have developed the stereoselective nickel-catalyzed
[2+2+2] cycloaddition of 1,6-enynes (28) and arynes (1) [23]. Particularly, 1,6-enynes
having heteroatoms such as nitrogen and oxygen efficiently participated in the reaction with arynes providing the expected cycloaddition products 29 in good yields
(Scheme 6.22). Notably, bulkier substitution on the olefin or alkyne of 1,6-enynes
has poor conversion or failed to undergo the reaction. The authors proposed that
the reaction mechanism proceeds via five- and seven-membered nickelacycle intermediates 22-I and 22-II.
In 2009, Xie and coworker reported a novel Ni-catalyzed [2+2+2] carboannulation reaction of activated alkenes with alkynes and arynes (Scheme 6.23)
[24]. This methodology offers an efficient route to 1,2-dihydronaphthalenes (30)
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
R1
24
+
3
X
R
R
R
I
+
24
R
5
R1
MeCN, 100 °C, 48 h
R
R
X = Br, I
R
R
[Ni(dppe)Br2]
dppe/ Zn
R
X
R = Et, 94%
O
R = Ph, 96%
R = CO2Me, 81%
R = CH2OMe, 73% O
R = n-Pr, 71%
CO2Me
CO2Me Ph
58%
R2
[Ni(dppe)Br2]
dppe/ Zn
R2
MeCN, 100 °C, 48 h
X
I
R
CO2Me Ph
CO2Me
R2
11
20
R2
Ph
Ph
Ph
Ph
Ph
64% Ph
R2 = H, X = O, 57%
R2 = Ph, X = CH2, 86%
X R2 = p-tolyl, X = CH2, 85%
R2 = H, X = C(CN)2, 64%
R
R′
I
R′
I
24a
N
[Ni(dppe)Br2] / Zn
RCN (2.5 mL)
100 °C, 36 h
R = Me, R′ = H, 76%
R = Et, R′ = H, 63%
R′ R, R′ = Me, 34%
R′
R′
25
R′
Scheme 6.19 Ni-catalyzed [2+2+2] cycloaddition of arynes with alkynes/eneynes. Source:
Based on Hsieh and Cheng [20].
from commercially available starting materials. The proposed reaction mechanism initiated by oxidative coupling of alkene and benzyne with a Ni(0) forms a
five-membered nickelacycle (23-I), which is possibly stabilized by an intramolecular coordination of the carbonyl group. Further, the insertion of an alkyne into
the Ni—C(aryl) bond affords a seven-membered nickelacycle (23-II). It undergoes
reductive elimination, gives the final product, and regenerates the Ni(0)-catalyst.
6.2.3
Au-Catalyzed Cyclotrimerization of Arynes
The gold(I) complex effectively catalyzes the cyclotrimerization of arynes providing
triphenylenes (2) under the mild reaction conditions (Scheme 6.24) [25]. It is important to note that this type of trimerization can also be done by gold as well as palladium catalysts. The silver-catalyzed trimerization reaction mechanism proceeds in
a similar way like gold- or palladium-catalyzed reactions. Particularly, unsymmetrical aryne precursors such as Me, OMe, and OCF3 gave regioisomeric triphenylenes
with a 1 : 3 ratio. This result has good agreement with a known Pd(0)-catalyzed
cyclotrimerization of arynes [4].
A gold-catalyzed cyclization of o-alkynyl(oxo)benzenes (31) with benzene diazonium 2-carboxylates (32) as benzyne precursor for the construction of a variety of
anthracenes (33) having a ketone group at the 9-position was reported by Asao and
197
198
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
N
1h
[Ni(cod)2] (10 mol%)
PPh3 (20 mol%)
R
SiEt3
+
3
CsF, MeCN, rt
OTf
R
R
R
R
N
N
R
R
R = H, 40%
R = CH2OAc, 14%
R = CH2OTHP, 70%
R
R1 R
R = CH2OMOM
R1 = OMe, 80%
R1 = CONEt2, 10%
R
N
26
24 examples, 10–81% yield
R
R
R
R1
R
R
R
N
R
n
Bu
N
R1
R
R
R = CH2OMOM, 68%
R = CH2OMe, 60%
R
nBu
R = CH2OMOM
R1 = OMe, 77%
OR′
R
R
N
R
OR′
Ni
OR′
OR′
R
OR′
R
or
OR'
R
Ni
Ni
N
20-III
R
N
OR′
20-III′
Ni
OR′
OR′
R
R
R
20-I
OR′
Ni
N
R
OR′
20-II
Scheme 6.20 Ni-catalyzed [2+2+2] cycloaddition of 3,4-pyridyne with 1,3-diynes. Source:
Modified from Iwayama and Sato [21].
Sato [26]. This transformation proceeds through the reverse electron demand-type
Diels–Alder reaction, followed by bond rearrangement, affording anthracene derivative 33 and regenerating AuCl for the next catalytic cycle (Scheme 6.25). It should be
noted that, in the absence of gold catalyst, no benzannulation product was obtained.
6.2.4 Au-Catalyzed [4+2] Cycloaddition of o-Alkynyl(oxo)benzenes
with Arynes
See Scheme 6.25.
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes
R
R
R
[Ni(cod)2] (10 mol%)
X
SIMes.HBF4 (10 mol%)
TMS
+
X
OTf
1
CsF (6 eqiuv)
MeCN, 50 °C, 6 h
27
X
+
Major R 15
Minor
R
R
R E = CO2Me
X
E
X
+
R
E
E
E
+
Minor
Major
R
Major
R
Minor
R
X = NTs, 25% X = NTs, 12% (1.5/1)
X = O, 25%
X = O, 9% (1.3/1)
R
16
R
R = OMe, 68%
R = OMe, 14% (2.5/1)
R = –OCH2O–, 57% R = –OCH2O–, 57% (2.6/1)
Scheme 6.21 Ni-catalyzed [2+2+2] cycloaddition of arynes with unactivated alkenes.
Source: Based on Saito et al. [22].
R1
TMS
R
X
+
1
OTf
R1
[Ni(cod)2] (20 mol%)
CsF (3.0 equiv)
R2
MeCN (0.05 M), 24 h
R
X
R2 29
28
R1
R1
Et
Et
OMe
F
EtO2C
O
TsN
TsN
TsN
EtO2C
O
F
R1
= Et, 73%
R1 = TMS, 50%
63%
39%
36%
Et
Streroselective products
Et
TsN
O
i-Pr
H
H
O
H
H
37%
61%
100%
MeO
R1
X
R
Scheme 6.22
X
R
NiLn
H
22-I
R1
R1
R1
[NiLn]
n-Bu
X
X
R
H
NiLn
R
22-II
Ni-catalyzed [2+2+2] cycloaddition of enynes and arynes.
H
199
200
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R
14
+
OTf
R3
R1
R
Ph
R
1
R2
3
R
R2
30 R3
19 examples, 3–78% yield
CH3CN, rt
CO2Me
Ph
CO2Me
CO2Me
R2
Ph
R3
Ph
Ph
R1 = CO2Me, 76%
R1 = COMe, 3%
R1 = CN, 15%
R1
[Ni(cod)2] (5 mol%)
CsF (3 equiv.)
R1
TMS
68%
2
3
63%
R = O–CH2–O, 29% R2, R = nBu,
1
R
=
Ph,
R3 = Et, 78%
R = F, 0%
R2 = Ph, R3 = CH2OMe, 3%
TMS
OTf
+
OMe R3
Ni[0]
CsF
[Ni]
CO2Me
CO2Me
R2
[Ni]
O
R
R3
23-II
23-I
2
Scheme 6.23 Ni(0)-catalyzed cycloaddition of arynes, activated alkenes, and alkynes.
Source: Based on Qiu and Xie [24].
R
TMS
PPh3AuCl (10 mol%)
R
OTf
1
R
CsF, MeCN, 6–12 h
R
R
R
R
2
7 examples, 45–88% yield
R
R
R
R
R
R = H, 88%
R = Me, 58%
Scheme 6.24
et al. [25].
+
R
R
R
ratio (1:3)
R = OMe, 45% R
R = Me, 85%
R = OCF3, 50%
Gold-catalyzed self-trimerization of arynes. Source: Based on Chen
30
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
R
R
O
31
+
R1
+N
2
–O
2C
cat. AuCl
DCE
40–60 °C, 1–9 h
32
33
R1
O
R
O
R = p-MeC6H4, R1 = Ph, 74%
R = p-CF3C6H4, R1 = Ph, 62%
R = p-MeC6H4, R1 = n-Pr, 87% C3H7
R = Ph, R1 = Ph, 72%
R
R = Ph, 73%
R = Si(iPr), 77%
R1
O
R
R
R
+
O
O
O
AuCl
–
R1
ClAu
R1
AuCl
+
R1
R
+
R
R1 O
O
R
–
ClAu
O
Scheme 6.25
R1
R1
AuCl
–
Au(I)-catalyzed benzannulation of o-alkynyl(oxo)benzenes with arynes.
6.3 Metal-Catalyzed Annulation with Arynes via C—H
and N—H Bond Activation
6.3.1 Palladium-Catalyzed Carbocyclization Reaction by C–H
Activation
Benzynes can be successfully used for the transition-metal-catalyzed annulation
reaction involving C—H bond activation as a key step.
A palladium-catalyzed carbocyclization of 2-halobiaryls 34 with benzynes giving
fused polycyclic aromatic compounds was reported by Larock’s group (Scheme 6.26)
[27]. The slow generation of benzyne is crucial to the success of this annulation
reaction. In this reaction, 5 mol% of Pd(dba)2 , 5 mol% of P(o-tolyl)3 , and 3.0 equiv
of CsF in 1 : 9 ratio of MeCN/toluene at 110 ∘ C for 24 hours are needed for better
transformation. This reaction was effective for the annulation of electron-donating
as well as electron-withdrawing substituted 2-halobiaryls. The annulation reaction
can also be applied to the synthesis of phenanthrenes by using the related vinyl
halides. The annulation reaction proceeds via the oxidative addition of 2-halobiaryls
with a Pd(0) and gives arylpalladium species 26-I (Scheme 6.26). Coordinative insertion of aryne with intermediate 26-I was followed by reductive elimination to afford
the desired product. To support the proposed mechanism, palladium intermediate
201
202
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
26-I was prepared and allowed to react with 2.0 equiv of the benzyne precursor 1
in the presence of 3.0 equiv of CsF. In the reaction, the desired annulation product
2 was obtained in 22% yield along with the trimerization product. This observation
clearly supports the proposed reaction mechanism. Further, this method can also
be extended to double annulation of arynes with electron-withdrawing aryl halides
(34). In the reaction, unsymmetrical triphenylenes were formed in good-to-moderate
yields.
Scheme 6.26 Palladium-catalyzed carbocyclization of 2-halobiaryls with arynes. Source:
Liu et al. [27a]; Liu and Larock [27b].
Cheng’s group also found a palladium-catalyzed intermolecular 1 : 2 cyclization of
aromatic iodides 34 with benzynes producing unsymmetrical triphenylene derivatives 2 in good yields (Scheme 6.27) [28]. TlOAc was crucial for the success of the
intermolecular reaction, which is used as iodide scavenger and also accelerates the
ortho metalation via C–H activation.
Further, Larock group’s reported a palladium-catalyzed intermolecular
annulation reaction of o-halobenzaldehydes (34c) with benzynes [29a]. This
annulation strategy provides a convenient route to fluoren-9-ones 10 in good yields
(Scheme 6.28). The authors proposed possible intermediates 28-I, 28-II, and 28-II′
for the formation of annulation product.
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
OTf
I
Pd(dba)2
CsF
OTf
+
34
TlOAc, 85 °C
SiMe3
R
SiMe3
R
R
CsF
Pd
2
ortho-metalation
1
Scheme 6.27 Palladium-catalyzed carbocyclization of aromatic halides with arynes.
Source: Based on Jayanth and Cheng [28].
CHO
5 mol% 5 mol%
Pd(dba)2/P(o-tolyl)3
CsF(5 equiv)
OTf
+ R1
R
I
34c
1
O
F
SiMe3
CH3CN:toluene (1 : 1)
110 °C, 12 h
O
R
O
O
R1
10
O
O
82%
75%
Me
O
71%
56%
PdI
O
H
CHO
Pd I
28-I
A
28-II
O
A′
A = insertion
A′ = oxidative addition
Scheme 6.28
B
28-II′
H
Pd
Me
O
10
I
B′
B = β-hydride elimination
B′ = reductive elimination
Pd-catalyzed annulations of o-halobenzaldehydes with arynes.
During the mechanistic investigation, a palladium-catalyzed intermolecular
sequential 1 : 1 : 1 carbocyclization of aromatic halides 34 with alkynes 3 and
benzynes 1 was reported (Scheme 6.29) [29b]. In the reaction, additive Tl(OAc)
was used to activate the C—H bond of aromatic iodides. The mechanism for the
carbocyclization involves the stepwise regio- and chemoselective carbopalladation
29-I of an aryl halide with internal alkyne, and subsequent insertion of aryne to give
a seven-membered palladacycle 29-II. It undergoes reductive elimination to give
the cyclized product and regenerates the Pd(0) catalyst for the next catalytic cycle.
Zhang and his coworkers demonstrated a palladium-catalyzed annulation of
1-(2-bromophenyl)-1H-indoles (35) with benzynes in the presence of CsF giving indolo-[1,2-f ]phenanthridines (36) in good yields (Scheme 6.30) [30]. The
intramolecular C—H bond activation as a key step was proposed in the annulation
reaction.
203
204
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R
I
OTf
+
+ R
SiMe3
R
34
1
R
3
Pd(dba)2, CsF
R
Tl(OAc)
MeCN: toluene (1 : 1)
90 °C, 8h
R
R
R
4
R
R
Pd I
29-I L
R
R
Pd
29-II
Scheme 6.29 Palladium-catalyzed three-component coupling of aromatic halides with
alkynes and arynes. Source: Based on Liu and Larock [29b].
R
R
H
FG
N
OTf
Pd(dba)3 (2.5 mol%)
dppp (5 mol%)
SiMe3
CsF, 110 °C
CH3CN/toluene (1 : 1)
+
Br
35
R
1
GF
R
N
36
Scheme 6.30 Pd-catalyzed annulation of 1-(2-bromophenyl)-1H-indoles with benzynes.
Source: Based on Xie et al. [30].
Cheng group observed very interesting and highly regioselective palladiumcatalyzed complete intermolecular 1 : 1 : 1 carbocyclization of aromatic iodides 34
with bicyclic/heterobicyclic alkenes 7 and benzynes (Scheme 6.31) [31a]. In the
reaction, external additive is not necessary to activate the C—H bond of aromatic
iodides. The carbocyclization product undergoes deoxyaromatization reaction in
the presence of BF3 ⋅OEt2 (1.5 equiv) in DCM at room temperature for one hour
providing polyaromatic hydrocarbons 2i and 2j in 85% and 90% yields, respectively.
The polycyclic aromatic hydrocarbons show strong photoluminescence in the solid
state as well as in solutions. This compound has potential application in material
chemistry as an electroluminescent and photoluminescent material [31b, c].
By employing a similar strategy, polycyclic dibenzocoronene bis(dicarboximide)
(38) and dinaphthocoronene tetracarboxdiimide (38a) were prepared in 80% and
46% yields, respectively (Scheme 6.32) [32]. Interestingly, the prepared compounds
showed excellent optical properties with absorption wavelengths ranging from 380
to 600 nm, high absorption coefficients, and high fluorescence quantum yields.
A palladium-catalyzed annulation of 2-(2-iodophenoxy)-1-substituted ethanones
(34) with arynes providing 6H-benzo[c]-chromenes (39) was reported (Scheme 6.33).
In this reaction, two new carbon–carbon bonds (sp2 and sp3 ) are formed through an
arylation/annulation strategy in one pot [33].
A palladium-catalyzed cyclization of 2-iodobenzyl-3-phenylpropiolates (40)
or 1-iodo-2-(2-(phenylethynyl)benzyloxy)benzenes (40a) with arynes to give
isochromen-6-ones (41) and phenanthro[1,10-bc]oxepines (42) in one pot was
described (Scheme 6.34). This transformation involves an interesting cascade
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
I
7
+
OTf
SiMe3
1
R
8
Pd(dba)2 /P(2-furyl)3
+
(or)
34
R
O
O
(or)
CsF, r t, CH3CN, 10 h
R
7b
8b
R3
R3
O
BF3·OEt2
CH2Cl2, rt, 1 h
8c: R3 = COCH3
8d: R3 = H
Me
2i: 85%
2j: 90%
Me
Me
Me
Scheme 6.31 Pd-catalyzed three-component coupling of aromatic iodides with
bicyclic/heterobicyclic alkenes and arynes. Source: Modified from Bhuvaneswari et al. [31a].
OTf
1i
O
SiMe3
R N
37
R
N
SiMe3
O
Br
+
Pd(dba)2, P(o-tol)3
CsF, toluene/CH3CN
Reflux, 18–24 h
O
O
R
N
38a
O
N
R
O
1
N R
O
O
OTf
Br
O
46% yield
R = diisopropylphenyl
O
38
O
N
R
80% yield
O
R = n-octyl
Scheme 6.32 Pd-catalyzed carbocylization strategy of arynes. Source: Avlasevich et al.
[32a]; Lütke Eversloh et al. [32b].
205
206
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
O
O
O
TMS
R1 +
R
TfO
I
34
R2
1
Pd(OAc)2
PPh3, CsF
MeCN/PhMe
45 °C, 30 h
O
R
R2
39
R = H, Me, Cl, NO2
R1 = Me, Ph, p-tolyl, p-anisyl
R2 = H, Me, 3,5-tBu
R1
Scheme 6.33 Palladium-catalyzed annulation of 2-(2-iodophenoxy)-1-substituted
ethanones with arynes.
biscarbocyclization of alkyne followed by benzyne through the intramolecular C—H bond activation [34]. The role of TlOAc was unclear in the reaction.
However, it may act as a halogen scavenger on the palladium center of the key
metallacycle.
R
O
R
O
40
I
Ph
TMS
TfO
O
40a I
X
X
R1
Pd(dba)2 /TI(OAc)
CsF, CH3CN/toluene
85 °C, 8 h
O
Ph
O
R2
R
O
R
R2
R2
X
41
R = H, Me, Ph
Scheme 6.34
X
X = O, CH2
R2 = H, 4,5-Me
X
R = H, Me
R1 = Ph, 4-OMeC6H4
R1 42
X
Pd-catalyzed cascade biscarbocyclization reactions.
In 2011, Wu and coworkers reported an easy protocol to synthesize 11-(diarylmethylene)-11H-benzo[b]fluorenes (44) via a palladium-catalyzed [3+2]
cycloaddition of (diarylmethylene)cyclopropa[b]naphthalenes (43) with arynes 1
(Scheme 6.35) [35]. The palladacyclobutene intermediate 35-I possibly formed by
the oxidative addition of palladium(0) with the highly strained three-membered ring
in (diarylmethylene)cyclopropa[b]naphthalenes followed by aryne coordinative
Ar
Ar
+
R
43
TMS
1
OTf
Ar
Ar
Ar
Ar
Pd(dba)2, PPh3
CsF, CH3CN, rt
Pd
44
R
35-I
Palladacyclobutene
Scheme 6.35 Pd-catalyzed [3+2] cycloaddition of (diarylmethylene)cyclopropa[b]naphthalenes with arynes. Source: Based on Lin et al. [35].
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
insertion and reductive elimination to give the desired product. It is important to note that the (diarylmethylene)cyclopropa[b]naphthalenes bearing
electron-donating as well as electron-withdrawing groups reacted with arynes
providing the expected products in good-to-excellent yields.
The intermolecular coupling of benzynes with propargylic carbonates (3) catalyzed by a palladium complex was reported by Ma and coworkers (Scheme 6.36).
The 5 mol% of Pd(OAc)2 and 10 mol% of TFP was needed for the formation
of 9-butyl-10-(prop-1-en-2-yl)phenanthrenes (4) in good yields [36]. Other palladium complexes such as Pd(O2 CCF3 )2 /TFP, PdI2 /TFP, PdCl2 (MeCN)2 /TFP,
Pd(PPh3 )4 , and Pd(OAc)2 with different phosphine ligands (PCy3 , (4-MeOC6 H4 )3 P,
and (2,4,6-MeOC6 H2 )3 P) were less effective. After the initial formation of
1,2-allenylpalladium (36-I) through oxidative addition of palladium(0) with 1a,
two molecules of arynes inserted into the palladium intermediate (36-II) to afford
phenanthrenes through cyclization and β-H elimination.
R1
R
R2
R
3
Pd(OAc)2, TFP
OTf
CsF, CH3CN, 60 °C
R1
Two arynes
insertion
R1
R2
R
36-I Pd OMe
Scheme 6.36
R2
TMS
+
OCO2Me
R
R1
4
R2
Pd OMe
Cyclization and
β-H elimination
36-II
Palladium-catalyzed reaction of arynes with propargylic carbonates.
Larock and Worlikar reported the palladium-catalyzed annulation of arynes
with substituted o-halostyrenes (34) giving substituted 9-fluoroenylidenes (44)
in good yields [37a]. This protocol tolerates various functional groups, including
ester, cyano, ketone, and aldehyde on the aromatic moiety. Interestingly, in the
reaction of o-halo allylic benzenes (45) with arynes, phenanthrene derivatives were
observed in good yields (Scheme 6.37). The reaction proceeds via the oxidative
addition of aryl iodide with a palladium complex followed by coordinative insertion
of arynes gives intermediate 37-II. The palladium–carbon bond of intermediate,
inserted into the C=C bond and followed by β-hydride elimination, provides the
cyclized product and regenerates the active palladium catalyst for the next cycle
[37b]. Later, this methodology was extended to synthesize 9-fluorenylidene (44) and
9,10-phenanthrenes (4) by the reaction of o-halostyrenes or o-halo allylic benzenes
with arynes in the presence of a palladium catalyst [37c]. The scope of the reaction
was examined with various functional groups such as cyano, ester, aldehyde, and
ketone-substituted aromatics. The proposed reaction mechanism was similar to
that of Larock and coworker [37a].
207
208
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R2
2
R
R1
R3
X
34 X = I, Br
R2
TMS
Pd catalyst
OTf
Ligand
CsF
R
+
1
R1
R3
R
44
CN
CO2Et
R2 = CN, 91%
R2 = CO2Et, 75%
R2 = CHO, 76% MeO
R2 = NO2, 0%
O
MeO
O
5%
CN
73%
CN
CN
F
OMe
82%, (1 : 11)
46%
R2
R2
I
Pd(0)
IPd
H
PdI
R2
37-II
R2
R3
+
X
45
TMS
Pd(dba)2 (10 mol%)
dppm (20 mol%)
OTf
CsF (3 equiv)
CH3CN/PhCH3 (1 : 1)
110 °C, 24 h
R
1
X = I, Br
Ph
20%
CO2Et
37-III
R2
R1
58%
R3
4
R
CN
CN
CO2Et
62%
R2
44
IPd
37-I
R1
OMe
78%, (4 : 1)
Me
50%
Me
Scheme 6.37
Palladium-catalyzed annulation of substituted o-halostyrenes with arynes.
The Pd-catalyzed facile method for the synthesis of hydrophenanthren-1(2H)-ones
4a and naphtho[2,1-c]furan-3(1H)-ones 4a′ has been explored through carboannulation of arynes with allyl-substituted iodocyclohexenones and iodofuranones
[38]. The poor regioselectivity was observed in the case of unsymmetrical arynes
(p-fluoro- or o-methylaryne), whereas o-methoxybenzyne precursor showed good
regioselectivity owing to the coordination of the methoxy group with the palladium
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
atom in the insertion step. However, the allyl moiety bearing a methyl group on
compound 45c failed to undergo β-hydride elimination with benzyne precursor
1, rather giving a complex mixture. Notably, when the same reaction was carried
out with trapping agent 14 (butyl acrylate), it underwent two benzyne insertion
followed by termination with butyl acrylate and afforded product 4A in 67% yield
(Scheme 6.38).
O
R2
O
R1
R1
I
45a (or)
O
TMS
Pd2dba3.CHCl3 (5 mol%)
dba (5 mol%)
OTf
Cs2CO3, CsF
MeCN/toluene 1:1, rt
+ R
1
O
R2
4a
(or)
R1
R3
O
R1 R1
4a′
I
45b
R
Regioselectivity of unsymmetrical benzyne
O
O
O
O
Me
Me
Me +
+ Me
Me
Me
Me
73% yield
Me
Me
Me
F
F
64% yield [46 : 54] ratio
[57 : 43] ratio
O
O
Me
Me
O
OMe +
Pd
I
O
MeO
55% yield
5 mol%
Me
Pd2(dba)3·CHCl3
Me
+
45c
I
Me
TMS
1
Me
38-I
[91 : 9] ratio
O
Complex
mixture
R2
O
R3
R1
R2
R1
R2
14
CO2nBu
5 mol%
Pd2(dba)3·CHCl3
O
Me
Me
Me
4A
CO2nBu
OTf
Scheme 6.38 Pd-catalyzed carboannulation of arynes with allyl-substituted
iodocyclohexenones and iodofuranones. Source: Based on Yang et al. [39].
The N-substituted-N-(2-halophenyl)formamides (46) effectively annulated with
benzynes in the presence of a Pd(OAc)2 and P(o-tolyl)3 to give N-substituted
phenanthridinones (47) in one-pot process (Scheme 6.39) [39]. The scope of
reaction was very broad and various N-substituted phenanthridinone derivatives
were prepared in good-to-excellent yields. This annulation strategy is useful to
209
210
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
construct two new C—C bonds via an arylation/annulation sequences from easily
available starting materials. The authors proposed that the acetamino coordination
on a key six-membered palladacycle intermediate (39-I) is crucial for the success of
cyclization reaction.
R1
N
R
I
O
R2
+
TMS
H
1
46
R = F, Cl, Me, CN
R1 = Me, n-Pr, Ph, 4-MeC6H4
R2 = H, 4-Me, 4-Cl, 4,5-Me, 4,5-F
R1
CHO
N
Pd I
Pd(OAc)2
P(o-tol)3, CsF
TfO
MeCN/toluene (1 : 1)
110 °C, 18 h
A
R2
R
39-I
N
A′
R
A = addition
A′ = oxidative addition
Scheme 6.39
R2
47
R1
N
B
R1
R2
O
R
PdI
O
H
R1
N
R
R1
N
O
R
O
H
B′
47
Pd
24–93%
yield
I
B = β-hydride elimination
B′ = reductive elimination
R2
R2
Palladium-catalyzed annulation of N-(2-halophenyl)formamides with arynes.
A selective synthesis of 9,10-phenanthrenes in moderate-to-good yields was
achieved through a palladium-catalyzed annulation of in situ–generated arynes
with o-halostyrenes (34) [40]. The reaction proceeds through the insertion of
arylpalladium(II) species into aryne followed by intramolecular endo-Heck reaction and isomerization of the exo olefin leading to the phenanthrene derivatives
(Scheme 6.40). The variety of functional groups such as nitrile, ester, amide, and
ketone on the aromatic moiety were well tolerated in the reaction. Further, this
annulation concept was successfully applied to the formal total synthesis of a
biologically active alkaloid (±)-tylophorine 48.
An efficient one-pot palladium-catalyzed cascade reaction of N-(2-phenylallyl)
sulfonamides (49) with arynes to provide spiro heterocyclic compounds in good
yields was demonstrated (Scheme 6.41). Pd(OAc)2 (10 mol%), PPh3 (20 mol%),
and CsF (3 equiv) in 1 : 1 mixture of toluene and MeCN at 90 ∘ C is the best
system for the formation of spiro heterocyclic compound [41]. This cascade
transformation proceeds via two possible pathways: in path (a): the first step
involves the intramolecular Heck reaction of the tethered alkene via 5-exo-trig
cyclization to give σ-alkyl Pd(II) species (41-I), which undergoes C–H activation
leads to spiro five-membered palladacycle (41-II). Then, the intermediate (41-II)
undergoes co-ordinative insertion with aryne followed by reductive elimination to
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
R2
TMS
R3
R1 +
R
PhMe/MeCN
110 °C, 14 h
TfO
I
R3
Pd(dba)2, dppm
CsF
34
R = H, F, 4,5–OMe; R1 = H, Me; R2 = CO2Et, CN, CONMe2
R3 = H, 3–OMe, 4-Me, 4,5-F, 4,5-OMe
CO2Et
Me
R2
R
4
31–98% yield
H
CO2Et
Pd
I
CO2Et
H
Pd I
Me
R1
Pd I
EtO2C
O
MeO
MeO
Me
MeO
NH2
MeO
N
Boc
I
OMe
OMe
MeO
MeO
TMS
MeO
OTf
+
Pd(dba)2, dppm
CsF
PhMe/MeCN
110 °C, 14 h
MeO
CO2Et
N
MeO
OMe
48
(±)-Tylophorine
Scheme 6.40
N Boc
MeO
OMe
Key intermediate
Palladium-catalyzed cascade reaction of ortho-halostryrenes with arynes.
give desired product. In path (b), the σ-alkyl Pd(II) species/aryne insertion/C–H
activation/reductive elimination sequences are followed for the formation of
product. In the case of longer tethered alkene, regioisomeric products 50 and 50a′
were observed in 44% and 25% yield. It is believed that the palladacycle (41-II′ )
is the possible key intermediate, which formed via Heck 6-exo-trig cyclization for
the formation of product 50a′ . As expected, unsymmetrical arynes afforded the
expected product in the regioisomeric mixtures.
Lautens and coworkers synthesized a range of spirooxindoles (50a) and spirodihydrobenzofurans (50b) in good-to-excellent yield via a palladium-catalyzed
intramolecular domino Heck spirocyclization (Scheme 6.42) [42]. This spiro
cyclization proceeds through the oxidative addition of aromatic iodide with a palladium followed by carbopalladation to generate alkylpalladium(II) intermediate. It
further undergoes domino-Heck spirocyclization via the C–H activation, benzyne
insertion, and reductive elimination to give the corresponding cyclized product.
211
212
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Br
X
R1
R
+
OTf
Ph
Ph
41-I
Br
Y
Ph
50
R2
X
41-II Pd
Ln
PdLn
Longer tether
N
Y
(i) Intramolecular Heck via 5-exo-trig cyclization
(ii) C-H activation
(iii) Aryne insertion
X
X
i
ii
iii
Pd Br
Ln
Me
X
R1
MeCN:Toluene (1 : 1)
90 °C
X = O, N-R
Y = CH2, C=O
X
Y
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
CsF (3 equiv)
TMS
2
Ph
49
Path (a)
Y
N
Ln
Me
Above
condition
Y
N
Pd
41-III
Me
Y
+
N Me
Ph
(25%)
(44%)
Y = CH2, C=O
50a
Ln
Ph
41-II′
Pd
50a′
path (b)
Aryne insertion
Unsymmetrical aryne
OMe
Br
As above
condition
Me
N
Me
Me
N
O
MeO
(77% 3 :1)
Me
O
Ph
As above
condition
Me
N
O
Me
N
O
O
+ Me
Me
+ Me
Me
Me
N
(93% 1 : 1)
OMe
Me
Me
Scheme 6.41 Palladium-catalyzed cascade reaction of N-(2-phenylallyl)sulfonamides with
arynes. Source: Based on Yoon et al. [42].
The authors have isolated the spiropalladacycle intermediate (42-I) to support
the proposed mechanism and the structure was confirmed by a single-crystal
X-ray crystallography. Further, the spiropalladacycle (42-I) was treated with in
situ–generated benzyne to give cyclized product 50 in 83% NMR yield. This result
clearly supports the proposed reaction mechanism. The observed spirocycles can be
expended into the cyclic product in the presence of a catalytic amount of peroxide
and NBS.
In 2017, Yao and He reported a novel Pd-catalyzed Heck/aryne carbopalladation/C–H functionalization reaction of arynes with iodo-aryl-alkene substrates
(52) for the synthesis of 9,10-dihydrophenanthrenes (53) [43]. This approach
offers a moderate-to-excellent yields of 9,10-dihydrophenanthrenes through a
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
R2
I
R1
TMS
+ R2
R
49a
O
OTf
Pd(PPh3)4, CsF
Cs2CHO3
PhMe/MeCN (2 : 1)
80 °C, 20 h
R
O 50a
R = H, Cl, Ph
R1 = H, F, 3,4-OCH2OR2 = H, 3,6-Me, 4,5-F, 3-OMe
R1
R2
I
O
R
R1+ R2
N
R3
TMS
OTf
Pd(PPh3)4, CsF
Cs2CHO3
PhMe/MeCN (2 : 1)
80 °C, 20 h
R
N
R3
R = H, Cl, Ph
R1 = H, F, 3,4-OCH2OR2 = H, 3,6-Me, 4,5-F, 3-OMe
Ph3HP
I
Toluene, 80 °C, 12 h
50% yield
N
Me
R1
PHPh3
Pd
Pd(PPh3)4 (1 equiv)
Cs2CO3 (1.5 equiv)
O
O
TMS
O
N 42-I
Me
confirmed by a single
crystal X-ray
OTf
CsF
PhMe/MeCN (2 : 1)
80 °C, 6 h
NBS (1.1 equiv)
Benzylperoxide (cat)
N
51
Me
Scheme 6.42
O
40% yield
Benzene, reflux
20 h
N O
Me 83% NMR yield
Palladium-catalyzed domino Heck spirocyclization of arynes.
three new C—C bond along with the formation of a carbon quaternary center.
The proposed reaction mechanism is shown in Scheme 6.43. The arylpalladium(II) intermediate (43-I) is generated from the oxidative addition of Pd(0) into
the aryl-iodide. It undergoes 6-exo-trig (n = 1) or 5-exo-trig (n = 0) cyclization
giving the key neopentyl-type Pd(II) σ-complex (43-II). In route (a), aryne can
undergo carbopalladation with intermediate (43-II) to give arylpalladium intermediate (43-III). Next, the intramolecular C–H activation through base-induced
palladation forms a seven-membered palladacycle (43-IV and 43-IV′ ). Further, it undergoes reductive elimination affording product 53 and regenerates
the Pd(0) catalyst. Alternatively, in route (b), initially intermediate (43-II) performs an intramolecular C–H activation to form five-membered palladacycle
(43-V), followed by aryne insertion on Caryl –Pd (VI) and subsequent reductive
elimination to form the cyclized product 53 and regenerates a Pd(0) catalyst
[43b].
213
214
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
+
R
OTf
1
Pd2(dba)3 (2.5 mol%)
P(o-tolyl)3 (10 mol%)
CsF (2.0 equiv)
I
TMS
B
A
52
R1
R
Me
CsOPiv (1.2 equiv)
PhCH3, MeCN
80 °C, 16 h
n Me
n = 0 and 1
R1
n
B
A
53 26 examples
OMe
Me n
Me
R1
N
X
R1 = H, X = O, 77%
R1 = H, X = NMs, 67%
R1 = F, X = O, 86%
MeO
Me
+
Me
Bn
CO2Me
CO2Me
O
N
Ms
N
Ms
90%, (5 : 1)
62%
71%
Me
PdI
IPd
PdI
A
B
Me
n
n Me
A
43-I
B
43-II
Me
n
path a
B
A
43-III
path b
Pd
Me
A
43-V
n
BH
Pd
Me
A
43-IV
B
Pd
n
Me
n
B
A
43-IV′
53
Scheme 6.43 Synthesis of 9,10-dihydrophenanthrenes by Pd-catalyzed carbopalladation
of arynes with iodo-aryl-alkenes.
Luan and his coworkers developed a Pd(0)-catalyzed chemoselective [3+2]
spiroannulation of 2-halobiaryls (34) with arynes providing spirofluorenes in
good-to-excellent yields (Scheme 6.44) [44]. This protocol proceeds through
the unusual [3+2] spiroannulation by dearomative 5-exo-trig cyclization,
distal-hydride elimination (or), base-mediated dearomatization followed by
reductive elimination. Particularly, the CH2 CO2 R on the naphthalene ring is
crucial for the spiro-cyclization reaction. After the detailed optimization studies, the authors found that the [Pd(cinnamyl)Cl]2 , P(o-anisyl)3 , in MeCN as
solvent at 90 ∘ C is the best condition for the annulation reaction. Interestingly, p-bromonaphthalene (34a) also underwent similar [2+2+1] annulation
with benzyne leading to the desired product 54a in 60% yield. Under the optimized reaction conditions, the nonacidic substrate 34b smoothly undergoes
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
cyclization with aryne to give a new type of spirocyclic product 55 in 56%
yield.
6.3.2
Palladium-Catalyzed Arynes in C–X Annulations (X = N, O)
Larock’s group described a palladium-catalyzed synthesis of N-substituted phenanthridinones (47) through annulation of arynes with N-substituted o-halobenzamides
(56). In the reaction, C—C and C—N bonds can be constructed in one pot
(Scheme 6.45). Various N-substituted o-halobenzamides worked well under the
reaction conditions. However, 2-bromobenzamide, N-phenyl-2-bromobenzamide,
and N-dimethyl-2-bromobenzamide failed to give the expected product [45].
A palladium-catalyzed selective synthesis of various N-acylcarbazoles was
reported in the reaction of 2-bromo/iodoacetanilides with arynes (Scheme 6.46)
[46]. To achieve this annulation, various mono- and bidentate phosphine ligands
were examined. Among them, dppf was found to be an effective ligand for the reaction. The cyclization reaction was compatible with various substituted benzamides.
However, N-(2-bromophenyl)pivalamide and methoxy and difluoro-substituted
benzyne precursors did not work in the annulation reaction. The same group
has also reported the carbocyclization of benzynes with 2-iodophenols providing
heterocyclic molecules in good-to-excellent yields.
A palladium-catalyzed domino annulation of benzophenone O-perfluorobenzoyl
oximes (58) with benzynes giving phenanthridines (25) was demonstrated
(Scheme 6.47). The optimization studies clearly reveal that in the absence of a Pd
catalyst, the reaction leads to mixture of products. Thus, the palladium catalyst is
necessary for selectivity as well as high yields. The reaction proceeds via oxidative
addition of Pd(0) into N—O bond of an oxime giving key aminopalladium species
(47-I). Then, the species (47-I) undergoes cyclization in two possible pathways: (i)
ortho C–H activation leads to five-membered palladacycle followed by benzyne
insertion to form a seven-membered palladacycle (47-IV). (ii) Alternatively, palladium species (47-I) undergoes co-ordinative syn insertion with benzyne to give
aryl palladium complex (47-III) followed by C–H activation to form intermediate
(47-IV). Later, intermediate (47-IV) undergoes reductive elimination to give
phenanthridine derivative 25 and regenerates a palladium catalyst for the next
catalytic cycle (Scheme 6.47) [47]. However, acetophenone O-perfluorobenzoyl
oxime reacted slowly with benzyne affording phenanthridine in the lower yield.
The aryl ketone O-acetyloximes also underwent the Pd-catalyzed annulation
with arynes providing synthetically useful phenanthridine derivatives (25) via the
C—H bond activation (Scheme 6.48). This conversion involved a C—H bond activation/aryne insertion/followed by cyclization and reductive elimination reaction
sequences. Under similar reaction conditions, various symmetrical and unsymmetrical acetophenone and benzophenone O-acetyloximes underwent annulation
smooth with arynes providing the expected products in good-to-excellent yields [48].
Interestingly, the reaction of 4-methoxy-4′ -chlorobenzophenone O-acetyloxime
with aryne afforded phenanthridine derivative as a sole product in 60% yield. It
is important to mention that the C–H activation/annulation occurred exclusively
215
216
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
R
R
I
R1
+
34
[Pd(cinnamyl)Cl]2 (5 mol%)
P(o-anisyl)3 (20 mol%)
TMS
K3PO4 (2 equiv)
CsF (4 equiv)
MeCN, 90 °C, 10 h
TfO
CO2Et
54
CO2Et
R = H, Me, Ph, F, Cl
R1 = H, Me, 3,6-Me, 4,5-F
Br
[Pd(cinnamyl)Cl]2
P(o-anisyl)3
TMS
+
K3PO4, CsF
MeCN, 90 °C, 10 h
60% yield
TfO
34a
1
CO2Et
54a
CO2Et
Me
Me
I +
TMS
[Pd(cinnamyl)Cl]2
P(o-anisyl)3
TfO
K3PO4, CsF
MeCN, 90 °C, 10 h
56% yield
Me
O
34b
Me
Me
O
55
Scheme 6.44 Pd(0)-catalyzed chemoselective [3+2] spiroannulation of 2-halobiaryls with
arynes. Source: Based on Zuo et al. [44].
O
R1
56
R2
N
H
Br(I)
+
Scheme 6.45
TMS
Pd(OAc)2, dppm
CsF, Na2CO3, 110 °C
OTf
4 : 1 Toluene/MeCN
16–24 h
R3
O
N
R1
R3
47
Palladium-catalyzed annulation of arynes with ortho-halobenzamides.
R2
O
H
N
R1
46
R2
I
O
R2
+ R3
TMS
1
OTf
Pd(dba)2, dppf
CsF, 110 °C
4 : 1 Toluene/MeCN
R1
24 h
N
57
R3
Scheme 6.46 Synthesis of N-acylcarbazoles by palladium-catalyzed cyclization of 2iodoacetanilides with arynes. Source: Lu et al. [46].
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
Ar
OCOF5C6
N
+
[{(allyl)PdCl}2]
P(o-tolyl)3
TfO
Me3Si
R1
58
1
Ar
N
CsF
Butyronitrile, 120 °C
R1
25
Ar
C–H
Ar
47-I
activation
N
Pd-X
Ar
Insertion
N
Pd
47-II
N
Pd
X 47-III
Insertion
Ar
N
C–H
activation
Pd
47-IV
Scheme 6.47 Synthesis of phenanthridines by palladium-catalyzed domino annulation of
benzophenone O-perfluorobenzoyl oximes with arynes. Source: Based on Gerfaud et al. [47].
on the –OMe substituted aryl ring. In the case of 3-methyl and 3-chloro acetophenone O-acetyloximes, mixture of regioisomeric products was observed. Similarly,
unsymmetrical aryne reacted with 4-methoxy acetophenone O-acetyloxime giving
regioisomeric products in 46% combined yield in a 1 : 1 ratio. The ratio of isomers
was determined by the 1 H NMR analysis of the crude sample.
A one-pot tricyclic phenanthridinones was efficiently synthesized by the cyclization of N-methyl or methoxybenzamides (56) with benzynes in the presence of
Pd(OAc)2 , 1-adamantanecarboxylic acid and K2 S2 O8 in CH3 CN. In this conversion,
the 1-adamantanecarboxylic acid (Adm-1-COOH) acted as an effective additive
and enhanced the yield of the cyclized product (Scheme 6.49) [49]. Benzyne acts
as a highly reactive organic π-component for this annulation reaction. Notably,
electron-donating substituted N-methoxy benzamides favors the ortho C—H
bond activation and cyclization reaction, whereas halogen and electron-deficient
aromatic benzamides give only direct N-arylated product 56a. The authors observed
that the palladacycle of 4-chloro benzamide reacted with benzyne 1 to give expected
cyclization product 47 in 45% yield. These observations clearly indicate that the
ortho C—H bond activation is very slow in the electron-deficient benzamides, and
the competitive nucleophilic N–H addition is very fast.
The palladium-catalyzed oxidative C–H annulation of N-methoxybenzamides
(56) with arynes was achieved for the synthesis of phenanthridinones (47) in the
presence of Cu(OAc)2 as a co-oxidant (Scheme 6.50) [50]. In this transformation,
electron-withdrawing and electron-donating substitutions were tolerated on both
benzamides and aryne-coupling partners. The authors have confirmed the proposed
mechanism by isolating the key five-membered palladacycle. It has been prepared
by treating 1 equiv of Pd(OAc)2 with benzamide in acetic acid at 120 ∘ C. The
palladacycle was further converted into the expected product under the optimized
217
218
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R2
R2
OAc
N
R4
TMS
Pd(OAc)2, PPh3
Cs2CO3, CuCl2, CsF
R3
OTf
Toluene:MeCN (3 : 1)
80 °C, 36 h
+
R1
58
R1 = H, Me, OMe, F, Cl
R2 = Me, Et
C–H
Aryne
N
Pd(II)
activation
insertion
TMS
OTf
Cl
OAc
N
OAc
N
Pd(II)
Reductive
elimination
R2
OAc
+
R
R4
48-II
48-I
Me
25
R3
Me
OAc
MeO
R1
R3, R4 = H, Me
Me
N
N
TMS
+
Pd(OAc)2, PPh3
Cs2CO3, CuCl2, CsF
N
Toluene:MeCN (3:1)
80 °C, 36 h
60% yield
As above
condition
MeO
R2 = 4-ClC6H4
Me
R
N
Me
N
+
OTf
R
R = Me: 50%
R = Cl: 25%
Me
N
+
MeO
OAc
OTf
TMS
Me
As above
condition
46% (1 : 1)
N
MeO
6%
20%
Me
+
N
MeO
Me
Me
Scheme 6.48
Me
Pd-catalyzed annulation of aryl ketone O-acetyloximes with arynes.
reaction conditions. Further, the observation of the KIE value of 4.7 revealed that
the C–H activation is the rate-determining step in the catalytic cycle.
This protocol was also applicable to synthesize various quinolinones (60) by
using substituted acrylamides (59) and benzynes (Scheme 6.51). This annulation
transformation is a very challenging task due to the less reactive nature of the
C—H bond of alkene [51]. The quinolinone formation was not observed in the
absence of a palladium catalyst. The reaction mechanism takes place via: (i) N–H
and C–H activation/benzyne insertion/reductive elimination (or) (ii) benzyne
insertion/6-endo-trig Heck cyclization/reductive elimination sequences. In either
pathway, after the reductive elimination step, the Pd(0) was released. It again
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
O
O
N
H
R
OMe
R1
TfO
+
TMS
56
X
Pd(OAc)2
Adm-1-COOH
X
K2S2O8, CsF, MeCN
100 °C, 12 h
R1
47
X = O, CH2
X
X
R = H, Me, OMe
R1 = H, 4,5-Me, 4,5-OMe
O
direct N-arylation
TfO
Pd(OAc)2
Adm-1-COOH
TMS
K2S2O8, CsF, MeCN
100 °C, 12 h
O
N
H
OMe +
R
OMe
N
R
56a
R = Cl (51%)
R = Br (47%)
R = Cl
R = Br
MeO
NH
O
OMe
N
R
O
O
1, CsF
Pd(OAc)2 (1 equiv)
AcOH
120 °C, 15min
N
N OMe
MeCN
Pd
100 °C, 10h
Ln
Cl
Cl
47
45%
Palladacycle
Cl
OMe
Scheme 6.49 Phenanthridinones by Pd-catalyzed C–H annulation of
N-methoxybenzamides with arynes. Source: Based on Pimparkar and Jeganmohan [49].
Pd(OAc)2 (5 mol%)
Cu(OAc)2 (2 equiv)
CsF (2.4 equiv)
O
N
H
R1
OMe
TMS
+
H
R2
OTf
56
O
1
R
TBAB (1 equiv)
DMSO/dioxane = 1/9
80 °C, 15 h
R1 = H (88%)
1
OMe R1 = Br (91%)
N
R = OMe (70%)
R1 = CO2Me (92%)
R1 = NO2 (61%)
R1 = CF3(51%)
N
H
Br
OMe Pd(OAc)2 (1 equiv)
HOAc, 120 °Cx
Br
Benzamide
Kinetic isotope effects
O
OMe
N
H +
D5
N
R1
47
R2
R1
N
OMe
R1 = Cl (81%)
R1 = Me(87%)
N
OTf
N OMe
Br
CsF (2.4 equiv)
Pd
DMSO/dioxane (1/9)
Ln
OMe
84%
Phenanthridinone
TMS
O
O
N
H
O
TMS
via palladacycle
OMe
OMe
O
O
O
O
OTf
H4/D4
N
OMe
Standard conditions, 1 h, 15%
KIE = 4.7
Scheme 6.50 Synthesis of phenanthridinones via palladium-catalyzed oxidative C–H
annulation of N-methoxybenzamides with arynes. Source: Peng et al. [50].
219
220
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
reoxidized into the active Pd(II) species in the presence of Cu(OAc)2 for the next
catalytic cycle.
O
R1
R2
N
H
OMe
TMS
+
R3
H
59
R1
R3
DMSO/Dioxane = 1/9
80 °C, 24 h
OTf
1
R2
Pd(OAc)2, Cu(OAc)2
CsF, TBAB
60
O
N
OMe
OMe
Ph
O
N
82% OMe
Ph
O
O
O
N
74% OMe
Scheme 6.51
O
N
70%
OMe
O
N
72% OMe
40%
O
N
OMe
Ph
F
F
O
N
35% OMe
Pd(II)-catalyzed synthesis of quinolinones by acrylamides and arynes.
An interesting and useful synthesis of coumestans 62 was reported by Gogoi and
his coworkers by the cyclization of 4-hydroxycoumarins (61) with arynes in the
presence of a palladium catalyst and Cu(OAc)2 as an external oxidant [52]. In the
reaction, Cu(OAc)2 was used to regenerate the active Pd(II) catalyst from Pd(0).
This cascade strategy proceeds via the C—H bond activation/C—O and C—C
bond formations in one pot. This methodology affords the expected products in
moderate-to-good yields. Further, this methodology was applied to the synthesis of
natural product flemichapparin C 62a (Scheme 6.52).
OH
R1
TMS
+
R
Pd(OAc)2 (5 mol%)
Cu(OAc)2·H2O (1.2 equiv)
CsF (2 equiv)
NaOAc (1.2 equiv)
CH3CN, 120 °C, 24 h
TfO
O
O
61
R = H, F, Cl, Br
R1 = H, 4,5-OMe, 4-Me
TMS
+
O
R
O
O
62
O
O
OH
MeO
R1
O
O
TfO
O
O
Same as above
conditions
O
MeO
O
O
62a
Flemichapparin C
Scheme 6.52
Synthesis of coumestans and natural product flemichapparin C.
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
A combination of palladium and photoredox catalysis was used for the synthesis
of phenanthridinones (47) at room temperature via annulation of benzamides (56)
with arynes (Scheme 6.53). The Na2 -eosin Y is reacted with molecular oxygen to give
superoxygen anion radical species with the blue LED [53]. Therefore, the superoxygen anion radical species regenerates the Pd(0) to Pd(II) catalyst for the next catalytic
cycle. To find the annulation mechanism, the authors have carried out the kinetic
isotopic effect experiment. The observed value of K H /K D = 5.9 indicates that the C–H
activation is the rate-determining step in this catalytic reaction. Controlled experiments such as without eosin Y, TEMPO experiments, and tapping for superoxygen
anion radical species supported the proposed annulation mechanism.
O
R
56
N
H
Pd(OAc)2
Na2 eosin Y
TMS
R1
2
R
+
TfO
O
N
R
CsF, acetone, rt, 12 h
O2 (balloon), blue LED
R1
R2
47
R = H, Me, Et, F, Cl
R1 = H, OMe, Ph
R2 = H, 4-Cl, 4,5-Me
Scheme 6.53
Pd(OAc)2 /photoredox-catalyzed synthesis of phenanthridinones.
One-pot palladium(II)-catalyzed oxidative annulation of N-methyl benzylamines (63) with arynes (1) in the presence of Cu(OAc)2 as a co-oxidant to give
5,6-dihydro-phenanthridine derivatives (64) through the C–H activation was
reported (Scheme 6.54) [54]. The electron-donating group substituted N-methyl
benzylamines provided the expected products in good yields, whereas the
electron-withdrawing substituted benzylamines gave the expected products in
the lower yields. This reaction proceeds through the five-(54-I) and seven-(54-II)
membered metallacycles as key intermediates.
N
H
R
63
Me
+
TMS
R1
H
OTf
R = H, Me, OMe, NO2
R1 = H, 4,5-Me, 4,5-OMe
Pd(OAc)2 (10 mol %)
Cu(OAc)2 (1 equiv)
CsF (3 equiv)
MeCN, 120 °C
24 h
64
Me
R1
58–91% yield
Me
N
Pd
Me
N
Pd
54-I OAc
N
R
54-II
Key intermediates
Scheme 6.54 Pd(II)-catalyzed oxidative annulation of N-methyl benzylamines with arynes.
Source: Modified from Asamdi et al. [54].
221
222
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Recently, a palladium-catalyzed cyclization of N-alkoxybenzsulfonamides (65)
with highly reactive benzynes affording dibenzosultams (66) in one pot was
reported (Scheme 6.55) [55]. The reaction proceeds via a Pd(II)-catalyzed directed
C–H/N–O alkyl activation to give consecutive C—C/C—N bond formation via the
unexpected N—O bond cleavage. The control experiment revealed that the use
of palladium catalyst, Cu(OAc)2 , CsF, and PivONa⋅H2 O is essential to increase
the efficiency of the reaction. The potential utility of this protocol was broad with
respect to benzsulfonamides as well as arynes. A mechanistic study shows that the
reaction proceeds through a rate-determining C—H bond cleavage as a key step.
O
O
R1
65
S
O
R2
R TfO
N +
H
TMS
X
X
Pd(OAc)2
Cu(OAc)2, CsF
PivNa.H2O
DMSO/dioxane (1 : 9)
110 °C, 24 h
S
R1
O
NH
R2
66
X = O, CH2
X
X
R = OMe, OEt, Ph, Bn
R1 = H, Me, OMe, CN, NO2
R2 = H, 4-Me, 4,5-Me
Scheme 6.55 Pd(II)-catalyzed direct synthesis of dibenzosultams by C-H activation.
Source: Modified from Feng et al. [55].
A new method for the synthesis of phenanthridinones (47) by a palladiumcatalyzed decarbonylative annulation of phthalimides (67) with arynes was developed (Scheme 6.56) [56]. The reaction proceeds through a palladium-catalyzed
decarbonylation by the assistance of a 8-amino quinoline group. Meanwhile, the
N-phenyl and methyl substitutions on the nitrogen atom also failed to undergo
decarbonylative annulation reaction. Further, the key five-membered Pd(II)
complex was isolated to support the mechanism. The structure of complex was
confirmed by a single crystal X-ray crystallography. This catalytic system was
compatible with various phthalimides and symmetrical benzynes. However,
unsymmetrical arynes gave a mixture of regioisomeric products. Surprisingly, the
reaction of 2-(quinolin-8-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (67)
with benzyne providing cascade aryne insertion/dehydroaromatization product
67a in 66% yield under similar reaction conditions (Scheme 6.56).
6.3.3
Ni-Catalyzed C–N Annulations by Denitrogenative Process
In 2018, Cheng and his coworkers demonstrated a Ni-catalyzed denitrogenative/annulation of 1,2,3-benzotriazin-4-(3H)-ones (68) with arynes providing structurally diverse phenanthridinones (47) in good-to-excellent yields (Scheme 6.57)
[57a]. A wide range of functional groups on the aromatic system was well tolerated. This protocol was successfully applied to synthesize natural product
N-methylchrinasiadine in 84% yield from the reaction of triazinone with arynes
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation
O
O
N
TMS
67
X
Pd(PPh3)4, CsF
tamylOH/PhCl
X
KOtBu, 120 °C
+
N
R
R1
TfO
O
N
R
N
47
R1
X = O, CH2
X
X
R = H, Me, F, tBu
R1 = H, 4-Me, 4-OMe
O
TMS
N
Pd(PPh3)4, CsF
+
N
Ph3HP
N
Pd
N
KOtBu, CH3CN, rt
OTf
O
Pd(II) Complex
O
O
O
TMS
N
Pd(PPh3)4, CsF
+
N
N
KOtBu
tamylOH/PhCl
OTf
N
O
67a 66%
O
Scheme 6.56 Palladium-catalyzed 8-amino quinoline directed decarbonylative annulation
of phthalimides with arynes.
R2
TMS
O
+
R
OTf
1
N
68
[Ni(cod)2] (10 mol%)
dppm (20 mol%)
KF (0.3 equiv)
R1
N
N
O
R1
N
R2
18–crown-6 (0.2 equiv)
THF, 100 °C, 12 h
47
R
38 example, 0–94% yield
O
O
N
O
R2
N
R1
O
N
O
N
Me
O
84%
R
R1 = o-Me, 79%
R1 = m-Me, 87%
R1 = p-Me, 94%
R
R = F, 84%
R = Me, 89%
R = O-CH2-O, 86%
O
N
O
N
N
Ar
Ni(L2)
–N2
L = dppm
N Ar
NiII
57-I
N-Methycrinasiadine
2
R = F, 85%
R2 = OMe, 84%
R2 = morpholine, 89%
O
Ar
N
NiII
47
57-II
Scheme 6.57 Ni-catalyzed denitrogenative/annulation of 1,2,3-benzotriazin-4-(3H)-ones
with arynes. Source: Based on Thorat et al. [57a].
223
224
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
[57b]. This reaction proceeds via the formation of a five-membered azanickelacycle
(57-I) by the reaction of triazinone and Ni(0) through the extrusion of molecular
nitrogen. Then, coordination of arynes with 57-I was followed by the insertion
of arynes into the Ni—C bond to form a seven-membered nickelacycle (57-II).
Finally, reductive elimination of (57-II) affords the final product 47 and regenerates
a Ni(0)-catalyst.
6.3.4
Cu-Catalyzed C–H and N–H Annulations of Arynes
A copper-mediated bidentate directed ortho-C–H/N–H annulation reaction of
benzamides (56) with arynes to give the corresponding phenanthridinone (47)
in good-to-excellent yields was reported (Scheme 6.58) [58]. The reaction was
conducted by using tetrabutylammonium iodide (TBAI) in a mixture of solvent
DMF:MeCN (1 : 1) under an O2 atmosphere. This protocol was highly regioselective
as well as compatible with various functional group substitutents on the benzamides. By employing this strategy, crinasiadine and phenaglydon natural products
were synthesized. The 8-aminoquinoline-directing group was cleaved by using BBr3
O
O
Q
N + R
H
R1
56
Q = 8-aminoquinoline
O
N
1
R
Q
TMS
Cu(OAc)2 (35 mol%)
CsF/ TBAI
OTf
DMF/MeCN (1 : 1)
80 °C, O2, 12 h
1
O
Q
O
N
R,R1 = OMe, 95%
R,R1 = O-CH2-O, 49%
R = OMe, R1 = F, 95%
Q
R
O
O
NH
O
N
O
Q
Phenaglydon, 62%
Q
N
H –2AcOH
+
Cu(OAc)2
NH
O
O
O
R
47
R
Natural product synthesis
N
Q
44 examples, 37–95% yield
R1 = o-Me, 37%
R1
R1 = m-Br, 85%
1
R = m-Ph, 62%
R1
R1 = p-Cl, 82%
R1 = p-CO2Me, 61%
O
N
R1
Crinasiadine, 55%
O
O
N
CuII N
57-I
N
CuIII N
OAc
47
58-II
Scheme 6.58 Copper-mediated C–H/N–H annulation reaction of benzamides with arynes
for the synthesis of phenanthridinones. Source: Based on Zhang et al. [58].
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
and PhI(TFA)2 reagents. The proposed reaction mechanism was almost similar to
the reported Pd-catalyzed reaction.
In 2018, the same group reported a Cu(II)-mediated ortho-C–H/N–H annulation
reaction of indolobenzamides (69) with arynes providing indoloquinoline alkaloids
(70) in good-to-excellent yields (Scheme 6.59) [59]. Notably, this protocol was
utilized to synthesize isocryptolepine and 5H-indolo[2,3-c]quinolin-6(7H)-one containing natural products by removal of directing group using BBr3 and PhI(TFA)2
reagents.
N
H
N
R2
R1
Q
TMS
Cu(OAc)2 50 mol%)
CsF, TBAI
OTf
DMF/MeCN, 80 °C,
O2, 12 h
R
R1
N
70
Q
R
N
R2
Q = 8-aminoquinoline
N
Q
3
4
+
69
O
1
2
O
O
R1
N
Me
O
Me
R = H, R1 = 1-Me, 42%
N
R = H, R1 = 2-Br, 95%
1
1
R = H, R = 3-CN, 77%
1
R = H, R = 4-Me, 44%
2
1
R = Me, R1 = H, 46%
R R = O-CH -O, R1 = H, 72%R 3 4
2
N
Q
R
R = H, R1 = 1-F, 41%
R = H, R1 = 2-F, 62%
R = H, R1 = 3-Me, 71%
R = H, R1 = 3,4-OMe, 85%
R = Me, R1 = H, 65%
R = OMe, R1 = H, 56%
R
R
Synthetic application
O
N
N
MOM
O
MQ
NH
H
N
O
NH
MOM
N
O
N
MQ
N
H
Isocryptolepine
5H-indolo[2,3-c]quinolin6(7H)-one
Scheme 6.59 Cu-mediated C-H/N-H annulation of indolobenzamides and arynes. Source:
Based on Zhang et al. [59].
6.4 Transition-Metal-Catalyzed Three-Component
Coupling Reactions
6.4.1
Palladium-Catalyzed Three-Component Coupling in Arynes
The transition-metal-catalyzed aryne involving three-component coupling is
particularly interesting in organic synthesis due to the fact that it can construct
two different chemical bonds at the ortho positions of an aromatic ring in one
pot. The construction of two different chemical bonds at the ortho positions of an
aromatic ring is extremely difficult in traditional organic synthesis. Particularly,
the palladium-catalyzed three-component coupling reaction has fundamentally
revolutionized the synthetic concepts, owing to the coupling of very reactive aryne
species with organic electrophiles and organometallic reagents for the formation of
carbon–carbon bonds exclusively at the ortho-position.
225
226
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Yamamoto’s group prepared 1,2-diallylated benzenes 72 via a palladium-catalyzed
bis-allylation of benzynes with a bis-π-allylpalladium complex (Scheme 6.60) [60].
In this reaction, amphiphilic bis-π-allylpalladium intermediate was prepared by
allylic chloride 6 and allylic stannane 71. In the substituted allyl chlorides and allyl
stannanes, very low chemoselectivity was observed (Scheme 6.60). For example, in
the reaction of methallyl chloride (6a) with allyltributylstannane (71) and benzyne,
three different types of bis allylated products 72, 72′ , and 72′′ were observed. This
is probably due to the ready σ–π exchange of the bis-allyl intermediates (59-I and
59-I′ ). It leads to the interchange of the nucleo- and electrophilicity of bis-allyl
intermediate.
SiMe3
+
Pd2(dba)2·CHCl3 / dppf
SnBu3
Cl +
CsF, CH3CN, 40 °C, 12 h
OTf
1
6
72
71
Me
Me
SnBu3
SiMe3
71
Pd2(dba)2·CHCl3 / dppf
+
OTf
+
CsF, CH3CN, 40 °C, 12 h
Me
Cl
1
72′
Me
72
6a
72′′′′
L
Pd
59-I
Scheme 6.60
Pd
L
59-I′
Pd-catalyzed bis-allylation of arynes. Source: Based on Yoshikawa et al. [60].
Subsequently, Cheng’s group demonstrated a series of three-component coupling
reaction of benzynes with electrophiles and nucleophiles in the presence of a
palladium catalyst (Scheme 6.61) [61]. Benzynes react with allylic halides 6 and
alkynyl stannanes 73 in the presence of Pd(dba)2 , dppe, CsF in CH3 CN to give
Me
R
OTf
1
Me
SiMe3
Cl
+
R
73
6a
SnBu3
Pd(dba)2 /dppe
Me
CsF, CH3CN
74
R = alkyl, aryl
R′-I
Pd(OAc)2
PPh3
TIH(OAc)
DMF, 120 °C
R′ = 1-naphthalene
Me
75 75%
Scheme 6.61 Pd-catalyzed three-component coupling of arynes with allylic halides and
alkynyl stannanes.
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
substituted 1-allyl-2-alkynylbenzenes 74 in good-to-excellent yields (Scheme 6.61).
In the three-component assembling reaction, a variety of allylic chlorides and
alkynyl stannanes are compatible with various benzyne precursors to construct two
new C—C bonds in one pot. Further, the 1-allyl-2-alkynylbenzenes 74 could be
converted to the multicyclic product 75 in 75% yield in the presence of Pd(OAc)2
(5 mol%), PPh3 (10 mol%), and Tl(OAc) (1.2 equiv) in DMF at 120 ∘ C for 10 hours.
In the coupling reaction, various organometallic reagents such as allenyl stannanes 73a, alkenyl metal reagents 73b, and aromatic metal reagents 78 were used
as nucleophilic reagents. In the reaction, organometallic reagents coupled with
benzynes and allylic halides to give 1,2-disubstituted benzenes 76, 77, and 79 in
good-to-excellent yields (Scheme 6.62) [62].
OTf
Cl +
+
SiMe3
1
Pd(dba)2 /dppe
CsF, CH3CN
Bu3Sn
6
76
73a
OTf
Cl
+
1
SiMe3
6
Pd(dba)2 /dppe
CsF, CH3CN
M
M = SnBu3, B(OH)2
77
73b
OTf
X
+
1
+
SiMe3
+
6
M
Pd(dba)2 /dppp
CsF, CH3CN
78
X = Cl, Br, OAc
79
M = B(OH)2, Si(OMe)3, SnBu3
General mechanistic sequences
M Ar
Pd
Insertion
Pd
Transmetalation
Ar
Benzyne
Scheme 6.62 Three-component Stille and Suzuki coupling reactions of arynes. Source:
Jeganmohan and Cheng [62a]; Jayanth et al. [62b].
Further, Cheng’s group reported a palladium-catalyzed Sonogashira-type coupling
of benzynes with allylic acetates or halides 6 and terminal alkynes 80 promoted by
CuI affording 1-allyl-2-alkynylbenzene derivatives 74 (Scheme 6.63) [63]. The coupling reaction shows several interesting features when compared with a previously
reported Pd-catalyzed three-component coupling of benzynes with allylic chlorides
and alkynyl stannanes.
In this type of three-component coupling reaction, allylic acetates, carbonates, and halides were used as an organic electrophile effectively. Cheng’s group
introduced allylic epoxide as an electrophile for this type of coupling reaction.
227
228
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
R
2
1
5
+ R
SiMe3
X
R
6
R6
+ H
3
Pd(PPh3)4, CuI
CsF, CH3CN
80
1
R
R2
50 °C, 5 h
22 examples
R3 = R4 = R5 = H, X = OAc
R3 = R5 = H, R4 = Me, X = OAc
R3 = Me, R4 =R5 = H, X = Cl
R1 = R2 = H
R1 = R2 = Me
R1 + R2 = –OCH2O–
Scheme 6.63
et al. [63].
R3
R4
OTf
R5
R4
74
R6
72–92% yields
R6 = alkyl, aryl
Pd-catalyzed Sonogashira-type coupling of arynes. Source: Bhuvaneswari
A cooperative palladium- and copper-catalyzed highly regio- and chemoselective
three-component coupling of benzynes with allylic epoxides 81 and terminal alkynes
80 to give 1,2-disubstituted benzenes 76 in good-to-excellent yields (Scheme 6.64)
[64]. Further, the observed 1,2-disubstituted benzenes were converted into substituted 1,4-dioxane derivatives 82 in the presence of [AuCl(PPh3 )] (2 mol%) and
AgSbF6 (6 mol%), in DCM at room temperature for six hours. The gold-catalyzed
reaction proceeds via intramolecular 6-endo-dig cyclization of the enyne group of 76
followed by a cationic intermediate (64-I) formation and subsequent dimerization.
R1
OTf
O
+
SiMe3
1
+
R1
Pd(dba)2, dppp
CuI, CsF
76
80
81
OH
[AuCl(PPh3)]/AgSbF6
DCM, rt, 6 h
OH
via
R1
64-I
R1
H
H
O
O
H
R1
82
H
R1 = 3-thienyl (79%)
R1 = 4-OMeC6H4 (83%)
R1 = CH2OMe (75%)
Scheme 6.64 Cooperative palladium- and copper-catalyzed three-component coupling of
benzynes with allylic epoxides and terminal alkynes. Source: Based on Jeganmohan
et al. [64].
Greaney and coworkers reported a palladium-catalyzed three-component
Heck-type coupling of benzynes with benzyl bromide (or) methyl bromoacetate 83
and activated alkenes 14 to give 1,2-disubstituted benzenes 84 in good-to-excellent
yields (Scheme 6.65) [65a]. This three-component coupling reaction worked with
two distinct palladium complexes. For example, methyl bromoacetate effectively
involved in the three-component coupling reaction to yield the corresponding
products in good yields in the presence of 5 mol% of PdCl2 dppf in DME at
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
50 ∘ C. The combination of Pd(OAc)2 and bidentate dppe ligand was effective
for three-component coupling of benzyl bromides with benzynes and acrylates.
Further, the synthetic utility of the palladium-catalyzed multicomponent reaction
of benzynes with aryl halides and activated alkenes was also developed by the same
group [65b]. By using this method, a wide range of biphenyls 16 were obtained in
good yields. The authors have proposed possible key intermediates (65-I to 65-IV)
for this three-component coupling reaction.
Br
R1
R
O
Br
R1
Pd(OAc)2, dppe
CsF (3 equiv)
R
DME, 50 °C
TMS
+
1
12 examples
83
CO2R2
58–92% yield
OTf
CO2R2
+
+
SiMe3
R
34
14
R = Cl, F, NO2, CO2R
Pd
65-I
Ar
L
CO2R2
Pd
OMe
R
O
DME, 50 °C
14
84
3 examples
70–80% yield
OTf
L
OMe
PdCl2(dppf)
CsF (4 equiv)
R1 = H, Me, OMe, Cl
I
1
CO2R2
R
5 mol% 10 mol%
Pd(OAc)2/P(o-tol) 3
CsF (6 equiv)
16
MeCN, 45 °C
23 examples
I
CO2R2
65-II
PdL2I
65-III
CO2R2
CO2R2
38-90% yield
CO2R2
PdL2I
H
65-IV
Possible key intermediates
Scheme 6.65 Pd-catalyzed three-component Heck-type coupling of arynes. Source: Based
on Henderson et al. [65a].
Werz and his coworker reported a three-component coupling of in situ–generated
arynes with terminal alkynes 80, and vinyl cyclopropanedicarboxylate 85 in the presence of a catalytic amount of Pd(dba)2 /dppp [66]. This protocol is specifically interesting and useful for the coupling of sp and sp3 bonds in one pot under mild reaction
conditions. Various electron-donating and electron-withdrawing group substituted
arylacetylenes worked very well. However, the ethyl propiolate did not participate
in the reaction. Meanwhile, aryne precursor 1 bearing two fluorine substituents
provided the expected coupling product 86f in only 11% yield (Scheme 6.66). The
unsymmetrical aryne precursors provided a mixture of regioisomeric products.
A cationic palladium complex and KF/18-crown-6 system was found to be effective for a three-component coupling of arynes, isocyanides 87, and cyanoformates
88 providing cyano-substituted iminoisobenzofurans 89 as well as unexpected
α-iminonitriles 90 (Scheme 6.67) [67]. In general, the synthesis of α-iminonitriles
is a very challenging task. In the present method, α-iminonitriles were prepared
effectively. The cyano-substituted imino isobenzofurans smoothly undergo skeletal
rearrangement to give α-iminonitriles with the aid of DIBAL-H or AlMe3 . However,
229
230
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R
TMS
R1
H
+
R
CO2Me
OTf
85
CO2Me
Pd(dba)2, dppp
KF, 18-crown-6
MeCN, 50 °C, 16 h
CO2Me
86
MeO2C
NO2
OMe
Ph
(73%)
(79%)
CO2Me
MeO2C
(60%)
CO2Me
CO2Me
MeO2C
MeO2C
F
OH
CO2Et
(69%)
CO2Me
MeO2C
R1
Ph
F
(11%)
(0%)
CO2Me
MeO2C
CO2Me
MeO2C
Scheme 6.66 Pd-catalyzed three-component coupling of arynes, terminal alkynes, and
vinyl cyclopropanedicarboxylate.
in the unsymmetrical aryne such as 1-(trimethylsilyl)naphth-2-yl triflate (1k),
mixtures of cyano-substituted iminoisobenzofurans and α-iminonitriles were
observed.
6.4.2
Nickel-Catalyzed Three-Component Coupling in Arynes
In 2007, Cheng and Jayanth reported a Ni-catalyzed three-component coupling of
enones with organoboronic acids and arynes providing biaryl frameworks 91 with
an alkyl chain in the ortho-position (Scheme 6.68) [68]. The proposed mechanism
initiated by the reaction Ni(0) with the aryne and enone to form a five-membered
nickelacycle (68-I). The protonation occurs at the α-carbon atom of the ketone group
with the aid of boronic acid followed by transmetalation of aryl group to the Ni-atom
gives intermediate 68-III. Subsequent reductive elimination provides the desired
product and regenerates the Ni(0) catalyst.
6.4.3
Copper-Catalyzed Three-Component Coupling in Arynes
Very recently, Xiao, Chen, and coworkers reported a Cu-catalyzed three-component
coupling of arynes with o-benzoxazolylhydroxylamines (92) and terminal alkynes
(80) (or) benzoxazoles 94. In this protocol, o-alkynyl anilines 93 and o-benzoxazolyl
anilines 95 were selectively achieved by using terminal alkynes (or) benzoxazoles
in one pot with two distinct reaction conditions (Scheme 6.69) [69]. The reaction
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
TMS
R1
OTf
1
R2 N C
87
+
O
NC
88
NR2
[Pd(NCPh)2(dppf)] (BF4)2
KF/ 18-crown-6
R1
THF, 50 °C, 18 h
89
OR3
NR2
CN
O + R1
R3
NC
90
DIBAL-H
(or)
COR3
AlMe3
N R
+
O
R N
TMS
1k
+
O
NC OEt
89a
35%
R
N
As above
O
NC
OTf
C
N R
condition
N
OEt
CN
R = CMe2CH2CMe3
90a
90a′
23% (83 : 17)
N
R1
+
R2
O
+
path a
R
R2
R3
NC
B
O
–Pd2+
NC
path b
+
N
R1
R2
+
N
R1
O Pd(II)
NC
R3
R2
R3
O
CO2Et
2
N R
R1
O Pd(II)
R3
NC
A
Pd(II)
N
1
R
CN
+
CO2Et
+
OEt
89a′ NC
13%
R1
N
R3
R2
CN
R3
2+
–Pd
O
Pd(II)
Scheme 6.67 Pd-catalyzed three-component coupling of arynes, isocyanides, and
cyanoformates. Source: Modified from Li et al. [67].
has excellent functional group compatibility and the reaction can be done from
readily available starting materials in one step. The reaction mechanism starts
with the R1 –Cu(I) intermediate (69-I), which is generated from terminal alkynes
(or) benzoxazoles in the presence of CuI and base. Then, R1 –Cu(I) intermediate
(69-I) undergoes addition with aryne giving aryl C—Cu bond (69-II). It reacts
with o-benzoxazolylhydroxylamine to give Cu(III) species (69-III). Reductive
elimination of intermediate 69-III affords coupling product and regenerates the
active Cu(I).
A copper(I)-catalyzed difunctionalization of arynes through the three-component
coupling reaction of terminal alkynes (80) with benzenesulfonothioates (96)
and arynes (1) was achieved successfully. This transformation consists of an
intermolecular C—C and C—S bond formation in one pot (Scheme 6.70) [70].
This three-component reaction offers an efficient method for the synthesis of
ortho-alkynylarylsulfides (97) from the commercially available starting materials.
231
232
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
TMS
R
14
+
OTf R2
1
B(OH)2
R1
B(OH)2 78
R
O
Et
Ph
R = Me, 93%
R = OMe, 95%
R = F, 67%
R = O–CH2–O, 88%
CN
R
Ph
R
Et R2 = o-OMe, 79%
R2 = m-OMe, 67%
R2 = p-OMe, 84%
R2 = H, 60%
71%
R2
O
O
+
R
CsF (3 equiv)
R2
91
MeCN, 40 °C, 8 h
14 examples, 60-84% yield
R2
O
R
R1
[Ni(cod)2] (10 mol%)
PPh3 (20 mol%)
+
Et
Et
Ni0
Ni
68-I
RB(OH)2
B(OH)2
Et
O
68-II
RB(OH)2
NiR
O
O=B-OH
NiR
Et
H H
68-III
91
Scheme 6.68 Ni(0)-catalyzed three-component coupling of arynes with α,β-unsaturated
ketones and organo boronic acids. Source: Based on Jayanth et al. [68].
The reaction was compatible with various substituted terminal alkynes, arynes,
and benzenesulfonothioates. The reaction proceeds via coordinative insertion of
benzyne with copper(I) acetylide (70-I) giving aryl copper intermediate (70-II)
in the presence of base. The aryl–C bond undergoes nucleophilic addition with
PhSO2 SR, affords the final product, and regenerates the active copper catalyst.
Pineschi and coworkers successfully developed three-component coupling of
vinylaziridines (98) with terminal alkynes and arynes in the presence of CuI/PPh3
under mild reaction conditions (Scheme 6.71) [71]. Various vinylaziridines
react efficiently with benzynes and terminal alkynes to afford functionalized
allylic amines 99 in moderate-to-good yields in a highly regio- and stereoselectivity. Notably, allylic aziridines undergo selective SN 2′ ring-opening catalyzed
by a copper–phosphine complex. On the other hand, a highly reactive ethyl
propiolate reacted with benzyne and cyclic allylic aziridine affording SN 2′
ring-opening product as well as tetrahydrophenanthridine 100 in 54% and 30%
yields, respectively.
Zhang and his coworkers reported the efficient Cu(I)-catalyzed two-component
coupling of terminal alkynes with arynes as well as three-component coupling of
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
R1
TMS
+
R
OTf
1
H
R3
+ BzO N
R2 THF, 60 °C, Ar, 10 h
92
80
R1
N
R2
O
R
OTf
1
R4 = Me, 65%
R4 = CO2Me, 72%
R4 = OMe, 81%
O
N
O
94
R4
TBABF4, Cs2CO3
R4 THF, 40 °C, 24 h
R2
N R3
O
R
N
O
95
R4
R = Me, 68%
R = OMe, 64%
N
76%
N
Ph
67%
CuI (10 mol%)
Brettphos (20 mol%)
O
R
N
OMe
N
OMe
R
R1
R1
N
R2
N
73%
O
N
R3
93
Ph
N
O
N
N
R2
N
R3
R1 = o-MeC6H4, 75%
R2,R3 = Et, 69%
R1 = p-OMeC6H4, 78% R2,R3 = Bn, 68%
R1 = m-MeC6H4, 84% R2,R3 = allyl, 59%
R3
BzO N +
R2
92
R
Ph
Ph
N
TMS
+
R1
CuI (5 mol%), KF
18-crown-6, Cs2CO3
[CuI]
(or)
Base
R3
H
[CuIII]
NR2
69-III
R1
[CuI]
N
O
= R1
H
69-I
R1
[CuI]
69-II
BzO-NR2
R1
Scheme 6.69 Copper-catalyzed three-component carboamination of arynes. Source: Based
on Niu et al. [69].
233
234
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
TMS
PhSO2
96
+
R
CuI (10 mol%)
CsF/18-crown-6
R1
K2CO3/BnBr
MeCN, 40 °C, 5 h
H
OTf
1
SR2
80
SPh
R1
SR2
R
97
24 examples, 52–87% yield
R1 = Ph, 87%
R1 = p-FC6H4, 83%
R1 = p-CNC6H4, 72%
R1 = CO2Me, 52%
Ph
[Cu]
R1
Base
R1
SR2
PhSO2SR2
[Cu]
70-I
Scheme 6.70
et al. [70].
R2 = Me, 71%
R2 = p-BrC6H4, 82%
R2 = p-NO2C6H4, 74%
R2 = allyl, 61%
SR2
H
CuI
R1
70-II
R1
R1
CuI-Catalyzed three-component reaction of arynes. Source: Based on Peng
R1
R
NTs
R1
TMS
+
1
CuI (6 mol%)
PPh3 (12 mol%)
OTf
98
H
R
CsF, MeCN:toluene (1 : 1),
55 °C, 16 h
99
8 examples, 57–84% yield
Ph
NHTs
OAc
NHTs
NHTs
NTs
TMS
CO2Et
CuI (6 mol%)
PPh3 (12 mol%)
+
H
NHTs
54%
Mechanism
R1
H
Cu(I)
CsF
–HF
NHTs
EtO2C
N
+
CsF (3.0 equiv)
MeCN, 55 °C, 20 h
OTf
EtO2C
74%
74%
70%, E/Z = 60 : 40
H
100
30%
Cu
NTs
R1
71-I
Cu
71-II
Ts
H
99
R1
Scheme 6.71 Copper-catalyzed multicomponent coupling reaction of arynes. Source:
Based on Berti et al. [71].
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
R1
TMS
+
R
OTf
1
CuI (10 mol%)
CsF, 110 oC, 24 h
MeCN:toluene (1:1)
H
80
8 examples, 72–92% yield
R1 3
R
R = H, R1 = Ph, 87%
R = H, R1 = Bu, 85%
R = H, R1 = CO2Et, 83%
R3
TMS
R
Cl
6
+
OTf
1
R2
R2
80
R4
CuI (10 mol%)
dppe (10 mol%)
R4
R
R3
CsF / K2CO3
MeCN, 60 °C, 12 h
R1
76
R1
15 examples, 46–82% yield
64%
66%
71%
OMe
OMe
Product
OMe
R1
Cu(I)
Cu Cl
72-IV
R1
Cu
R1
Cu
72-I
Cl
Cu
72-III
R1
72-II
R1
Cl
Scheme 6.72 Multicomponent reactions of terminal alkynes, arynes, and allylic chlorides
by copper catalyst. Source: Modified from Xie et al. [72].
terminal alkynes with allylic chlorides and arynes under mild reaction conditions
(Scheme 6.72) [72]. This method provides a facile and novel route for the synthesis
of substituted acetylenes 3 and 1,6-enyne derivatives 76 in moderate-to-good
yields. Initially, alkynyl-Cu(I) intermediate (72-I) is formed from the alkyne and
Cu(I), followed by the insertion of benzyne gives an alkynylated-aryl copper
species (72-II). Subsequently, allyl chloride undergoes oxidative addition with
intermediate 72-II providing intermediate 72-III. Further, this intermediate rearranged into an allyl-copper complex (72-IV). Finally, the reductive elimination
235
236
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
of intermediate 72-III or 72-IV affords the expected product. In the substituted
allyl chlorides, the elimination selectively takes place at the less hindered end of
the π-allylic system. For example, 3-chlorobut-1-ene gave a similar product like
chlorobut-2-ene in the reaction. Notably, the phosphine ligand plays a crucial role
in the reactivity/selectivity of the reaction.
In 2008, Cheng and his coworkers reported the three-component coupling of
arynes with terminal alkynes (80) and activated alkenes (14) in the presence of
CuI/PCy3 system in a mixture of MeCN:THF giving 1-alkyl-2-alkynylbenzenes
(101) in good yields [73]. A possible mechanism of this reaction was shown in
Scheme 6.73. Alkynyl cuparation of arynes with copper acetylide complex (72-I)
affords arylcuprous intermediate (72-II). The conjugate addition of intermediate
72-II with alkene gives intermediate (72-III). Later, the protonation of intermediate
72-III provides the expected product and regenerates the active catalyst.
H
R
R′
TMS
+
1
OTf
+
2
R
80
R3
14
CuI (10 mol%)
PCy3 (2 mol%)
CsF, MeCN/THF
50 °C, 5 h
R2
R
101
R3
R′
17 examples, 32–82%
Bu
R2
Bu
COEt
COEt
R3
R
R′
R, R′ = H, 80%
R, R′ = Me, 82%
R, R' = –OCH2O–, 75%
R, = Me, R′ = H,
R, = H, R′ = Me+ (1 : 1) 79%
H
R
R2 = n-octyl, 77%
R2 = Ph, 59%
R2 = t-Bu, 75%
R2 = 3-thienyl, 56%
R
Cu
R3 = CO2Et, 65%
R3 = CN, 39%
R3 = SO2Ph, 32%
R
R
Cu
–HF
R
73-I
R or HCO3–
Cu
73-II
+ HF
101
73-III
Scheme 6.73 Cu-catalyzed multicomponent coupling of arynes with terminal alkynes and
activated alkenes.
Kobayashi and coworkers developed a copper-catalyzed three-component coupling of terminal alkynes with arynes and carbon dioxide providing isocoumarins
in moderate-to-good yields (Scheme 6.74). Notably, the NHC-copper complex plays
a crucial role in controlling the selectivity and yielding the expected isocoumarins
102 in a highly selective manner [74]. The reaction was well tolerated with substituted aryne precursors as well as aryl/alkyl-substituted terminal alkynes. In the catalytic cycle, the first copper-acetylide complex (74-1) was generated by NHC-copper
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
carbonate or hydroxide with terminal alkyne. Coordinative insertion of benzyne
with copper-acetylide complex (74-I) provides ortho-alkynyl copper complex (74-II).
Next, the intermediate (74-II) undergoes insertion with CO2 generates copper carboxylate intermediate (74-III). It further undergoes a 6-endo-dig cyclization and
gives an endocyclic copper heterocycle (74-IV). Finally, the transmetalation of intermediate (74-IV) with a cesium salt (73-V) followed by protonation gives the expected
isocoumarin 102 and regenerates the active catalytic for the next catalytic cycle.
TMS
R1
+ H
R
OTf
1
MeCN/THF (1 : 1), 90 °C
O
O
Me
O
R
O
R1
Me
R1 = Ph, 72%
R1 = 2-napthyl, 74%
R1 = p-ClC6H4, 52%
R1 = p-OMeC6H4, 70%
O
R
O
O
O
+
Ph
Ph
84%
102
R1
15 examples, 33–84% yield
80
O
O
[(IPr)CuCl] (10 mpl%)
Cs2CO3/CsF, CO2 (15 atm)
R
Ph
R = Me, 77% (1 : 1.1)
R = Cl, 48% (1 : 1)
O
[(IPr)CuCl]
102
H+
O
Cs2CHO3
Ph
74-V [Cs]
H
Ph
[Cu]
[Cs]
O
H2O
O 74-IV
[Cu]
Ph
74-I
Ph
[Cu]
O
O
74-III
[Cu]
[Cu]
Ph
74-II
Ph
CO2
Scheme 6.74 [(IPr)CuCl]-catalyzed synthesis of isocoumarins from multicomponent
reaction between alkynes, arynes, and CO2 .
A copper-mediated three-component coupling of arynes, allyl bromides, and a
CF3 source providing trifluoromethylated allylbenzenes 103 in good yields was
237
238
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
reported (Scheme 6.75) [75a]. This protocol provides a wide range of structurally
diverse trifluoromethylated allylarenes in good-to-excellent yields. Unsymmetrical
benzynes afforded a mixture of regioisomeric products with different ratios. In
addition, this method was successfully applied to the synthesis of CF3 -containing
analogue of the antispasmodic drug papaverine [75b]. The [CuCF3 ] reagent is
generated from the cheap industrial byproduct fluoroform (CF3 H). Initially, the
insertion of the Cu—CF3 bond to aryne affords the ortho-trifluoromethyl arylcopper
intermediate 75-I. Similar types of metal–CF3 bond [75c] or Cu—C bond [70] to
arynes have been known in the literature. The intermediate 75-I is transformed
into a Cu-π-allyl type (75-II) through oxidative addition with allyl bromide. Finally,
the reductive elimination of 75-II affords the corresponding trifluoromethylated
allylarenes 103.
TMS
R
1
OTf
R2
R3
Br
R4
6
R1
[CuCF3]
TBAF · 3H2O
R1
R = tBu, 41%, (57 : 43)
R = Ph, 84%, (50 : 50)
R = OMe, 79%, (25 : 75)
R = Cl, 30%, (19 : 81)
R = TMS, 68%, (63 : 37)
+
O
CF3
R
CF3
CF3
80%
R2
O
O
CF3
CO2Et
O
O
R2 = 4-Me, 75%
R2 = 4-OMe, 80% O
R2 = 4-Br, 74%
O
CF3
60%
OMe
CF3
69%
OMe
OMe
OMe
Derivatization
O
O
R2
103
CF3
30 examples, 30–92% yield
R
O
R3
R
DMF, 23 °C, 15 h
R4
O
O
CF3
N
CF3
CF3–papavarine (antispasmodic)
O
Mechanism
Cu
[CuCF3]
75-I
CF3
Br
Cu
CF3
75-II
CF3
Scheme 6.75 Trifluoromethylation–allylation of aryne with [CuCF3 ]. Source: Based on
Yang and Tsui [75a].
A copper-catalyzed versatile synthesis of o-alkynyl aryl iodides (105) has been
developed via three-component coupling of arynes with terminal alkynes and NIS
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions
[76]. Phenyl acetylenes having an electron-donating or electron-withdrawing substituents on benzene ring smoothly participated in the three-component reaction
in good (Scheme 6.76). Moreover, this catalytic reaction is highly compatible with
amino, thioether, halides, ester, carbonyl, trifluoromethyl, cyano, and nitro functional group on the aromatic moiety.
TMS
O
+
R
1
I
N
80
OTf
H
R1
I
R1
O
104
R
MeCN, 60 °C, 12 h
105
R1
47 examples, 54–83%
I
R1 = H, 78%
R1 = o-CO2Me, 75%
R1 = m-Cl, 78%
R1 = p-tBu, 81%
I
I
IMesCuCl (10 mol%)
Cs2CO3, CsF
R1
I
R1 = 3-thienyl, 61%
R1 = 3-pyridyl, 60%
R1 = mesityl, 57%
N
I
R
R
56%
R = OMe, 68%
R = Me, 69%
TMS
R
OTf
+
O
I
N
55%
I
O Condition
I
R = OMe, 68%
R = Me, 69%
Br
S
S
Synthesis of polycyclic aromatics
Scheme 6.76
NIS.
6.4.4
106
Br
Copper-catalyzed iodoalkynylation reaction of arynes, terminal alkynes, and
Silver-Catalyzed Three-Component Coupling in Arynes
Wu and coworkers reported the multicomponent reaction of alkynylbenzaldehyde
(31) with tosylhydrazine (107), and benzyne 1 in the presence of a silver catalyst providing substituted pyrazolo[5,1-a]isoquinolines 108 in good-to-excellent
yields (Scheme 6.77) [77]. The catalytic reaction proceeds via the formation of
isoquinolinium-2-ylamide intermediate by the reaction of tosylhydrazine with
alkynylbenzaldehyde in the presence of Ag. It further undergoes [3+2] cycloaddition with the benzyne unit that affords pyrazolo[5,1-a]isoquinoline 108 and
regenerates the silver catalyst for the next catalytic cycle.
239
240
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
TsNHNH2
107
CHO
R
TMS
+
OTf
1
R
OMe
F
AgOTf (10 mol%)
CsF, Et3NBnCl
MeCN:1,4-dioxane
108
R
8-examples, 83–98% yield
N N
N N
Ph
98%
98%
N N
1
F
MeO
N N
R
N N
Ph
Ph
94%
90%
CHO
N N
1
R
R1
TsNHNH2
AgOTf
+
N
Aromatization
–
NTs
R1
H
[3+2] Cycloaddition
N N
Ts
R1
Scheme 6.77 Synthesis of H-pyrazolo[5,1-a]isoquinolines via three-component reaction of
2-alkynylbenzaldehyde, tosylhydrazine, and benzyne. Source: Based on Yang et al. [77].
6.5 Metal-Catalyzed Addition of Metal–Metal (or)
Metal–Carbon and C—X bonds into Arynes
The direct addition of metal–metal (or) metal–carbon bond to the organic
π-components remains the challenging task in metal-catalyzed organic synthesis.
This method provides for the direct synthesis of C—X (X = B, Sn, and Si) bonds from
various E—E (E = B, Sn, and Si) interelemental bonds. This type of product has
widespread synthetic application across the chemical field, including the synthesis
of pharmaceuticals, natural products, agrochemicals, etc.
6.5.1
Palladium-Catalyzed C—Sn Bond Addition to Arynes
Hiyama and his coworkers reported a palladium-catalyzed σ-bond addition of C–Sn
of alkynylstannane with benzynes (Scheme 6.78) [78]. Treatment of benzyne precursors 1 with tributyl(phenylethynyl)tins (75) in the presence of a palladium catalyst
and CsF at 50 ∘ C for three hours in CH3 CN produced carbostannylation products
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
109 in 30–54% yields. In this reaction, a palladium-catalyzed direct crosscoupling of
C—OTf bond of 1 with alkynylstannane 75 followed by fluoride ion–induced protodesilylation was also observed. In the reaction, unsymmetrical aryne precursor
provided a mixture of two regioisomeric products 109 and 109′ .
+
SnBu3
SiMe3
+
1j
[Pd2Cl2(n3-C3H5)2]
Ligand
R
SnBu3
Ph
PPh2
ligand
109
75
OMe
SnBu3
30–54 %
R = aryl, alkyl
OTf
N
CsF, 50 °C, CH3CN
OTf
1
R
[Pd2Cl2(n3-C3H5)2]
Ligand
R
SiMe3
OMe
OMe
SnBu3
R
+
CsF, 50 °C, CH3CN
R
SnBu3
Ph
R=
80
58% ( 46 : 54 ratio)
109
109′
Scheme 6.78 Palladium-catalyzed carbon–Sn bond addition to arynes. Source: Based on
Yoshida et al. [78].
6.5.2
Palladium-Catalyzed Sn—Sn/Si—Si Bond Addition to Arynes
Kunai and coworkers described a palladium-catalyzed addition reaction of
σ-bonded Si–Si with benzynes (Scheme 6.79) [79a]. When benzyne precursor
1 was treated with disilane 110 in the presence of Pd(OAc)2 , t-OcNC, KF, and
18-crown-6 in tetrahydrofuran (THF), substituted disilane 111 was observed
in good-to-moderate yields. The reaction proceeds via oxidative addition of
silicon–silicon bond with a metal to give disilyl-palladium species. Coordinative
insertion of aryne with disilyl-palladium species followed by reductive elimination provides bis-silylation product 111. The bis-stannylation reaction was also
achieved with arynes as well as cyclohexynes in moderate yields under similar reaction conditions. Interestingly, the bisaryne precursor 1 converted into
bis[3,4-bis(tributylstannyl)phenyl] ether 113a, in which four carbon–Sn bonds
are formed in one pot. When the palladium-catalyzed reaction was carried in the
presence of ETPO (4-ethyl-2,6,7-trioxa-1-phosphabicyclo-[2.2.2]octane) ligand 79A,
dimerization–distannylation product 113 was observed along with a minor amount
of 114 [79b].
6.5.3
Palladium-Catalyzed Ar—SCN Bond Addition to Arynes
The direct ArS–CN addition to aryne C—C multiple bond with the aid of a palladium catalyst has been reported by Werz and coworkers (Scheme 6.80) [80]. In this
conversion, the new C—SAr and C—CN bonds are formed in one step with the combination of Pd(OAc)2 and a large bite angle having Xantphos ligand. Interestingly,
under oxygen atmosphere, the yields increased besides minimizing the formation
241
242
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R
Me
Me
Me Si
Me Si
Me
SiMe3
+
OTf
1.20
Pd(OAc)2, t-OcNC
KF, 18-crown-6, THF
20 °C, 1.5 h
R
110
Me
Si
R = H (81% yield)
R = 6-Me (70% yield)
R = 3-OMe (72% yield)
R = 4-Me (63% yield)
Si
Me Me
111
SiMe3
R
1.20
(or)
OTf
+
OTf
SnR′3
SnR′3
KF, 18-crown-6, THF
R
O
TfO
113
SiMe3
+
Bu3Sn SnBu3
OTf
Pd(OAc)2, t-OcNC
Bu3Sn
KF, 18-crown-6, THF
24 h
Bu3Sn
SiMe3
1
Me3Sn SnMe3
OTf
112
O
SnBu3
113a
SnBu3
30% yield
112
+
SnR′3
SnR′3
R′ = Me (or) Bu
SiMe3
Me3Si
(or) R″
112
R″
SnR′3
SnR′3
Pd(OAc)2, t-OcNC
Pd(OAc)2, KF
SnMe3
SnMe3
18-crown-6, THF
Et
O
78A
P
O
O ETPO
+ 113
114
Scheme 6.79 Palladium-catalyzed bis-silylation/bis-stannylation of arynes. Source: Based
on Yoshida et al. [79a].
of side products. The electron-withdrawing 4-CF3 -thiobenzonitrile was less reactive
for the cyclization with aryne. Meanwhile, two aryne-bearing fluorine substituents
gave the desired thio-cyanation product in less than 5% yield, which was measured
by GC-MS.
SCN
R
TfO
R1
+
115
CN
Pd(OAc)2, Xantphos
TMS
CsF, MeCN, O2
40 °C, 18 h
S
R1
R
116
R = H, Me, OMe, F, Br
R1 = 3-Me, 4-Me, 4,5-F, 4,5-OMe
Scheme 6.80 Direct ArS–CN addition to aryne C—C multiple bonds by Pd catalyst. Source:
Pawliczek et al. [80].
In 2014, Ma and Yuan developed a cascade reaction for the synthesis of
2,3-disubstituted benzofuran derivatives in moderate-to-good yields from the
alkynyl-substituted arynes with aryl halides in the presence of a Pd(0) catalyst
(Scheme 6.81) [81]. This protocol offers an efficient and different approach to benzofurans. This heterocyclic compound has potential application in pharmacological
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
and biological chemistry. The reaction proceeds via intramolecular ene reaction
of benzyne-yne intermediate (81-I) giving allene intermediate (81-II). Further, the
ArPdI undergoes insertion with (81-II) forming a π-allylic palladium intermediate
(81-III). Subsequent, β-H elimination of intermediate (81-III) affords unexpected
isomeric benzofuran derivatives [81].
R1
O
OTf
R
TMS
117
+
R2
34
O
R2
Pd(PPh3)4 (5 mol%)
CsF (3.0 equiv)
I
MeCN, reflux
16 examples, 34–55% yield
R2 = Ph, 55%
R2 = p-MeC6H4, 46%
R2 = p-FC6H4, 46%
R2 = p-BrC6H4, 47%
O
O
C
81-I
R1
O
R = Me, 50%
R = Et, 48%
R
ArPdI
Ene reaction
ArI
O
81-II
Ar
CsF
O
O
R2
118 R
Pd(0)
PdI
81-III
TMS
OTf
HPdI
Ar =
R2
Ar
O
Scheme 6.81 Synthesis of 2,3-disubstituted benzofurans by palladium catalyst. Source:
Modified from Yuan and Ma [81].
6.5.4
Platinum-Catalyzed Boron–Boron Bond Addition to Arynes
It is known that the Pt(0) complex was effective for the addition of E—E interelement bonds into the C—C multiple bonds. With this idea, Yoshida et al. developed
a platinum-catalyzed addition of B2 pin2 to arynes giving 1,2-diborylarenes in
good-to-excellent yields [82]. This transformation is effective only with the
platinum-isocyanide complex. Various other arynes were found to undergo the
same transformation with bis(pinacolato)-diboron. It is significant to note that the
1,2-diborylarenes are relatively stable to air, moisture, and column chromatography
and thus offer various synthetic advantages. For example, 1,2-diborylarene was
converted into symmetrical and unsymmetrical ortho-terphenyls via a Pd-catalyzed
Suzuki–Miyaura crosscoupling reaction (Scheme 6.82).
243
244
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
SiMe3
+
R
1
OTf
Me
Me
O
Me
Me
O
O
Me
Me
Pt(dba)2, 1-AdNC
KF, 18-crown-6
O
Me
Me
DME, 80 °C
B B
119
R
R = 4-Me (73%)
B(pin) R = 4-OMe (78%)
R = 4-F (73%)
B(pin) R = 4-Ph (67%)
R = 3,6-Me2(44%)
120
Symmetrical and unsymmetrical o-terphenyls through Pd-catalyzed Suzuki–Miyaura coupling
Ar–I
Pd[P(t-Bu)3]2
Cs2CO3
Ar
DME/H2O, 80 °C
121
B(pin)
B(pin)
Ph–I
Pd(PPh3)4
KOH
DME/H2O, 40 °C
Scheme 6.82
Ar
Ph
18a
B(pin)
Ar–I
Pd[P(t-Bu)3]2
Cs2CO3
DME/H2O, 80 °C
Ph
121a
Ar
Platinum-catalyzed addition of B2 pin2 to arynes.
Similarly, a platinum-catalyzed diborylation reaction of indolynes with
bis(pinacolato)diboron in the presence of tBuNC ligand was reported (Scheme 6.83)
[83]. This protocol is useful for the synthesis of unprecedented indole-building
blocks. The reactivity of two boron sites in the 6,7-bis[(pinacolato)boryl]indole
120a moiety can be differentiated by a stepwise Suzuki–Miyaura crosscoupling
reaction. In the reaction, the arylation was done site-selectively at the C7 position of indole without disturbing the C6 position. Later, the C6 position was
also subjected to Suzuki–Miyaura crosscoupling in the presence of a palladium
catalyst and Cs2 CO3 base. On the other hand, the authors have observed that the
4,5-bis[(pinacolato)boryl]indole 120b (or) 4,5-bis[(pinacolato)boryl]indole 120c
provided mixtures of crosscoupling products under similar reaction conditions.
6.5.5
Copper-Catalyzed B—B Bond Addition to Arynes
In 2012, Yoshida et al. developed an efficient copper-catalyzed vicinal-diborylation
of arynes with B–B reagent [84]. This transformation is highly selective with a
different mono- and di-substituted arynes. In this transformation, the expected
vic-diborylarenes were observed in good yields. The borylcopper species 84A is a key
intermediate for the diborylation of benzyne was proposed. It has been generated
by the reaction of copper acetate with the diboron reagent (Scheme 6.84).
6.5.6
Copper-Catalyzed Ar—Sn Bond Addition to Arynes
Yoshida and his coworkers developed a Cu-catalyzed coupling of arylstannes with
benzynes giving ortho-stannylbiaryls and teraryls in good yields [85]. In this reaction, electron-deficient (fluoro (or) trifluoro arenes) substituted tin played a vital
role for the efficient conversion. Notably, no product was formed with phenylstannane under similar reaction conditions. To prove this, the authors estimated the
tin electron deficiency by 119 Sn NMR chemical shift, which indicates upfield shift
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
Me
N
1k
Me N
–
Pt(dba)2 (5–7.5 mol%)
tBuNC (25–35 mol%)
KF (2 equiv)
18-crown-6 (2 equiv)
(Bpin)2 (1.5 equiv)
DME, 85 °C
SiMe3
1l
1m
Me N
Pt(dba)2 (5–7.5 mol%)
tBuNC (25–35 mol%)
KF (4 equiv)
18-crown-6 (2 equiv)
(Bpin)2 (1.5 equiv)
DME, 75 °C
Bpin
Me
N
SiMe3
OTf
OTf
SiMe3
OTf
Pt(dba)2 (10 mol%)
tBuNC (45 mol%)
KF (2.5 equiv)
18-crown-6 (2.5 equiv)
(Bpin)2 (2.5 equiv)
DME, 85 °C
Bpin
Bpin
Bpin
Bpin
120a
Me N
6,7-Bis[(pinacolato)boryl]indole
Ar1-I (1 equiv)
PdCl2(dppf) (10 mol%)
KOH (1.7 equiv)
DME/H2O (30 : 1)
40 °C
70%
4,5-Bis[(pinacolato)boryl]indole
Ar1
Me
N
Bpin 120b
Bpin No regioisomer and
18b no biscoupling
120c
Me N
55%
5,6-Bis[(pinacolato)boryl]indole
Suzuki–Miyaura coupling gives
neither regio (nor) chemoselective
product
Ar2–I (1 equiv)
Same as above
condition
Ar1
Me
N
Ar2
121b
Scheme 6.83 Platinum-catalyzed diborylation reaction of indolynes with
bis(pinacolato)diboron. Source: Based on Pareek et al. [83].
TMS
+ B(pin) B(pin)
R
1
R
R
OTf
119
[(PPh3)3CuOAc] (2 mol%)
KF (3 equiv)
R
18-crown-6 (1.5 equiv)
1,2-Diethoxyethane, 100 °C
R
B(pin)
B(pin)
Scheme 6.84
R = –(CH2)3–, 24 h, 73%
R = Me, 12 h, 69%
B(pin)
B(pin)
120
B(pin)
B(pin)
B(pin)
Cu
(PR3)n
84A
R = Me, 14 h, 79%
R = Ph, 20 h, 55%
R = TMS, 22 h, 69%
Cu-catalyzed vicinal-diborylation of arynes.
of a number of fluorine decreases. It should be noted that other electron-deficient
substitution on the arylstannanes showed less reactive (or) no reaction with arynes.
For example, 2-cyanophenylstannane gave the expected product in 24% yield. However, 4-pyridylstannane failed to give the expected product. The selective formation
of ortho-stannylbiaryls and teraryls can be achieved by changing the equivalent of
aryne precursor (Scheme 6.85).
245
246
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Step-I
R
TMS
+
OTf
1.0 equiv
F5
78
F5
SnBu3
Me
78%
F5
Me
Me
122
R
SnBu3
18-crown-6 (1.0 equiv)
DEE, 130 °C, 6 h
1.0 equiv
Me
F5
CuTC (5 mol%)
KF (2.0 equiv)
SnBu3
SnBu3
F5
F
F
F5
Cl
SnBu3
SnBu3
OMe
66%
40%
68%
Step-II
TMS
R
F5
F5 CuTC (5 mol%)
KF (2.0 equiv)
R
+
OTf
SnBu3
F5
R
18-crown-6 (1.0 equiv)
DEE, 130 °C, 6 h
F5
Bu3Sn
F5
F5
Me
OMe
Bu3Sn
Bu3Sn
87%
55%
OMe
Bu3Sn
54%Me
Cl
Bu3Sn
63%
Ar
Ar–SnBu3
Bu3Sn
Ar
F–SnBu3
Ar–Cu
Cu
F–SnBu3
Cycle–2
Cycle–1
CuF
F-SnBu3
Ar
Ar
Cu
Ar
Cu
F–SnBu3
SnBu3
Scheme 6.85 Copper-catalyzed synthesis of ortho-stannylbiaryls from arynes and
arylstannanes.
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
6.5.7
Copper-Catalyzed sp C—H Bond Addition to Arynes
In 2009, Biehl and his coworker reported a copper(I)-catalyzed coupling of terminal alkynes with arynes in a mixture of acetonitrile:toluene (1 : 1) solvent under
the microwave-assisted heating for 30 minutes at 150 ∘ C (Scheme 6.86) [86]. This
method offers symmetrical and unsymmetrical alkynes in a short reaction time in
moderate-to-excellent yields as compared with the conventional methods.
TMS
R
1
R1
+
OTf
80
R1
R1 = NO2, 94%
R1 = F, 86%
R1 = Me, 95%
CuI (2.8 mol%)
CsF, MW
CH3CN/Tol (1 : 1)
150 °C, 30 min
R
3
59–97% yield
R1
R1
R1 = CO2Et, 63%
R1 = Me, 86%
R1 = 2-Py, 77%
MeO
97%
Scheme 6.86 Copper-catalyzed terminal alkynes sp C—H bond addition to arynes. Source:
Based on Akubathini and Biehl et al. [86].
6.5.8
Gold/Copper-Catalyzed sp C—H Bond Addition to Arynes
In 2008, Zhang and coworkers developed a gold(I)- and copper(I)-catalyzed coupling
of terminal alkynes (80) with arynes leading to 2-alkynylated biaryl frameworks
(123) in good-to-excellent yields (Scheme 6.87) [87]. The catalytic cycle involves
the initial coordination of an aryne to the Au(I)-catalyst gives aryne-gold complex.
Meanwhile, an alkynyl-Cu(I) intermediate (87-I) that reacted with benzyne gives
a alkynylated-aryl copper species (87-II). Finally, the nucleophilic addition of
alkynylated-aryl copper to the aryne-Au(I) complex (87-III) affords intermediate
(87-IV). Later, intermediate (87-IV) undergoes protonation giving the 2-alkynylated
biaryl compounds.
Similarly, Yoshida et al. reported a copper(I)-catalyzed coupling of terminal
alkynes with two arynes under the modified reaction conditions (Scheme 6.88)
[88]. Terminal alkynes bearing a m-tolyl, methyl propargyl ether, and t-butyl
substituents selectively gave 2 : 1 coupling products 123 in reasonable yield.
1-Naphthylacetylene afforded 2 : 1 coupling product along with 13% of direct
addition product 3. Interestingly, ethyl propiolate with benzyne gave ethyl
2-(9H-fluoren-9-ylidene)-2-phenylacetate (44) in 26% yield under standard reaction
conditions. The product 44 is constructed through arylcopper intermediates (88-I
and 88-II) and arynes.
247
248
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
R1
TMS
R
+
1
Au(PPh3) (10 mol%)
CuI (10 mol%)
CsF, THF, 40 °C, 1 h
OTf
52–89%
H
R1
R1
Me
123
R
R1 = 2-Py, 57%
R1 = p-Tolyl, 68%
R1 = p-OMe-C6H4, 70%
R1 = n-Bu, 88%
Me R1 = p-Tolyl, 68%
R1 = p-F-C6H4, 74%
Me
Me
R1
Au
1
R
R1
86-III
Cu(I)
–HI
Au(I)
Au
Cu
Cu
87-I
H
R1
87-IV
87-II
123
Scheme 6.87 Gold and copper cocatalyzed coupling reactions of terminal alkynes with
arynes. Source: Based on Xie et al. [87].
R
+
H
TMS
1
CuCl (5 mol%)
KF, 18-Crown-6
OTf
THF, 50 °C, 4 h
H 80
R1
11 examples, 32–71%
R
+
R
123
R1
Minor
Major
R1
3
OMe
60% + 3 (13%)
53%
CO2Me
CO2Me
Cu
5-exo-dig
Cyclization
88-I
40%
Cu
88-II
32%
CO2Me
Ph
44
Scheme 6.88 Copper-catalyzed two-component coupling reactions. Source: Based on
Yoshida et al. [88].
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
6.5.9
Copper-Catalyzed C—Br Bond Addition to Arynes
Subsequently, Yoshida and his coworkers reported a copper-catalyzed bromo alkynylation of arynes with bromoalkynes giving mixtures of 2-bromo-alkynyl-biphenyls
123 (major) and 2-bromo-alkynylarene 105 (minor) in good yields with high
selectivity (Scheme 6.89) [89]. The catalytic reaction proceeds through the bromocuparation (89-I) of an aryne with CuBr2 . The second insertion of aryne
moiety into the Cu—C bond leads to the intermediate (89-II). It undergoes
further coupling with the bromo-alkyne and provides the substituted-biphenyl
product. In the reaction, 2-bromo-alkynylarene was also formed as a side product. In the reaction of aryl-substituted allyl bromide as well as aryl-substituted
propargyl bromide, mixture of regioisomeric products, 2-bromo aromatics, were
observed.
6.5.10 Copper-Mediated 1,2-Bis(trifluoromethylation) of Arynes
A novel copper-mediated 1,2-bis(trifluoromethylation) of arynes with [CuCF3 ]
was reported (Scheme 6.90) [90]. This protocol provides structurally diverse
1,2-bis(trifluoromethylation) in one pot under mild and safe conditions. Furthermore, estrone-based aryne was also successfully involved in the reaction
giving 1,2-bis(trifluoromethylated) derivative in good yields. In the reaction,
CuCl reacts with CF3 H in the presence of base giving fluoroform [CuI CF3 ]. It is
highly reactive and quickly oxidized by DDQ to [CuII CF3 ]. The [CuII CF3 ] reacts
with aryne providing an aryl radical intermediate 90-I. The formation of radical
intermediate was supported by the radical clock experiment [90b, c]. Intermediate
(90-I) combined with a second equivalent of [CuII CF3 ] provides a [CuIII CF3 ]
species (90-II) [90d]. Finally, reductive elimination of intermediate (90-II) affords
1,2-bis(trifluoromethylation) product.
In general, the introduction of the CF3 group into an adjacent aromatic ring is
a challenging and important task for the synthetic chemist. In 2013, Hu and his
coworkers developed a method for the synthesis of ortho-trifluoromethyl iodoarenes
129 by the three-component assembling of arynes with 1-iodophenylacetylene 80c
and AgCF3 in the presence of 2,2,6,6-tetramethylpiperidine (TMP) [75c]. This
method offers a facile and efficient route for several ortho-trifluoromethyl
iodoarenes in excellent yields, which is difficult to achieve with other methods
(Scheme 6.91) [91]. It was found that the TMP has played an important role in
the vicinal difunctionalization of the aryne. The possible catalytic cycle involves
the formation of intermediate 91-I by the reaction of aryne with AgCF3 and TMP.
The intermolecular hydrogen bond of TPM of intermediate 91-I with another TMP
unit gives intermediate 91-II. Next, the abstraction of H+ from 91-II followed by
coordination of 91-I group of 1-iodophenylacetylene forms intermediate 91-III.
Finally, the “ate” complex 91-IV was formed by intramolecular nucleophilic attack,
which reshuffles to afford the expected ortho-trifluoromethyl iodoarenes. It is
noteworthy that the m-phenyl- and methyl group substituted aryne precursors
provided mixtures of regioisomers in 1 : 1 ratio.
249
250
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R
CuBr2 (20 mol%)
KF, 18-crown-6
OTf
+
R1
R
123
DME, 25 °C, 10–20 h
80a
Br
Me
R
R
+
105
Br
Me
Me
Me
+
R1
Minor
Major
1
16 examples, 38–81% yield R
Br
Br
Br
+
Me
R1
Me
R1
Br
Br
TMS
1
R1 = 2-Napthyl, 86%
(20 h, ratio = 81 : 19)
R1
R1
= p-Me-C6H4, 81%
(14.5 h, ratio = 72 : 28)
R1
Br
Br
+
R1
R1 = p-CN-C6H4, 63%
(18 h, ratio = 68 : 32)
R1
Br
Br
R
R
CuBr2
R1
R1
R1
R1
Br
Br
R
Br
R
Br
R
BrCu
89-II
CuBr2 (20 mol%)
KF, 18-Crown-6
OTf
+
DME, 25 °C
124
Ph
Ph
Br
TMS
OTf
+
Ph
Scheme 6.89
et al. [89].
Br
Br
TMS
+
CuBr
89-I
Br
(56%, ratio = 77 : 23) Ph
Br
CuBr2 (20 mol%)
KF, 18-Crown-6
DME, 25 °C
125
Br
+
Ph
126
Ph
127
(49%, ratio = 31 : 69)
Copper-catalyzed bromo alkynylation of arynes. Source: Based on Morishita
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
TMS
R
1
OTf
CF3
[CuCF3]/ DDQ
R
DMF: DMSO, rt, 24 h
128
CF3
24 examples, 0–82% yield
R
CF3
R
CF3
R
62%
CuCl
+
CF3
CF3
R
R = Ph, 48%
CF3H
2 t-BuOK
R
CF3
R
CF3
R
CF3 R = Ph, 78%
R = OMe, 60%
CF3 R = Cl, 50%
R = TMS, 50%
R = –O–CH2–O, 78%
R = OMe, 62%
O
[CuICF3]
O
Et3N(HF)3
DDQ
[CuIICF3]
TMS
R
R
R
CF3
90-I
CuIII
CF3
CuII
CF3
H
H
Estrone
F3 C
OTf
R
H
F3 C
R
CF3
90-II
CF3
R
CF3
H
R
CF3
Scheme 6.90 Copper-mediated 1,2-bis(trifluoromethylation) of arynes. Source: Yang and
Tsui [90a]; Okuma et al. [90b]; Yang et al. [90c]; Zhang et al. [90d].
Efficient silver-catalyzed insertion of perfluoroalkene-halide (Rf —I) bond
with arynes was achieved. This methodology provides an easy access to
ortho-perfluoroalkyl iodoarenes as well as I atom that has also transferred
efficiently (Scheme 6.92) [92]. The reaction mechanism proceeds via the insertion
of arynes into perfluoroalkyl-metal (MRf ) forming arylmetal intermediate. It
readily undergoes s-bond metathesis with Rf I affording the expected product and
regenerates the MRf . Notably, unsymmetrical benzyne gave mixture of regioisomers
in 8 : 1 ratio.
6.5.11 Copper- and Silver-Catalyzed Hexadehydro-Diels–Alder-Cycloaddition of a Triyne (or) Tetrayne (HDDA Arynes) with Terminal Alkynes
Interesting HDDA benzyne generation has been achieved by hexadehydro-Diels–
Alder-cycloaddition of a suitable triyne (or) tetrayne 131 by heating conditions
251
252
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
TMS
+
OTf
R
1
R
CF3
R
I
Ph
I
R = –O–CH2–O, 86%
R = –(CH2)3, 43%
R = H, 71%
R = Me, 51%
Ph
+
I
Ag
129
Ph
I
94%, (50 : 50)
CF3
R
+ Ph
I
Ag
I
AgCF3–TMP
R
I
CF3
CF3
AgCF3-TMP
Ph
R
MeCN, 50 °C, 5 h
10 examples, 35–94% yield
80c
R
CF3
CsF, TMP
+ [AgCF3]
Ag species
Ph
TMP
I Ar
91-IV
CF3
91-I
Ar Ag N
H H
B:
N
91-II
B: = F-
Ar Ag N
H
N
Ph
Ar Ag N
H
I N
91-III
Scheme 6.91 Synthesis of ortho-trifluoromethyl iodoarenes from the multicomponent
reactions of arynes, with 1-iodophenylacetylene, TMP, and AgCF3 . Source: Based on
Uchiyama et al. [91].
[93]. This benzyne is efficiently converted into bromoalkynylation 132 and
hydroalkynylation 133 by using Cu(I) catalyst (Scheme 6.93). 1-Bromo-1-alkynes
reacted with benzynes in the presence of CuBr (10 mol%), CH3 CN at 80 ∘ C
giving bromoalkynylation products in good-to-excellent yields, whereas CuCl
(5 mol%) induces the addition of terminal alkyne to HDDA benzyne to give
hydroalkynylation products in good yields. However, the regiochemistry of both
formed products is entirely different from one another. In the mechanism, the
aryl copper(I) species was formed by nucleophilic addition of CuBr with benzyne.
Then, it reacts with a bromoalkyne to generate the Cu(III) species followed
by reductive elimination giving desired product with a regeneration of Cu(I)
source for the next catalytic cycle. On the other hand, hydroalkynylation reaction
initiated through the formation of Cu-alkyne from arylcopper species of one
benzyne with CuCl. The Cu-acetylide undergoes addition with HDDA benzyne to
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes
TMS
CF3I
+
R
I
130
R
CF3
MeCN, rt, 12–24 h
OTf
R
I
[Phen-AgNO3-TMSCF3]
(5 mol%)
24 examples, 47–87% yield
R
I
Me
I
I
C2F5
R
C2F5
R
CF3
C2F5
R = H, 65%
R = H, 77%
Me
R = Me, 83%
60%
R = Me, 83%
R = –O–CH2–O, 71% R = –O–CH2–O, 69%
I
C2F5
+
N
Me
74%, (8.4 : 1)
N
Me
AgLn
R
TMS
Rf
Rf transfer
I+ transfer
R
R
Rf-I
OTf
I
R
[LnAgRf]
CF3
Scheme 6.92 Silver-catalyzed formal insertion of arynes into Rf —I bonds. Source: Based
on Zeng and Hu [92].
produce aryl copper(I) species, which abstracts the proton from terminal alkyne,
leading to the product with the regeneration of Cu-acetylide for the next catalytic
cycle.
An interesting approach for fluorinated, trifluoromethylated, and trifluoromethylthiolated indoline and isoindoline derivatives 134 has been efficiently
achieved by silver catalysts or silver-containing stoichiometric reagents
(Scheme 6.94) [94]. In this transformation, stoichiometric amount of AgBF4 in
toluene afforded fluoroarenes in good yields. The trifluoromethylation was achieved
by in situ generation of AgCF3 with the combination of AgF and TMSCF3 in acetonitrile solvent. The trifluoromethylthiolation reaction worked very efficiently in
toluene solvent with AgSCF3 . The reaction proceeds via the formation of arylcation
intermediate 94-II from Ag+ co-ordinated aryne species 94-I through thermal hexadehydro Diels–Alder reaction (or) vinyl cation 94A. Then, the addition of fluoride
ion or trifluoromethyl or trifluoromethyl-thiol group onto the aryl cation 94-II leads
to organosilver species 94-III. It undergoes subsequent protodeargentation giving
the final product and regenerates the active Ag(I)-catalyst.
6.5.12 Copper-Catalyzed P—H Bond Addition to arynes
A P-arylation of phosphine oxides via a ligand-free copper-catalyzed addition
of H—P(O) bond to aryne at room temperature was reported by Chen et al.
253
254
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
Me
Bromoalkynylation 132
CuBr (10 mol%)
CH3CN, 80 °C, 16 h
R1
Me
+
TsN
Me
Me
Br
131
N
Ts
4
N
Ts
5
Me
6
Br
7
132
1
via
Me
R
Me
TMS
Me
Me
Br
O
N
Ts
R1
Br R1 = Cl-pC6H4, 80%
R1 = CO2Me-pC6H4, 58%
R1 = TBS, 84%
R1 = CO2Et, 56%
Br
N
Ts
46%
68%
Me
Me
R′
Me
Me
rds
HDDA
N
Ts
N
Ts
Br
[CuI]
R′
R′
N
Ts
H
Ph
Then H2O
R′
Me
n-BuLi
N
Ts
Me
N
Ts
Br
Ph
R1
Br
CuBr
Me
Ph
Ph
R′
TsN
Me
R1
Br
CuIII
Br
Scheme 6.93 Copper-catalyzed bromoalkynylation and hydroalkynylation from
HDDA-generated benzynes.
[95]. This protocol was very effective for the preparation of arylphosphine
oxides 136 in good yields (Scheme 6.95). Arylphosphine oxides are key motifs
found in materials science and medicinal chemistry. The reaction proceeds
via the reaction of CuI with P—H bond of secondary phosphine oxide giving [R2 2 P(O)Cu] intermediate. Next, the aryne inserts into the Cu—P bond
of active intermediate to give arylcopper intermediate. Further, the protonation of intermediate (95-I) with another moiety of secondary phosphine oxide
affords a desired product and regenerates the active catalyst for the next catalytic
cycle.
6.6 Metal-Catalyzed CO Insertion Reactions of Arynes
Hydroalkynylation 133
R1
Me
TsN
4
5
+
Me
Me
Br
N
Ts
N
Ts
7
Me
6
H
via
133
R1
AcO
Me
R1 = F-pC6H4, 70%
R1 = CO2Me-pC6H4, 51%
R1 = TBS, 61%
Me R1 = CO Et, 59%
2
N
Ts
Me
CuCl (5 mol%)
NaAsc (50 mol%)
CH3CN, 80 °C, 16 h
TMS/H
O
H
R1
H
46%
TsN
Rds
Me
HDDA
Ph
N
Ts
H
83%
Ph
R′
Me
Me
OAc
R′
Me
R1
Me
CuCl
+
N
Ts
N
Ts
Cl
H
[CuI]
R′
Rds = Rate determining steps
Me
N
Ts
Me
Cl
H
R′
R1
Cu
Me
Me
N
Ts
N
Ts
R1
H
R′
Me
1
R
Scheme 6.93
H
N
Ts
[CuI]
R1
(Continued)
6.6 Metal-Catalyzed CO Insertion Reactions of Arynes
6.6.1 Cobalt-, Rhodium-, and Palladium-Catalyzed CO Insertion
of Arynes
Transition-metal-catalyzed carbonylation reaction of various organometallic species
with π-acceptor property of CO (gas) is a fundamental chemical transformation,
which is useful method for the synthesis of wide range of carbonyl-containing compounds. In this context, aryne is also an effective organic species with CO (gas) in
the presence of metal-catalyst.
Murai and his coworkers reported cobalt-, rhodium-, and palladium-catalyzed
carbonylative cycloaddition of benzynes with CO (Scheme 6.96) [96]. For example,
255
256
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
R1
Source
[AgX]
R1
Toluene, 90 °C, 4 h Y
Y
R
Z
131
Z
134
X = F, or, CF3, or SCF3
n-Bu
n-Hex
R
AgBF4
X
AgSCF3
AgCF3
Ph
n-Bu
n-Hex
TsN
N
Ts
X
X = F, 93%,
X = CF3, 76%, (o:m) (3 : 2)
X = SCF3, 78%, (o:m) (3 : 2)
Cl
N
Ts
X
X
X = F, 93%,
X = CF3, 75%
X = SCF3, 81%
X = F, 90%,
X = CF3, 75%
X = SCF3, 85%
Trapping of the putative organosilver intermediate
TMS
R1
TMS
NXS
AgBF4
TsN
R
TMS
Toluene
TsN
TMS
TsN
X = Br, 80%
X = I, 55%
X = Cl, 50%
X
Ag
F
X
R1
R1
HDDA
TsN
TsN
R
Ag
R1
R1
TsN
94-I Ag
R1
R1
94-II
+
TsN
bis-1,3-diyne
+
Ag
R
Ag 94A
R1
R1
TsN
ArX
H+
Ar = Indoline (or) isoindoline
Ag
X
94-III
X–
Scheme 6.94 Silver-mediated fluorination, trifluoromethylation, and
trifluoromethylthiolation of arynes. Source: Based on Wang et al. [94].
treatment of benzyne precursors 1 with CO (5 atm) in CH3 CN in the presence of Co2 (CO)8 and CsF at 60 ∘ C for 12 hours gave anthraquinones 137 in
good-to-excellent yields. The same reaction was carried out in the presence of
[RhCl(cod)]2 complex. In the reaction, a mixture of cyclized products 137 in 13%
and fluorenone 10 in 30% yields were observed. Similarly, when benzyne precursor
1 was treated with allyl acetate 6 under CO (1 atm) in CH3 CN in the presence of
[(π-C3 H5 )PdCl]2 , dppe, and CsF at 80 ∘ C for four hours, a 2-methyleneindanone 138
was observed in good-to-excellent yields.
6.6 Metal-Catalyzed CO Insertion Reactions of Arynes
+
R
R1
R1
TMS
OTf
CuI (5 mol%)
O P H
CsF, MeCN, rt
O P
135
R1
O P
R1
38 examples, upto 98% yield
R1 = 3-Me, 98%
R1 = H, 95%
R1 = 4-F, 99% O P
R1 = 4-Me, 82%
R1
R1
R1
O
P R1
H
R
R1
R1
136
R = Me, R1 = 3-OMe, 91%
R = Me, R1 = H, 95%
R R = OMe, R1 = H, 71%
R = (CH2)3, R1 = 3-OMe, 88%
R = (CH2)3, R1 = H, 99%
R
O
R1 P R1
Cu
CuI
O
R1 P R1
H
O
R1 P R1
Cu
95-I
Scheme 6.95 Synthesis of triarylphosphine oxides from diarylphosphine oxides and
arynes by copper catalyst.
Interestingly, aryne is selectively inserted into a Pd—C bond of six-membered
palladacycle in the presence of CsF, acetonitrile at room temperature giving a stable
eight-membered palladacycle 142 (Scheme 6.97) [97]. This insertion reaction allows
to synthesize various dimeric eight-membered palladacycles in good-to-excellent
yields. The eight-membered palladacycle can also be further stabilized by ligands such as 4-picoline (or) PPh3 . The structure of eight-membered palladacycle
141 was confirmed by a single-crystal X-ray analysis. This eight-membered palladacycle can be converted into various useful organic molecules. For example,
2,2′ -functionalized biaryls can be prepared in good yields in the presence of
CO/MeOH combination. A similar concept can be extended to synthesize
ten-membered heterocycles 143 by the reaction with CO. It is important to
note that the ten-membered heterocycles 144 can be formed by the reaction of
two molecules of benzynes with the ortho-metalated primary phenethylamines
(Scheme 6.97).
257
258
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
SiMe3
O
cat Co2(CO)8
CsF
+ CO (5 atm)
CH3CN, 60 °C
12 h
OTf
1
O
137
+ CO (2 atm)
OTf
O
[RhCl(cod)]2
CsF
SiMe3
137
CH3CN, 60 °C
12 h
+
10
1
SiMe3
OAc
+
O
[(allyl)PdCl]2
dppe, CO (1 atm)
CH3CN, 80 °C
OTf
6
1
138
Scheme 6.96 Metal-catalyzed carbonylative coupling of arynes with CO or allylacetate.
Source: Based on Chatani et al. [96].
R
R
R Y
NH3
CO2Me
X
X
CO
MeOH
X
–Pd(0)
X
R
R
NH
Pd Y
2
L
X
141
Dimer complex
Y
R
Me
H
140b Br
H
OMe
X
Me
H
141b
NH2
Pd
SiMe3
CsF
1
Y
2 MeCN, rt
139
Benzyne (2 equiv)
Br
H
X
O
X
CO
-Pd(0)
X
R
Cl
R
R
OTf
+
NH2
X
Y
141a
Benzyne (1 equiv)
X
140a Cl
X
NH2 Y
Pd
L
4-pic
OMe PPh3
NH2 Y
Pd
X
2
X
L
2
X
X = OMe
X = OMe
Y = Br
143
R
NH2
Pd Y
L
X
142
144
Y = Br
Scheme 6.97 Aryne reactions with six-membered palladacycle. Source: García-López et al.
[97a]; Oliva-Madrid et al. [97b]; Oliva-Madrid et al. [97c].
6.6 Metal-Catalyzed CO Insertion Reactions of Arynes
A palladium-catalyzed three-component reaction of arynes with carbon monoxide and 2-iodoanilines 48 was developed to construct phenanthridinone (47) and
acridone derivatives (145) [98]. The product formation is achieved under two distinct
reaction conditions (Scheme 6.98). For example, the phenanthridinones are selectively formed under the ligand-free conditions. But, a slow generation of benzyne in
the presence of dppm ligand exclusively affords acridones. Further, this method can
also be applied to synthesize phenanthridinones and acridones alkaloids. A plausible mechanism was suggested based on the control experiments.
TMS
O
N
R2
2
Pd(OAc)2, K2CO3 R
CsF, TBAI
R
MeCN (10% H2O)
CO (balloon)
100 °C, 12 h
47
R1
+
R1
R1
R2
MeCN, CO (balloon)
100 °C, 12 h
I
N
48 H
O
Pd(OAc)2, K2CO3
dppm, KF
OTf
N
R
145
R
Phenanthridinone alkaloids
O
R
O
N
Acridone alkaloid
O
O
O
N-methylcrinasiadine (R = Me)
N-isopentylcrinasiadine (R = –CH2–CH2–CH(CH3)2)
N-benzylcrinasiadine (R = Bn)
O
N
Me
2,3-methylenedioxy-10-methyl-9-acridanone
Scheme 6.98 Palladium-catalyzed reaction of aryne, CO, and 2-iodoaniline for the
construction of phenanthridinone and acridone alkaloids.
Li and his coworkers observed a ligand-controlled selective synthesis of
2-methylene-3-substituted 2-benzylidene-2,3-dihydro-1H-inden-1-ones 138 and
2,3-dihydro-1H-inden-1-ones 138a through a palladium-catalyzed three-component
coupling of arynes with allyl carbonates and carbon monoxide (CO) [99]. The reaction proceeds via the formation of π-allylPd(II) intermediate (98-I and 98-II) from
allyl carbonates. The π-allyl Pd(II) intermediate undergoes sequential coordinative
CO (1 atm, bubbled)
O
PdCl2, P(o-tol)3
CsF
R
138
1
MeCN, 80 °C
O
Me
TMS
+
R
OTf
R
Pd L
CO
R1
O
CO (1 atm, bubbled)
O
PdCl2, PPh3
CsF
MeCN, 80 °C
99-II
R
138a
146
Pd L
R1
insertion
O
CO
insertion
R1
99-I
Scheme 6.99 Pd-catalyzed cyclocarbonylation of arynes for the synthesis of
1H-inden-1-ones.
R1
259
260
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
insertion with benzyne and CO followed by subsequent reductive elimination
providing the expected product (Scheme 6.99).
6.7 Metal-Catalyzed [3+2] Cycloaddition of Arynes
6.7.1
Silver-Catalyzed [3+2] Cycloaddition of Arynes
In 2018, Guo and his coworkers reported a tandem nucleophilic addition and [3+2]
cycloaddition of iminoesters (147) with arynes for the synthesis of highly substituted
imidazolidine frameworks (148) in the presence of a silver catalyst (Scheme 6.100)
[100]. This asymmetric transformation provides imidazolidine derivatives with
excellent regio-, diastereo-, and enantioselectivities in high yields. Notably, most of
the reactions gave only one diasteromer in good yields. As expected, in the reaction
of m-Me or p-Me unsymmetrical benzynes, mixture of two regioisomers (m-Me and
p-Me) was observed in a 1 : 1 ratio.
TMS
+
R
OTf
N
R1
N
R2O2C
147
N
R1
N
CsF/ 18-crown-6
MeCN, –10 °C
N
R2O2C
R1 = Ph, R2 = Et, 75% (93% ee)
R1 = 3-FC6H4, R2 = Me, 99% (84% ee)
R1 = 4-BrC6H4, R2 = Et, 82% (91% ee)
R2O2C
PPh2
N
Fe
R1 148
R
N
Me
m-Me, and p-Me 69%
(60:40)
R2O
2C
L1
CO2R2
R1
N
R1
N
CO2R2
CO2R2
R1
CO2R2
R1
R1
CO2R2 Ag(Tf N) (10 mol%)
2
L1 (11 mol%)
N
R1
R
R
R = Me, 70% (94% ee)
R = –O–CH2–O, 70% (96% ee)
R = F, 62% (97% ee)
Scheme 6.100 Silver-catalyzed [3+2] cycloaddition reaction of iminoesters with arynes.
Source: Jia et al. [100].
In 2011, Wu and his coworkers reported a silver-catalyzed unusual reaction of
2-alkynylbenzaldoxime (149) with arynes under mild reaction conditions [101].
This reaction proceeds via 6-endo-cyclization, followed by [3+2] cycloaddition,
and unusual rearrangement providing 2-oxa-6-azabicylco[3.2.2]nona-6,8-diene
derivatives 150 in moderate-to-good yields (Scheme 6.101). Particularly,
substituted 2-alkynylbenzaldoxime having electron-withdrawing as well as
electron-donating group on the aromatic moieties were well tolerated. Among
them, methoxy-substituted arynes gave the expected product in high yield as well as
regioselectivity. It indicates that the electronic effect of OMe group on the aromatic
moiety played an important role for the high selectivity.
6.7 Metal-Catalyzed [3+2] Cycloaddition of Arynes
R
N
R1
OH
+
R2
149
TMS
AgOTf (10 mol%)
OTf
TBAF (3.0 equiv.)
THF, 50 °C
R
R1
O
N
R2
150
19 examples, 5–84% yield
R
R
R1
R1
O
N
O
MeO
O
N
R1
O
N
N
+
O
N
R2
Ph
Ph
Ph
Ph
14 h, 45% R1 = F, 12 h, 81% R = tBu, R1 = Me, 12 h, 48% (1 : 1)
R2 = Ph, 12 h, 56%
2
1
1
R = p-ClC6H4, 10 h, 62%
R = Cl, 10 h, 62% R = OMe, R = Cl, 12 h, 81% (1 : 5)
R = OMe, R1 = H, 10 h, 57% (1 : 99)
R
N
R1
OH
TMS
+
OTf
R2
AgOTf
+
R
1
N
R
–
O
+
R
N
R
1
N
R
O
O
R2
R1
N
AgOTf-catalyzed reaction of 2-alkynylbenzaldoximes with arynes.
Abbreviations
BINAP
n-BuLi
CsF
dba
DCE
DCM
DIBAL-H
DDQ
DME
DMF
DMSO
DPEphos
dppe
dppf
O
R2
TBAF
R2
Scheme 6.101
R1
AgOTf
R
2,2′ -Bis(diphenylphosphino)-1,1′ -binaphthalene
n-Butyllithium
cesium fluoride
dibenzylideneacetone
dichloroethane
dichloromethane
diisobutylaluminum hydride
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
dimethyl ether
dimethylformamide
dimethylsulfoxide
bis(2-diphenylphosphinophenyl)ether
1,2-Bis(diphenylphosphino)ethane
1,1’-Bis(diphenylphosphino)ferrocene
R2
261
262
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
dppp
dppm
GC-MS
HMDS
HRMS
KIE
LED
MALDI
NHC
NBS
NIS
ppm
PPh3
TBAB
TBAI
TEMPO
THF
TFP
TlOAc
NMR
1,3-Bis(diphenylphosphino)propane
1,1-Bis(diphenylphosphino)methane
gas chromatography-mass spectrometry
hexamethyldisilazane
high-resolution mass spectrometry
kinetic isotope effect
light emitting diodes
matrix-assisted laser desorption/ionization
N-Heterocyclic Carbene
N-Bromosuccinimide
N-Iodosuccinimide
parts per million
tri-phenylphosphine
tetrabutylammonium bromide
tetrabutylammonium iodide
2,2,6,6-Tetramethyl-1-piperidinyloxy
tetrahydrofuran
tri(2-furyl)phosphine
thallous acetate
nuclear magnetic resonance
References
1 (a) Wenk, H.H., Winkler, M., and Sander, W. (2003). Angew. Chem. Int.
Ed. 42: 502–528. (b) Sanz, R. (2008). Org. Prep. Proced. Int. 40: 215–291. (c)
Gandeepan, P., Müller, T., Zell, D. et al. (2019). Chem. Rev. 119: 2192–2452. (d)
Winkler, M., Wenk, H.H., and Sander, W. (2004). Recent Applications of Aryne
Chemistry to Organicsynthesis. A Review (eds. R.A. Moss, M.S. Platz and M.J.
Jones), 741–794. Hoboken, NJ: Wiley.
2 Yoshio, H., Takaaki, S., and Hiroshi, K. (1983). Chem. Lett. 12: 1211–1214.
3 Ruiz-Castillo, P. and Buchwald, S.L. (2016). Chem. Rev. 116: 12564–12649.
4 (a) Peña, D., Escudero, S., Pérez, D. et al. (1998). Angew. Chem. Int. Ed. 37:
2659–2661. (b) Peña, D., Pérez, D., Guitián, E., and Castedo, L. (1999). Org.
Lett. 1: 1555–1557. (c) Peña, D., Cobas, A., Pérez, D. et al. (2000). Org. Lett. 2:
1629–1632.
5 (a) Peña, D., Pérez, D., Guitián, E., and Castedo, L. (1999). J. Am. Chem. Soc.
121: 5827–5828. (b) Peña, D., Pérez, D., Guitián, E., and Castedo, L. (2000). J.
Org. Chem. 65: 6944–6950.
6 Alonso, J.M., Díaz-Álvarez, A.E., Criado, A. et al. (2012). Angew. Chem. Int. Ed.
51: 173–177.
7 (a) Radhakrishnan, K.V., Yoshikawa, E., and Yamamoto, Y. (1999). Tetrahedron
Lett. 40: 7533–7535. (b) Yoshikawa, E., Radhakrishnan, K.V., and Yamamoto, Y.
(2000). J. Am. Chem. Soc. 122: 7280–7286. (c) Yoshikawa, E. and Yamamoto, Y.
(2000). Angew. Chem. Int. Ed. 39: 173–175.
References
8 (a) Jayanth, T.T., Jeganmohan, M., and Cheng, C.-H. (2004). J. Org. Chem. 69:
8445–8450. (b) Hayes, D.M. and Hoffmann, R. (1972). J. Phys. Chem. 76: 656.
(c) Epiotis, N.D. (1974). Angew. Chem. Int. Ed. Engl. 13: 751.
9 Peña, D., Pérez, D., Guitián, E., and Castedo, L. (2003). Eur. J. Org. Chem. 2003:
1238–1243.
10 Sato, Y., Tamura, T., and Mori, M. (2004). Angew. Chem. Int. Ed. 43: 2436–2440.
11 Liu, Y.-L., Liang, Y., Pi, S.-F. et al. (2009). J. Org. Chem. 74: 3199–3202.
12 Quintana, I., Boersma, A.J., Peña, D. et al. (2006). Org. Lett. 8: 3347–3349.
13 Kim, H.S., Gowrisankar, S., Kim, E.S., and Kim, J.N. (2008). Tetrahedron Lett.
49: 6569–6572.
14 Cant, A.A., Roberts, L., and Greaney, M.F. (2010). Chem. Commun. 46:
8671–8673.
15 (a) García-López, J.-A. and Greaney, M.F. (2014). Org. Lett. 16: 2338–2341.
(b) Retbøll, M., Edwards, A.J., Rae, A.D. et al. (2002). J. Am. Chem. Soc. 124:
8348–8360.
16 Patel, R.M. and Argade, N.P. (2013). Org. Lett. 15: 14–17.
17 Lin, J.B., Shah, T.K., Goetz, A.E. et al. (2017). J. Am. Chem. Soc. 139:
10447–10455.
18 Hsieh, J.-C. and Cheng, C.-H. (2005). Chem. Commun. 2459–2461.
19 Hsieh, J.-C., Rayabarapu, D.K., and Cheng, C.-H. (2004). Chem. Commun.
532–533.
20 Hsieh, J.-C. and Cheng, C.-H. (2008). Chem. Commun. 2992–2994.
21 Iwayama, T. and Sato, Y. (2010). Hetrocycles 80: 917–924.
22 Saito, N., Shiotani, K., Kinbara, A., and Sato, Y. (2009). Chem. Commun.
4284–4286.
23 Candito, D.A. and Lautens, M. (2011). Synlett 22: 1987–1992.
24 Qiu, Z. and Xie, Z. (2009). Angew. Chem. Int. Ed. 48: 5729–5732.
25 Chen, L., Zhang, C., Wen, C. et al. (2015). Catal. Commun. 65: 81–84.
26 Asao, N. and Sato, K. (2006). Org. Lett. 8: 5361–5363.
27 (a) Liu, Z., Zhang, X., and Larock, R.C. (2005). J. Am. Chem. Soc. 127:
15716–15717. (b) Liu, Z. and Larock, R.C. (2007). J. Org. Chem. 72: 223–232.
28 Jayanth, T.T. and Cheng, C.-H. (2006). Chem. Commun. 894–896.
29 (a) Zhang, X. and Larock, R.C. (2005). Org. Lett. 7: 3973–3976. (b) Liu, Z. and
Larock, R.C. (2007). Angew. Chem. Int. Ed. 46: 2535–2538.
30 Xie, C., Zhang, Y., Huang, Z., and Xu, P. (2007). J. Org. Chem. 72: 5431–5434.
31 (a) Bhuvaneswari, S., Jeganmohan, M., and Cheng, C.-H. (2006). Org. Lett.
8: 5581–5584. (b) Shih, H.-T., Shih, H.-S., and Cheng, C.-H. (2001). Org. Lett.
6: 881. (c) Shih, H.-T., Lin, C.-H., Shih, H.-H., and Cheng, C.-H. (2002). Adv.
Mater. 14: 1409–1412.
32 (a) Avlasevich, Y., Müller, S., Erk, P., and Müllen, K. (2007). Chem. Eur. J. 13:
6555–6561. (b) Lütke Eversloh, C., Li, C., and Müllen, K. (2011). Org. Lett. 13:
4148–4150.
33 Li, R.-J., Pi, S.-F., Liang, Y. et al. (2010). Chem. Commun. 46: 8183–8185.
34 Parthasarathy, K., Han, H., Prakash, C., and Cheng, C.-H. (2012). Chem. Commun. 48: 6580–6582.
263
264
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
35 Lin, Y., Wu, L., and Huang, X. (2011). Eur. J. Org. Chem. 2011: 2993–3000.
36 Ni, S., Shu, W., and Ma, S. (2013). Synlett 24: 2310–2314.
37 (a) Worlikar, S.A. and Larock, R.C. (2009). Org. Lett. 11: 2413–2416. (b)
Yoshida, H., Tanino, K., Ohshita, J., and Kunai, A. (2004). Angew. Chem. Int.
Ed. 43: 5052–5055. (c) Worlikar, S.A. and Larock, R.C. (2009). J. Org. Chem. 74:
9132–9139.
38 Huang, X., Sha, F., and Tong, J. (2010). Adv. Synth. Catal. 352: 379–385.
39 Yang, Y., Huang, H., Wu, L., and Liang, Y. (2014). Org. Biomol. Chem. 12:
5351–5355.
40 Yao, T., Zhang, H., and Zhao, Y. (2016). Org. Lett. 18: 2532–2535.
41 Pérez-Gómez, M. and García-López, J.-A. (2016). Angew. Chem. Int. Ed. 55:
14389–14393.
42 Yoon, H., Lossouarn, A., Landau, F., and Lautens, M. (2016). Org. Lett. 18:
6324–6327.
43 (a) Yao, T. and He, D. (2017). Org. Lett. 19: 842–845. (b) Cámpora, J., López,
J.A., Palma, P. et al. (1999). Angew. Chem. Int. Ed. 38: 147–151.
44 Zuo, Z., Wang, H., Diao, Y. et al. (2018). ACS Catal. 8: 11029–11034.
45 Lu, C., Dubrovskiy, A.V., and Larock, R.C. (2012). J. Org. Chem. 77: 8648–8656.
46 Lu, C., Markina, N.A., and Larock, R.C. (2012). J. Org. Chem. 77: 11153–11160.
47 Gerfaud, T., Neuville, L., and Zhu, J. (2009). Angew. Chem. Int. Ed. 48:
572–577.
48 Tang, C.-Y., Wu, X.-Y., Sha, F. et al. (2014). Tetrahedron Lett. 55: 1036–1039.
49 Pimparkar, S. and Jeganmohan, M. (2014). Chem. Commun. 50: 12116–12119.
50 Peng, X., Wang, W., Jiang, C. et al. (2014). Org. Lett. 16: 5354–5357.
51 Wang, W., Peng, X., Qin, X. et al. (2015). J. Org. Chem. 80: 2835–2841.
52 Neog, K., Borah, A., and Gogoi, P. (2016). J. Org. Chem. 81: 11971–11977.
53 Zhao, J., Li, H., Li, P., and Wang, L. (2019). J. Org. Chem. 84: 9007–9016.
54 Asamdi, M., Chauhan, P.M., Patel, J.J., and Chikhalia, K.H. (2019). Tetrahedron
75: 3485–3494.
55 Feng, S., Li, S., Li, J., and Wei, J. (2019). Org. Chem. Front. 6: 517–522.
56 Meng, Y.-Y., Si, X.-J., Song, Y.-Y. et al. (2019). Chem. Commun. 55: 9507–9510.
57 (a) Thorat, V.H., Upadhyay, N.S., Murakami, M., and Cheng, C.-H. (2018).
Adv. Synth. Catal. 360: 284–289. (b) Cahiez, G., Moyeux, A., Buendia, J., and
Duplais, C. (2007). J. Am. Chem. Soc. 129: 13788–13789.
58 Zhang, T.-Y., Lin, J.-B., Li, Q.-Z. et al. (2017). Org. Lett. 19: 1764–1767.
59 Zhang, T.-Y., Liu, C., Chen, C. et al. (2018). Org. Lett. 20: 220–223.
60 Yoshikawa, E., Radhakrishnan, K.V., and Yamamoto, Y. (2000). Tetrahedron
Lett. 41: 729–731.
61 Jeganmohan, M. and Cheng, C.-H. (2004). Org. Lett. 6: 2821–2824.
62 (a) Jeganmohan, M. and Cheng, C.-H. (2005). Synthesis 2005: 1693–1697.
(b) Jayanth, T.T., Jeganmohan, M., and Cheng, C.-H. (2005). Org. Lett. 7:
2921–2924.
63 Bhuvaneswari, S., Jeganmohan, M., Yang, M.-C., and Cheng, C.-H. (2008).
Chem. Commun. 2158–2160.
References
64 Jeganmohan, M., Bhuvaneswari, S., and Cheng, C.-H. (2009). Angew. Chem.
Int. Ed. 48: 391–394.
65 (a) Henderson, J.L., Edwards, A.S., and Greaney, M.F. (2006). J. Am. Chem.
Soc. 128: 7426–7427. (b) Henderson, J.L., Edwards, A.S., and Greaney, M.F.
(2007). Org. Lett. 9: 5589–5592.
66 Garve, L.K.B. and Werz, D.B. (2015). Org. Lett. 17: 596–599.
67 Li, J., Noyori, S., Nakajima, K., and Nishihara, Y. (2014). Organometallics 33:
3500–3507.
68 Jayanth, T.T. and Cheng, C.-H. (2007). Angew. Chem. Int. Ed. 46: 5921–5924.
69 Niu, S.-L., Hu, J., He, K. et al. (2019). Org. Lett. 21: 4250–4254.
70 Peng, X., Ma, C., Tung, C.-H., and Xu, Z. (2016). Org. Lett. 18: 4154–4157.
71 Berti, F., Crotti, P., Cassano, G., and Pineschi, M. (2012). Synlett 23: 2463–2468.
72 Xie, C., Liu, L., Zhang, Y., and Xu, P. (2008). Org. Lett. 10: 2393–2396.
73 Bhuvaneswari, S., Jeganmohan, M., and Cheng, C.-H. (2008). Chem. Commun.
5013–5015.
74 Yoo, W.-J., Nguyen, T.V.Q., and Kobayashi, S. (2014). Angew. Chem. Int. Ed. 53:
10213–10217.
75 (a) Yang, X. and Tsui, G.C. (2018). Org. Lett. 20: 1179–1182. (b) Chu, H., Sun,
S., Yu, J.-T., and Cheng, J. (2015). Chem. Commun. 51: 13327–13329. (c) Zeng,
Y., Zhang, L., Zhao, Y. et al. (2013). J. Am. Chem. Soc. 135: 2955–2958.
76 Cao, W., Niu, S.-L., Shuai, L., and Xiao, Q. (2020). Chem. Commun. 56:
972–975.
77 Yang, J., Yu, X., and Wu, J. (2014). Synthesis 46: 1362–1366.
78 Yoshida, H., Honda, Y., Shirakawa, E., and Hiyama, T. (2001). Chem. Commun.
1880–1881.
79 (a) Yoshida, H., Ikadai, J., Shudo, M. et al. (2003). J. Am. Chem. Soc. 125:
6638–6639. (b) Yoshida, H., Tanino, K., Ohshita, J., and Kunai, A. (2005).
Chem. Commun. 5678–5680.
80 Pawliczek, M., Garve, L.K.B., and Werz, D.B. (2015). Org. Lett. 17: 1716–1719.
81 Yuan, W. and Ma, S. (2014). Org. Lett. 16: 193–195.
82 Yoshida, H., Okada, K., Kawashima, S. et al. (2010). Chem. Commun. 46:
1763–1765.
83 Pareek, M., Fallon, T., and Oestreich, M. (2015). Org. Lett. 17: 2082–2085.
84 Yoshida, H., Kawashima, S., Takemoto, Y. et al. (2012). Angew. Chem. Int. Ed.
51: 235–238.
85 Tanaka, H., Kuriki, H., Kubo, T. et al. (2019). Chem. Commun. 55: 6503–6506.
86 Akubathini, S.K. and Biehl, E. (2009). Tetrahedron Lett. 50: 1809–1811.
87 Xie, C., Zhang, Y., and Yang, Y. (2008). Chem. Commun. 4810–4812.
88 Yoshida, H., Morishita, T., Nakata, H., and Ohshita, J. (2009). Org. Lett. 11:
373–376.
89 Morishita, T., Yoshida, H., and Ohshita, J. (2010). Chem. Commun. 46:
640–642.
90 (a) Yang, X. and Tsui, G.C. (2018). Chem. Sci. 9: 8871–8875. (b) Okuma, K.,
Sonoda, S., Koga, Y., and Shioji, K. (1999). J. Chem. Soc., Perkin Trans. 1
2997–3000. (c) Yang, X., He, L., and Tsui, G.C. (2017). Org. Lett. 19: 2446–2449.
265
266
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry
91
92
93
94
95
96
97
98
99
100
101
(d) Zhang, B.-S., Gao, L.-Y., Zhang, Z. et al. (2018). Chem. Commun. 54:
1185–1188.
Uchiyama, M., Naka, H., Matsumoto, Y., and Ohwada, T. (2004). J. Am. Chem.
Soc. 126: 10526–10527.
Zeng, Y. and Hu, J. (2014). Chem. Eur. J. 20: 6866–6870.
Xiao, X., Wang, T., Xu, F., and Hoye, T.R. (2018). Angew. Chem. Int. Ed. 57:
16564–16568.
Wang, K.-P., Yun, S.Y., Mamidipalli, P., and Lee, D. (2013). Chem. Sci. 4:
3205–3211.
Chen, Q., Yan, X., Wen, C. et al. (2016). J. Org. Chem. 81: 9476–9482.
Chatani, N., Kamitani, A., Oshita, M. et al. (2001). J. Am. Chem. Soc. 123:
12686–12687.
(a) García-López, J.-A., Oliva-Madrid, M.-J., Saura-Llamas, I. et al. (2012).
Chem. Commun. 48: 6744–6746. (b) Oliva-Madrid, M.-J., Saura-Llamas,
I., Bautista, D., and Vicente, J. (2013). Chem. Commun. 49: 7997–7999.
(c) Oliva-Madrid, M.-J., García-López, J.-A., Saura-Llamas, I. et al. (2014).
Organometallics 33: 6420–6430.
Feng, M., Tang, B., Wang, N. et al. (2015). Angew. Chem. Int. Ed. 54:
14960–14964.
Pi, S.-F., Yang, X.-H., Huang, X.-C. et al. (2010). J. Org. Chem. 75: 3484–3487.
Jia, H., Guo, Z., Liu, H. et al. (2018). Chem. Commun. 54: 7050–7053.
Ren, H., Luo, Y., Ye, S., and Wu, J. (2011). Org. Lett. 13: 2552–2555.
267
7
Molecular Rearrangements Triggered by Arynes
Lu Han and Shi-Kai Tian
University of Science and Technology of China, Department of Chemistry, 96 Jinzhai Road, Hefei, Anhui
230026, China
7.1
Introduction
Arynes are electronically neutral yet highly electrophilic species due to the presence
of a highly strained carbon–carbon triple bond. While arynes can be generated in situ in the reaction mixtures under several sets of conditions, most of
which include the use of strong bases, potentially explosive precursors, and toxic
metals [1], their preparation from 2-silylaryl triflates via fluoride ion-induced
1,2-elimination, developed by Kobayashi et al. in 1983 [2], remains the most
convenient, mild, and efficient method. The Kobayashi method is compatible with
a wide variety of functional groups and significantly expands the scope for arynes in
various carbon–carbon and carbon–heteroatom bond-forming processes, including
molecular rearrangements.
A wide range of carbon and heteroatom nucleophiles, even weak ones such as
enolizable ketones, amides, and imides, can add to arynes under mild reaction
conditions and the resultant zwitterionic intermediates serve as versatile precursors
for a number of rearrangements, delivering structural diverse organic compounds
that might otherwise be difficult to be prepared. The aryl moieties of the zwitterionic
intermediates originated from the arynes may or may not engage in the following
skeletal rearrangements. Exclusion of the original aryne moieties from the skeletal
rearrangements leads to the monofunctionalization of arynes. On the other hand,
the original aryne moieties are ready to engage in the skeletal rearrangements
toward the 1,2-difunctionalization or 1,2,3-trifunctionalization of arynes, often
involving the formation of strained cycles as key intermediates. In addition,
rearrangement precursors can be formed by cycloaddition between arynes and
unsaturated systems, and rearrangements are also involved in the multicomponent
reactions with two or more aryne molecules. These aryne-triggered rearrangements enable a variety of synthetically important operations, including skeletal
construction, functional group transposition, ring formation, ring expansion, ring
contraction, and chirality transfer.
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
268
7 Molecular Rearrangements Triggered by Arynes
This book chapter summarizes various molecular rearrangements triggered by
arynes in the absence of transition metals [3]. It is organized according to the
functionalization modes of arynes forming one, two, or three carbon–carbon and
carbon–heteroatom bonds via a variety of reaction pathways.
7.2 Rearrangements Involved in the
Monofunctionalization of Arynes
The addition of heteroatom nucleophiles to arynes can significantly weaken the
carbon–heteroatom bonds of the heteroatom nucleophiles. Owing to charge acceleration, the resultant zwitterionic intermediates are amenable to engage in rearrangements via carbon–heteroatom bond cleavage under mild reaction conditions. These
rearrangements proceed without the participation of the original aryne moieties,
resulting in the monofunctionalization of arynes.
7.2.1
Reactions of Arynes with Nitrogen Nucleophiles
As early as 1943, Wittig and Merkle reported that the reaction of triethylamine with
benzyne (2a) (generated in situ from haloarene 1a in the presence of phenyllithium)
afforded a minor product [4], which was later identified as tertiary amine 3 [5]. This
minor product was proposed to be generated via a [1,2]-Stevens rearrangement as
depicted in Scheme 7.1. Nucleophilic addition of triethylamine to benzyne (2a) leads
to the formation of zwitterion 4, which undergoes proton transfer to form quaternary
ammonium ylide 5. Subsequent [1,2]-migration of the ethyl group affords tertiary
amine 3. A similar rearrangement was observed by Lepley et al. in the addition
of N,N-dialkylanilines to benzyne (2a), generated in situ from haloarene 1a in the
presence of n-butyllithium [6].
F
Et
N
NEt3
PhLi, ether
Et
3, 2%
2a
1a
Me
[1,2]
Et Et
N
Me
4
Scheme 7.1
H
Et Et
N
Me
H 5
Reaction of benzyne with triethylamine. Source: Based on Wittig and Benz [5].
In the addition of (aminomethyl)silane 6a to benzyne (2a) (generated in situ from
haloarene 1b in the presence of sodium amide), Sato et al. isolated the [1,2]-Stevens
rearrangement product 7a in 60% yield (Scheme 7.2) [7]. The rearrangement reaction
is dramatically affected by the substituents on the silicon atom. In sharp contrast,
7.2 Rearrangements Involved in the Monofunctionalization of Arynes
the addition of (aminomethyl)silane 6b to benzyne (2a) afforded the rearrangement
products 7b and 8b in 5% and 9% yields, respectively. In this case, the [1,2]-Stevens
rearrangement competes with a skeletal rearrangement involving the migration of
the silyl group to the benzene ring (originated from benzyne (2a)) accompanied by
the shift of a phenyl group from silicon to the adjacent carbon.
Me
N
SiR3
Me
6a, R = Me
6b, R = Ph
Br NaNH2, THF
Reflux
Me
N
NMe2
SiR3
Me
1b
Scheme 7.2
et al. [7].
2a
7a, R = Me, 60%
7b, R = Ph, 5%
R
Si
R R
8a, R = Me, 0%
8b, R = Ph, 9%
Reaction of benzyne with (aminomethyl)silanes. Source: Based on Sato
The scope of aryne-triggered [1,2]-Stevens rearrangement of tertiary amines
has been expanded dramatically through increasing the acidity of amine α-C—H
bonds as well as using the Kobayashi method for the generation of arynes
under mild reaction conditions [2]. In 2016, Biju and coworkers disclosed the
[1,2]-migration of the benzyl group in the reaction of N-benzyl glycinate 9
with benzyne (2a) (generated in situ from 2-silylaryl triflate 10a in the presence of KF and 18-crown-6), delivering α-benzyl glycinate 11 in 41% yield
(Scheme 7.3) [8]. Pan and Liu extended the aryne-triggered [1,2]-Stevens rearrangement to 1,2,3,4-tetrahydroisoquinolines 12, resulting in ring expansion to
afford 3-aryl-3-benzazepines 13 in moderate-to-good yields (Scheme 7.4) [9].
Arynes 2 are generated from 2-silylaryl triflates 10 using CsF and 18-crown-6,
and the addition of potassium bicarbonate minimizes side reactions such as the
Hofmann elimination and the C-arylation. Interestingly, lowering the temperature
from 80 to 40 ∘ C enables the arylation of the amine α-C—H bonds as the major
reaction albeit α-arylated products 14 were obtained in low yields. Mechanistically,
both 3-aryl-3-benzazepine 13 and α-arylated product 14 were proposed to be
formed via the [1,2]-Stevens rearrangement of quaternary ammonium ylide 16.
Aryne 2 is generated in situ by fluoride ion–induced 1,2-elimination of 2-silylaryl
triflate 10, and then nucleophilic addition of 1,2,3,4-tetrahydroisoquinoline 12
to aryne 2 followed by proton transfer forms quaternary ammonium ylide 16.
[1,2]-migration of the benzyl group of the ammonium ylide occurs at 80 ∘ C to afford
3-aryl-3-benzazepine 13, and [1,2]-migration of the aryl group occurs at 40 ∘ C to
afford α-arylated product 14.
Although the Sommelet–Hauser rearrangement has not been mentioned in the
above reactions of tertiary benzylic amines with arynes (Schemes 7.3 and 7.4), it
emerges as a major reaction pathway for the substrates having electron-deficient
benzyl groups under milder conditions. In 2019, Biju and coworkers reported
the aryne-triggered Sommelet–Hauser rearrangement of tertiary benzylic amines
17 bearing an ester, a cyano, a nitro, or a trifluoromethyl group at the amine
269
270
7 Molecular Rearrangements Triggered by Arynes
Ph
Ph
KF, 18-crown-6
THF, 30 °C
TMS
+
N
CO2Et
OTf
10a
9
Scheme 7.3
et al. [8].
CO2Et
Ph
11, 41%
Reaction of benzyne with an N-benzyl glycinate. Source: Based on Roy
TMS
R1
Ph
Ph
N
N
EWG
CsF, 18-crown-6, KHCO3, dioxane
+ R
12
OTf
10
F
R
40 °C
80 °C
R
R1
2
N
13
R1
N
EWG
14
EWG
R
R1
N
EWG
R1
N
EWG
[1,2]-benzyl
migration
[1,2]-aryl migration
15
R
16
N
CO2Et
70%
R
N
Cl
CN
74%
N
CO2Et
Ph
37%
Scheme 7.4 Aryne-triggered [1,2]-Stevens rearrangement of
1,2,3,4-tetrahydroisoquinolines. Source: Based on Pan and Liu [9].
α-C position, taking place at a lower temperature to afford tertiary amines 18
in moderate-to-good yields (Scheme 7.5) [10]. In this case, arynes 2 are generated in situ from 2-silylaryl triflates 10 in the presence of KF and 18-crown-6.
Mechanistically, quaternary ammonium ylide 20, generated from tertiary benzylic
amine 17 and aryne 2, undergoes a [2,3]-sigmatropic rearrangement, involving
the aryl ring of benzylic amine 17, to form dearomatized intermediate 21, which
upon a [1,3]-hydrogen shift results in the formation of tertiary amine 18. In
many cases, the yields are not satisfactory due to the competing [1,2]-Stevens
rearrangement. When the reaction was performed on benzylic amine 22 bearing
an N-cyclohexyl group, tertiary amine 23 was obtained in 40% yield (Scheme 7.6).
Hypothetically, the initially formed quaternary ammonium ylide 24 prefers to
undergo [1,4]-migration of the cyanomethyl group to generate intermediate 25,
which undergoes aromatization to afford tertiary amine 23.
The arynes generated from 2-silylaryl triflates via fluoride ion–induced
1,2-elimination can efficiently trigger the [2,3]-Stevens rearrangement of tertiary allylic amines having acidic α-C—H bonds. In 2016, Tian and coworkers
reported that the use of 2-silylaryl triflates 10 as aryne precursors in the presence of
7.2 Rearrangements Involved in the Monofunctionalization of Arynes
R2
KF, 18-crown-6
THF, –10 °C to rt
TMS
R1
N
EWG
+ R
17
R1
N
EWG
R
Me
OTf
10
18
R2
F
R
2
R2
R2
R1
EWG
N
19
Ph
R
Me
N
R1
N
20
CO2tBu
Ph
EWG
[2,3]
R1
N
R
(CH2)11 Me
N
CO2tBu
Me
N
Me
MeO2C
54%
= CO2Me, 70%
R2 = CN, 60%
R2 = NO2, 54%
R2 = CF3, 61%
CO2tBu
Me
MeO2C
R2
21
R2
Me
R2
EWG
R
70%
Scheme 7.5 Aryne-triggered Sommelet–Hauser rearrangement of tertiary benzylic
amines. Source: Based on Roy et al. [10].
TMS
MeO2C
N
CN
+
MeO2C
N
OTf
22
10a
MeO2C
NC
[1,4]
N
24
Scheme 7.6
KF, 18-crown-6
THF, –10 °C to rt
Ph
Ph
23, 40%
MeO2C
N
CN
NC
Ph
25
Benzyne-induced [1,4]-rearrangement. Source: Based on Roy et al. [10].
tetrabutylammonium fluoride (TBAF) enables the [2,3]-Stevens rearrangement of
tertiary allylic amines 26 bearing an ester, a ketone, an amide, a cyano, a phosphonate, a benzoxazole, or a p-nitrophenyl group at the amine α-C position, delivering
a range of functionalized homoallylic amines 27 in moderate-to-good yields
(Scheme 7.7) [11]. Mechanistically, the reaction proceeds via a [2,3]-sigmatropic
271
272
7 Molecular Rearrangements Triggered by Arynes
rearrangement of quaternary allylic ammonium ylide 29, generated by nucleophilic
addition of tertiary allylic amine 26 to aryne 2 and subsequent proton transfer.
Although quaternary allylic ammonium ylide 29 bears an N-aryl group, the corresponding aza-Claisen rearrangement product was not observed under the standard
reaction conditions.
R5
N
R3
R1
R2
26
R4
TBAF, THF
rt or 60 °C
TMS
EWG + R
R6
10
R2
OTf
EWG
R1
27
[2,3]
R
R
2
R3 R5
N
R1
R2
N
R6
R4
F
Me
R
R5
N
R3
R4
EWG
28
R2
OMe
Me
N
OMe
CO2Et
75%
N
R3 R5
N
R1
R6
Ph
EWG
EWG, yield
CO2Et, 85%
COMe, 62%
CONH2, 69%
CN, 88%
PO(OEt)2, 60%
benzo[d]oxazol-2-yl, 78%
4-nitrophenyl, 43%
R
R4
Me
EWG
29
N
R6
Ph
CO2Et
Ph
66%, 94:6 dr
Ph
CO2Et
50%
CO2Me
N
Ph
60%, 90% ee
Scheme 7.7 Aryne-triggered [2,3]-Stevens rearrangement of tertiary allylic amines.
Source: Based on Zhang et al. [11].
The aryne-triggered [2,3]-Stevens rearrangement has been applied to optically
active tertiary allylic amines. The rearrangement reaction of L-proline derived
tertiary allylic amine provides a nitrogen-substituted quaternary stereocenter
with inversion of configuration and excellent retention of enantiopurity (90% ee)
(Scheme 7.7) [11]. The high efficiency of chirality transfer, from carbon to nitrogen
and then back to carbon, is attributable to the highly diastereoselective attack
of the cyclic tertiary amine on benzyne and the concerted nature of subsequent
[2,3]-sigmatropic rearrangement. Independent investigation by Biju and coworkers
uncovered that higher enantiopurity (96% ee) was achieved in the benzyne-triggered
rearrangement of the same L-proline-derived tertiary allylic amine by treating the
benzyne precursor, 2-silylaryl triflate 10a, with KF and 18-crown-6 [8].
In addition to chirality transfer, the aryne-triggered [2,3]-Stevens rearrangement of tertiary allylic amines serves as a powerful protocol for ring contraction,
7.2 Rearrangements Involved in the Monofunctionalization of Arynes
ring expansion, and ring reconstruction. As demonstrated by Tian and coworkers,
treatment of 1,2,3,6-tetrahydropyridine-2-carboxylate 30, a cyclic allylic amine, with
2-silylaryl triflate 10a in the presence of CsF afforded functionalized cyclopropane
31 in 65% yield as a single diastereomer (Scheme 7.8a) [11]. In contrast, the studies
by Sweeney and coworkers show that installation of a 2-malonyl group on the nitrogen of the 1,2,3,6-tetrahydropyridine ring resulted in ring opening and subsequent
formation of a new nitrogen-containing heterocycle, providing convenient access
to various N-aryl-2-acylpyrrolidines (Scheme 7.8b) [12]. In 2018, Liu and coworkers
reported the ring expansion of 1-vinyl-1,2,3,4-tetrahydroisoquinolines triggered by
arynes, leading to the formation of (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines
(Scheme 7.8c) [13].
CO2Et
(a)
N
TMS
+
Ph
30
10a
CsF, MeCN, 60 °C
N
Me
31, 65%, >99:1 dr
32
(c)
N
34
TMS
CO2Me +
MeO2C
TBAF, MeCN, rt
OTf
CO2Me
10a
TMS
CN +
10a
NPh2
CO2Et
OTf
Me
(b)
H
OTf
Me
Ph N
Me
MeO2C
33, 95%
CsF, 18-crown-6
dioxane, rt
Ph
N
CN
35, 72%
Scheme 7.8 Aryne-triggered [2,3]-Stevens rearrangement of cyclic allylic amines. (a) Ring
contraction. Source: Based on Zhang et al. [11]. (b) Ring reconstruction. Source: Based on
Moss et al. [12]. (c) Ring expansion. Source: Pan et al. [13].
The aryne-triggered [2,3]-Stevens rearrangement has been extended to tertiary
propargylic amines having acidic α-C—H bonds (Scheme 7.9) [14]. Quaternary
propargylic ammonium ylide 40 can be generated in a similar reaction pathway from
tertiary propargylic amine 36 and aryne 2 (generated in situ from 2-silylaryl triflates
10 in the presence of KF and 18-crown-6), and undergoes a [2,3]-sigmatropic
rearrangement to afford 1-(α-aminoalkyl)allene 37. Under the mild basic reaction
conditions, monosubstituted allene 41 isomerizes to 1-amino-1,3-diene 38. The
chemistry was applied to an L-pipecolinic acid derived optically active tertiary
propargylic amine, and significant erosion of enantiopurity (73% ee) was observed
in the construction of a nitrogen-substituted quaternary stereocenter.
A Curtius-type rearrangement has been developed by Tian and coworkers
according to the selective addition of N ′ ,N ′ -disubstituted acyl hydrazides 42 to
benzyne (2a), generated in situ from 2-silylaryl triflate 10a in the presence of CsF
(Scheme 7.10) [15]. The resulting zwitterion 44 undergoes proton transfer followed
by a Curtius-type rearrangement to afford isocyanate 46. Trapping the isocyanate
273
274
7 Molecular Rearrangements Triggered by Arynes
R
R1
KF, 18-crown-6
EtO(CH2)2OEt, rt
TMS
N
R2
EWG
36
R1
+ R
•
OTf
10
R
R1
N
N
EWG
R2
EWG
38
37
F
R
R2 ≠ H
R
R
R1 N
39
EWG
EWG
40
R1
R2 = H
R1 N
R2
R
[2,3]
2
R2
N
•
[2,3]
EWG
41
OMe
Me
N
•
Ph
OMe
Me
N
•
CO2Et
NH
Me O
84%
Ph
57%
Me
•
N
CO2Me
Ph
74%, 73% ee
Ph
N
CO2Et
65%, >99:1 Z/E
Scheme 7.9 Aryne-triggered [2,3]-Stevens rearrangement of tertiary propargylic amines.
Source: Based on Zhou et al. [14].
TMS
O
R
Ph
N
+ NuH
N
Me
H 42
10a
F
OTf
O
CsF, MeCN, 60 °C
R
Nu
43
N
H
10a
NuH
O Ph Me
N
R
N
H
44
O
Ph
N
H
2a
O Ph Me
N
R
N
86%
R N C O
46
45
O
O
– Ph2NMe
N
OBn
H
76%, 98% ee
H
N
O
O
92%
Cl
O
Ph
N
H
N
H
95%
Scheme 7.10 Benzyne-promoted Curtius-type rearrangement of acyl hydrazides. Source:
Based on Guo et al. [15].
with an alcohol affords a carbamate product. Complete retention of configuration
was observed in the reaction of enantioenriched α-chiral alkanoyl hydrazides. An
N ′ -methyl-N ′ -phenyl acyl hydrazide tethered with a hydroxyl group proved suitable
for the benzyne-promoted Curtius-type rearrangement. Replacing the alcohol
7.2 Rearrangements Involved in the Monofunctionalization of Arynes
with an amine, an N ′ -unsubstituted acyl hydrazide, or an alkoxyamine in the
Curtius-type rearrangement reaction provides convenient access to unsymmetric
ureas and analogues.
In addition to tertiary amines and N ′ ,N ′ -disubstituted acyl hydrazides, pyridines
have been identified as suitable nitrogen nucleophiles in the molecular rearrangements through nucleophilic addition to arynes. In 2013, Biju and coworkers
disclosed a novel three-component reaction of pyridines 47, arynes 2 (generated in
situ from 2-silylaryl triflates 10 in the presence of KF and 18-crown-6), and isatins
48, delivering structurally diverse 3,3-disubstituted indolin-2-ones 49 in good yields
(Scheme 7.11) [16]. Mechanistically, the reaction is initiated with the nucleophilic
addition of pyridine 47 to aryne 2 to generate zwitterion 50, which undergoes
proton transfer to generate pyridylidene 51. Nucleophilic addition of pyridylidene
51 to isatin 48 forms zwitterion 52, which undergoes intramolecular nucleophilic
aromatic substitution to afford indolin-2-one 49 via spirocycle 53.
O
TMS
+ R2
R1 + R
N
47
10
O
KF, 18-crown-6
THF, 30 °C
N
O
N
R3
F
R
R1
R1
R
N
H
51
R2
O
N
R3
H
N
O
O
N
50
R1
N
R
49
R
R1
R
2
R1
O
R2
N
48 R3
OTf
R
R2
O
N
R3 53
52
F
Me2N
F
PhO
PhO
N
O
N
Bn
74%
MeO
PhO
N
O
N
Me
77%
O
N
O
N
Me
89%
N
O
N
Me
71%
Scheme 7.11 Three-component reaction of pyridines, arynes, and isatins. Source: Based on
Bhunia et al. [16].
7.2.2
Reactions of Arynes with Sulfur Nucleophiles
Analogous to tertiary amines, thioethers having acidic α-C—H bonds can be triggered by arynes to participate in [1,2]- and [2,3]-Stevens rearrangements. In 2017,
Guo, He, and coworkers reported the aryne-triggered [1,2]-Stevens rearrangement
of benzylic thioethers 54 bearing an acyl group at the thioether α-C position,
delivering functionalized thioethers in moderate-to-good yields (Scheme 7.12) [17].
In this case, arynes 2 are generated in situ from 2-silylaryl triflates 10 in the presence
275
276
7 Molecular Rearrangements Triggered by Arynes
of KF and 18-crown-6. Mechanistically, the reaction proceeds via the nucleophilic
addition of benzylic thioether 54 to aryne 2. The resulting zwitterion 56 undergoes
proton transfer to generate sulfur ylide 57, which participates in a [1,2]-Stevens
rearrangement to afford thioether 55.
O
Ar + R
S
R1
R2
54
R1
R2
OTf
10
Ar
O
KF, 18-crown-6
THF, 65 °C
TMS
S
R
55
[1,2]
F
R
O
O
R2
Ph
O
56
R2
SPh
61%
57
Ph
O
O
Ph
Ar
S
R1
OMe
Ph
Ph
R1
SPh
R1 = Ph, 82%
R1 = OMe, 53%
R1 = NMe2, 57%
Ar
S
R1
O
R
R
2
SPh
71%
Cl
S
OMe
63%
Scheme 7.12 Aryne-triggered [1,2]-Stevens rearrangement of benzylic thioethers. Source:
Based on Xu et al. [17].
Guo, He, and coworkers also noted that allylic thioethers 58 bearing an acyl
group at the thioether α-C position underwent a [2,3]-Stevens rearrangement in
the presence of benzyne (2a) (generated in situ from 2-silylaryl triflate 10a in the
presence of KF and 18-crown-6) under the same reaction conditions (Scheme 7.13)
[17]. In this case, sulfur ylide 61 is generated from allylic thioether 58 and benzyne (2a), and undergoes a [2,3]-Stevens rearrangement to afford thioether 59.
This transformation was also reported independently by two other groups to
occur under different reaction conditions. Biju and coworkers employed CsF to
promote 2-silylaryl triflates 10 at 25 ∘ C for the generation of arynes 2 and their
conditions worked well with cyclic ketone-derived allylic thioethers [18]. Tan, Xu,
and coworkers also employed CsF for the generation of arynes 2 but at 70 ∘ C and
dramatically expanded the scope of allylic thioethers (Scheme 7.14) [19]. Their
reaction conditions are applicable to a variety of functionalized allylic thioethers 62
bearing a vinyl, an acetylenyl, a ketone, an ester, an amide, a cyano, a phosphonate,
or a benzoxazole group at the thioether α-C position.
Moreover, Tan, Xu, and coworkers investigated the benzyne-trigger [2,3]-Stevens
rearrangement of two propargylic thioethers under similar reaction conditions
(Scheme 7.15) [19]. The reaction of benzyne (2a) with dipropargyl sulfide (64)
afforded α-allenyl propargylic thioether 65 in 75% yield. In contrast, the reaction
7.2 Rearrangements Involved in the Monofunctionalization of Arynes
TMS
O
S
58
+
R
59
R R = Ph, 86%
R = OEt, 62%
O
R = NMe2, 53%
SPh
KF, 18-crown-6
THF, 65 °C
OTf
10a
[2,3]
F
O
2a
O
S
S
R
R
61
60
Scheme 7.13 Benzyne-triggered [2,3]-Stevens rearrangement of allylic thioethers. Source:
Based on Xu et al. [17].
R
R3
R1
S
R2
TMS
R4 + R
62
10
R3
CsF, MeCN, 70 °C
S
R4
OTf
R1 R2
SPh
63
SPh
Br
R4
R4, yield
CH=CH2, 90%
C≡CH, 80%
COPh, 71%
CO2Et, 51%
CONEt2, 84%
CN, 84%
PO(OEt)2, 81%
benzo[d]oxazol-2-yl, 86%
SPh
CO2Et
CO2Et
94%
Ph
88%, 1:1 dr
O
SPh
S
CO2Et
Me Me
83%
O
73%
Scheme 7.14 Aryne-trigger [2,3]-Stevens rearrangement of various allylic thioethers.
Source: Based on Tan et al. [19].
TMS
S
+
64
S
66
10a
CsF, MeCN, 30 °C
OTf
TMS
CO2Et +
10a
SPh
•
65, 75%
SPh
CsF, MeCN, 30 °C
CO2Et
OTf
67, 56%
Scheme 7.15 Aryne-trigger [2,3]-Stevens rearrangement of propargylic thioethers. Source:
Based on Tan et al. [19].
277
278
7 Molecular Rearrangements Triggered by Arynes
of propargylic thioether 66, bearing an ester group at the thioether α-C position, afforded dienyl thioether 67 in 56% yield. In the latter case, the originally
formed α-allenyl thioether isomerizes to the dienyl thioether under the weak basic
conditions.
7.3 Rearrangements Involved in the
1,2-Difunctionalization of Arynes
A variety of rearrangements occur in the 1,2-difunctionalization of arynes either
by formal insertion of arynes into σ-bonds or by other complicated processes
for the vicinal formation of two σ-bonds. These rearrangements are very powerful for the synthesis of various functionalized arenes that might otherwise be
difficult to access.
7.3.1
Formal Insertion of Arynes into Carbon–Carbon Bonds
Enolizable carbonyl compounds have long been employed in the vicinal difunctionalization of arynes through formal insertion into their carbon–carbon σ-bonds.
In earlier studies, carbonyl compounds are preactivated as alkali enolates prior to
attack arynes, which are generated from haloarenes in the presence of a strong
base. For example, Danheiser and Helgason reported in 1994 a ring-expansive
carbon–carbon bond-insertion reaction between cyclic ketone 68 and benzyne (2a)
under basic conditions, delivering benzocycloheptanone 69 in addition to α-arylated
product 70 in a 7 : 3 ratio (Scheme 7.16) [20]. Ketone 68 is converted to enolate 71
O
O
Br
Me +
O
Ph
Me
NaNH2, THF, 45–67 °C
1b
68
NaNH2
O
69:70
56–75%
O
+
Me +
71
70
(7:3)
Me 69
Me
2a
H
Work-up
70
72
O
O
H
+
Work-up
73
Me
Me
69
74
Scheme 7.16 Formal insertion of benzyne into a cyclic ketone. Source: Based on Danheiser
and Helgason [20].
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
with high regioselectivity and benzyne (2a) is generated from bromobenzene (1b) in
the presence of sodium amide. Nucleophilic addition of enolate 71 to benzyne (2a)
affords phenyl anion 72, which cyclizes via intramolecular nucleophilic addition to
the carbonyl group. This formal [2+2] cycloaddition affords benzocyclobutoxide 73,
which participates in fragmentation followed by protonation (during work-up) to
afford benzocycloheptanone 69.
The generation of arynes from haloarenes in the presence of a strong base is
applicable to the formal aryne insertion into some other activated carbonyl compounds and analogues such as an α-lithiated malonate generated from malonate 75
(Scheme 7.17a) [21] and α-lithiated nitrile 78 (Scheme 7.17b) [22]. These reactions
proceed via similar tandem formal [2+2] cycloaddition and fragmentation.
CO2Me
(a)
OMOM
Br
+
CO2Me
75
CO2Me
O
Me
78
Me
Me
1) BuLi, pentane
Et2O, –80 to –20 °C
2) EtOH
N
+
Li
OMOM
77, 71%
OMOM
76
Me
(b)
LiTMP, THF, –78 °C
OMOM
CO2Me
O
Me
N
Me
CN
Cl
79
CN
80, 68%
Scheme 7.17 Formal insertion of an aryne into an α-lithiated malonate or an α-lithiated
nitrile. (a) Formal insertion of an aryne into an α-lithiated malonate. Source: Based on Shair
et al. [21]. (b) Formal insertion of an aryne into an α-lithiated nitrile. Source: Based on
Meyers and Pansegrau [22].
The use of 2-silylaryl triflates as aryne precursors permits the formal insertion
of arynes into the carbon–carbon σ-bonds of carbonyl compounds under mild conditions, thus dramatically enhancing the selectivity and expanding the substrate
scope. In 2005, Tambar and Stoltz reported a mild, direct, and efficient process for
the 1,2-acylalkylation of arynes 2 with β-ketoesters 81 (Scheme 7.18) [23]. In this
case, arynes 2 are generated in situ from 2-silylaryl triflates 10 in the presence of
CsF, and CsF also activates β-ketoester 81 to enolate 83. Nucleophilic addition of enolate 83 to aryne 2 affords phenyl anion 84, which cyclizes via intramolecular nucleophilic addition to the carbonyl group to form benzocyclobutoxide 85. This intermediate undergoes fragmentation followed by protonation to afford 1,2-disubstituted
arene 82. This protocol provides convenient access to a variety of functionalized
arenes and benzannulated structures that would otherwise be difficult to obtain. It is
noteworthy that cyclic β-ketoesters can be expanded to generate medium-sized carbocycles. In the cases of α-substituted β-ketoesters, α-arylation constitutes a major
side reaction.
279
280
7 Molecular Rearrangements Triggered by Arynes
O
O
O
R1
TMS
OR3
CsF, MeCN, 80 °C
+ R
R2
81
10
OTf
O
CsF
R2 82
O
R1
OR3
+ R
+
H
R2 83
84
R2
CO2R3
85
Me
Me
Me
R2
(CH2)5Me
H
86 R2
O
Me
O
O
Me
CO2Me
H
CO2Me
69%
O
75%
Scheme 7.18
Stoltz [23].
R1
CO2R3
R
H
H
O
O
R1
CO2R3
R
R1
O
Me
2
O
O
R
R1
CO2R3
R
95%
Formal insertion of arynes into β-ketoesters. Source: Based on Tambar and
Soon after Stoltz’s publication, Yoshida, Kunai, and coworkers reported a similar
insertion reaction of arynes (Scheme 7.19) [24]. The carbon–carbon triple bonds of
arynes 2 (generated in situ from 2-silylaryl triflates 10 in the presence of KF and
18-crown-6) can be inserted into a range of dialkyl malonates and 1,3-diketones
at room temperature. The reaction of arynes with cyclic dialkyl malonates has
been demonstrated to be efficient in the construction of large-sized rings. In 2016,
R2
O
O
TMS
O
R1
R2
87
O
+ R
10
OEt
O
R
OTf
O
O
61%
R1
88
O
O
OEt
O
71%
KF, 18-crown-6
THF, rt
Me
O
O
Me
O
56%
Ph
Ph
OMe O
66%
Scheme 7.19 Formal insertion of arynes into malonates and 1,3-diketones. Source: Based
on Yoshida et al. [24].
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
Mehta and coworkers disclosed the synthesis of medium-sized carbocycles from
cyclic 1,3-diketones and arynes 2, generated in situ from 2-silylaryl triflates 10 in
the presence of CsF (Scheme 7.20a) [25]. Later, Okuma and coworkers reported
the insertion of arynes into trifluoromethylated 1,3-diketones, delivering polysubstituted isocoumarins in moderate-to-good yields (Scheme 7.20b) [26]. In this case,
carbanion 93 is generated from 1,3-diketone 91 and benzyne (2a) and participates
in cyclization to form hemiacetal anion 94, which extrudes trifluoromethyl anion
to afford isocoumarin 92.
O
Me
(a)
TMS
O +
O
89
CsF, MeCN, 80 °C
OTf
10a
Me
90, 75%
O
O
O
(b)
F3C
O
TMS
Ph
+
91
10a
CsF, MeCN, reflux
OTf
O
O
O
Ph
Ph
92, 70%
CF3
CF3
93
O
O
94
–
CF3
Ph
Scheme 7.20 Formal insertion of arynes into 1,3-diketones. (a) Formal insertion of
benzyne into a cyclic 1,3-diketone. Source: Based on Samineni et al. [25]. (b) Formal
insertion of benzyne into a trifluoromethylated 1,3-diketone. Source: Based on Okuma
et al. [26].
With 2-silylaryl triflates as aryne precursors, arynes can be inserted into
the carbon–carbon σ-bonds in a number of other carbonyl compounds having
at the α-position a cyano (Scheme 7.21a) [27], a nitro (Scheme 7.21b) [28].
phosphonate (Scheme 7.21c) [29], a sulfonyl (Scheme 7.21d) [30], a trifluoromethylthio (Scheme 7.21e) [31], or even an aryl group (Scheme 7.21f) [32].
Moreover, Chandrasekhar and coworkers disclosed the insertion of arynes into
N-tosylacetimidates or N-tosylacetimidamides bearing aryl groups at the α-position
(Scheme 7.22) [33]. Hypothetically, these reactions proceed via sequential formal
[2+2] cycloaddition and fragmentation.
7.3.2
Formal Insertion of Arynes into Carbon–Heteroatom Bonds
Analogous to the acyl–carbon σ-bonds, a variety of acyl–heteroatom σ-bonds
can participate in the 1,2-difunctionalization of arynes through formal insertion
involving stepwise [2+2] cycloaddition and fragmentation. In 2005, Liu and Larock
281
282
7 Molecular Rearrangements Triggered by Arynes
OMe
O
(a)
TMS
CN +
tBu
95
KF, 18-crown-6
THF, rt
tBu
CN
OTf
10b
OMe O
96, 82%
O
TMS
O
(b)
NO2 +
Et
97
10a
KF, MeCN, 80 °C
OTf
Et
NO2
98, 95%
O
O
(c)
TMS
O
P(OMe)2 +
Me
99
10a
O
(d)
O
S
Me
101
O
10a
Me
PO(OMe)2
100, 84%
OTf
TMS
Ph +
CsF, THF, 60 °C
KF, 18-crown-6
THF, rt
OTf
O
Me
SO2Ph
102, 81%
O
O
TMS
SCF3 +
(e)
S
SCF3
104, 65%
COiPr
O
TMS
iPr
+
(f)
10a
KF, 18-crown-6
THF, rt
OTf
105
106, 97%
TMS
O
+
107
S
OTf
10a
103
KF, 18-crown-6
THF, 0 °C
10a
CsF, THF, 105 °C
OTf
O
108, 69%
Scheme 7.21 Formal insertion of arynes into α-substituted ketones. (a) Formal insertion of
3-methoxybenzyne into an α-cyano ketone. Source: Based on Yoshida et al. [27]. (b) Formal
insertion of benzyne into an α-nitro ketone. Source: Based on Hu and Zheng [28]. (c) Formal
insertion of benzyne into dimethyl (2-oxopropyl)phosphonate. Source: Based on Liu et al.
[29]. (d) Formal insertion of benzyne into an α-sulfonyl ketone. Source: Based on Zhang
et al. [30]. (e) Formal insertion of benzyne into an α-trifluoromethylthio ketone. Source:
Based on Ahire et al. [31]. (f) Formal insertion of benzyne into α-aryl ketones. Source: Based
on Yoshida et al. [32a]; Yoshida et al. [32b]; Rao et al. [32c]; Rao et al. [32d].
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
NTs
OEt
NTs
TMS
OEt
Br
CsF, MeCN, rt
+
10a
109
Br
OTf
110 , 75%
NTs
NTs
Ph
TMS
N
H
111
CO2Me
+
CsF, MeCN, rt
N
H
CO2Me
OTf
10a
Ph
112 , 83%
Scheme 7.22 Formal insertion of arynes into N-tosylacetimidates or
N-tosylacetimidamides. Source: Based on Kranthikumar et al. [33].
reported the insertion of arynes into the C—N bond of N-aryl trifluoroacetamides
using 2-silylaryl triflates as aryne precursors in the presence of CsF [34]. Later,
Pintori and Greaney expanded the scope from this specific substrate class to
common secondary amides by using tetrabutylammonium triphenyldifluorosilicate
(TBAT) for the generation of arynes 2 from 2-silylaryl triflates 10, delivering
2-aminoaryl ketones in good yields (Scheme 7.23) [35]. Mechanistically, the weakly
nucleophilic nitrogen of amide 113 can attack on aryne 2, and the resulting zwitterion 115 cyclizes via intramolecular nucleophilic addition to the carbonyl group
to afford benzazetidinium ion 116, which participates in fragmentation to afford
2-aminoaryl ketone 114.
O
O
R1
TMS
NHR2
113
+ R
10
TBAT, PhMe, 50 °C
R1
R
NHR2
114
OTf
F
R
2
O
R1
R
R
N
O
R2 H
115
O
116
O
Ph
N
H
O
CO2Et
85%
O
76%
R1
N H
R2
O
Ph
Ph
NHPh
NHPh
78%
Scheme 7.23 Formal insertion of arynes into secondary amides. Source: Based on Pintori
and Greaney [35].
283
284
7 Molecular Rearrangements Triggered by Arynes
Pintori and Greaney further applied the same reaction conditions to imide
117 and found that the insertion was selective for the amide over the carbamate
linkage, delivering Boc-protected amine 118 in 70% yield (Scheme 7.24a) [35]. In
2018, Heretsch, Christmann, and coworkers disclosed a regioselective insertion
of arynes into unsymmetric imides (Scheme 7.24b) [36]. The yield of 2-aminoaryl
ketone 120 was increased from 25% in batch to 52% when conducted in flow, and a
regioselectivity of 2.9 : 1 (120:121) was observed. The selective insertion of arynes
into C—N bonds is also applicable to ureas (Scheme 7.24c) [37] and cyanamides
(Scheme 7.24d) [38].
O
O
(a)
O
Ph
N
H
117
TMS
OtBu
+
Ph
TBAT, PhMe, 50 °C
NH
OTf
O
OtBu
118 , 70%
10a
MeO
O
O
(b) Ph
O
TMS
+
N
H
119
OMe
10a
OTf
O
Ph
TBAT, MeCN
65 °C
NH
NH
MeO
Ph
O
121
O
120 , 52%
120/121 (2.9:1)
O
O
(c)
Me N
TMS
+
N Me
CsF, 20 °C
N
Me
123 , 62%
OTf
10a
122 (solvent)
N
(d)
N
H
124
TMS
CN +
OTf
10a
Me
N
CN
CsF, THF, 70 °C
N
N
H
125 , 62%
Scheme 7.24 Formal insertion of arynes into imides, ureas, and cyanamides. (a) Formal
insertion of benzyne into imide 117. Source: Based on Pintori and Greaney [35]. (b) Formal
insertion of benzyne into imide 119. Source: Based on Schwan et al. [36]. (c) Formal
insertion of benzyne into a urea. Source: Based on Yoshida et al. [37a]; Saito et al. [37b];
Kaneko et al. [37c]. (d) Formal insertion of benzyne into a cyanamide. Source: Based on Rao
and Zeng [38].
In sharp contrast to secondary amides, bulkier tertiary amides 126 were reported
by Miyabe and coworkers to prefer to attack on arynes as oxygen nucleophiles
(Scheme 7.25) [39]. The resulting zwitterion 128 cyclizes via intramolecular nucleophilic addition of the phenyl anion to the iminium ion to afford
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
benzoxetane 129, which undergoes fragmentation followed by hydrolysis to afford
2-hydroxyaryl ketone 127. A low yield (34%) was achieved from the reaction of
N,N-dimethylacetamide (126, R = Me) due to competitive insertion of the aryne
into the C—N bond. The corresponding C—N bond insertion product was obtained
in 10% yield.
OMe
O
(1) TBAF, rt
(2) H2O, rt
TMS
+
R
NMe2
OTf
126 (Solvent)
10b
OMe
F
127
R R = H, 84%
R = Me, 34%
OH
HNMe2
H2O
OMe
OMe
2b
R
128
Scheme 7.25
et al. [39].
OMe O
O
NMe2
NMe2
R
O
129
Formal insertion of arynes into tertiary amides. Source: Based on Yoshioka
In addition to acyl–nitrogen σ-bonds, both acyl–oxygen and acyl–halogen σ-bonds
can undergo formal insertion of arynes, generated from 2-silylaryl triflates in the
presence of a fluoride ion, via stepwise [2+2] cycloaddition and fragmentation
(Scheme 7.26). Both carboxylic acids [40] and silyl-protected carboxylic acids [41]
are converted to carboxylate ions under the basic reaction conditions prior to the
O
MeO
(a)
TMS
OH +
O
10a
130
O
CsF, THF
125 °C
OMe
O
OH
131, 58%
OTf
O
O
TMS
+
(b)
MeO
CO2TIPS
OMe
132
TMS
O
(c)
R
X
134
+
10a
OTf
10a
MeO
OTf
KF, 18-crown-6
THF, 0 °C
O
KF, 18-crown-6
PhMe, rt
O
OMe
133, 52%
O
135
R = Ph, X = Cl, 68%
R
R = Ph, X = Br, 54%
R = OEt, X = Cl, 56%
X
Scheme 7.26 Formal insertion of arynes into acyl–oxygen and acyl–halogen σ-bonds.
(a) Formal insertion of benzyne into a carboxylic acid. Source: Based on Dubrovskiy and
Larock [40]. (b) Formal insertion of benzyne into a silyl-protected carboxylic acid. Source:
Based on Dhokale and Mhaske [41]. (c) Formal insertion of benzyne into an acid chloride, an
acid bromide, or a chloroformate. Source: Based on Yoshida et al. [42].
285
286
7 Molecular Rearrangements Triggered by Arynes
aryne insertion (Scheme 7.26a,b). Arynes can be inserted into the acyl–halogen
σ-bonds in acid chlorides, acid bromides, and chloroformates, providing convenient
access to various 2-haloaryl ketones (Scheme 7.26c) [42].
Alternatively, the aryne insertion is applicable to the carbon–heteroatom σ-bonds
in active methylene compounds bearing heteroatom–oxygen double bonds, which
might play roles similar to the carbonyl groups as shown above. In 2005, Yoshida,
Kunai, and coworkers reported the 1,2-carbophosphinylation of arynes with
cyanomethyldiphenylphosphine oxide (Scheme 7.27a) [43], and in 2017, Xu and
coworkers disclosed the 1,2-carbosulfonylation of arynes with aryl trifluoromethyl
sulfones (Scheme 7.27b) [44]. Moreover, the C—S bonds of sulfonium salts can also
participate in aryne insertion for the synthesis of functionalized aryl thioethers
(Scheme 7.27c) [45].
O
Ph2P
(a)
TMS
CN +
136
137, 67%
TMS
+
CO2Et
138
O
(c) Ph
140
Me
+
S
Me
Br
10a
KF, 18-crown-6
THF, 50 °C
SO2CF3
OTf
TMS
10a
O
PPh2
CN
OTf
10a
SO2CF3
(b)
KF, 18-crown-6
THF, rt
139, 75%
KF, 18-crown-6
Cs2CO3, DME, 40 °C
CO2Et
Me
S
O
OTf
Ph
141, 57%
Scheme 7.27 Formal insertion of arynes into C–P and C–S bonds. (a) Formal insertion of
benzyne into cyanomethyldiphenylphosphine oxide. Source: Based on Yoshida et al. [43].
(b) Formal insertion of benzyne into a sulfone. Source: Based on Zhao et al. [44]. (c) Formal
insertion of benzyne into a sulfonium salt. Source: Based on Ahire et al. [45a]; Li et al. [45b].
In addition to four-membered rings, five-membered rings have also been proposed
to be formed as intermediates via stepwise [3+2] cycloaddition in the insertion of
arynes into carbon–heteroatom σ-bonds. In 2011, Guitián and coworkers reported
a highly chemo- and regioselective insertion of arynes 2 (generated in situ from
2-silylaryl triflates 10 in the presence of CsF) into the C—O bond of ethoxyacetylene
(142), delivering 2-ethynylaryl ethers 143 in moderate-to-good yields (Scheme 7.28)
[46]. According to density functional theory (DFT) calculations, the reaction proceeds via the nucleophilic addition of the triple bond of ethoxyacetylene (142) to
aryne 2. The resulting zwitterion 144 cyclizes to afford benzofuran ylide 145, which
evolves through simultaneous [1,2]-hydrogen migration and ring opening via C—O
bond cleavage to afford 2-ethynylaryl ether 143.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
TMS
142
OEt
CsF, MeCN, rt
+ R
EtO
R
OTf
10
143
F
R
Et
O
Et
• O
2
R
R
144
145
H
OMe
OEt
OEt
51%
OEt
54%
73%
Scheme 7.28 Formal insertion of arynes into ethoxyacetylene. Source: Based on
Łaczkowski et al. [46].
The insertion of arynes into carbon–heteroatom σ-bonds may proceed without
involving stepwise cycloaddition and fragmentation. In 2019, Jones and coworkers
reported the insertion of arynes 2 (generated in situ from 2-silylaryl triflates 10 in the
presence of CsF) into the C—N bonds of aminals 146 (Scheme 7.29) [47]. The aryne
insertion results in the ring expansion of imidazolidines 146, leading to the formation of benzodiazepines 147. The yields are moderate due to competitive formation
R1
N
TMS
CsF, MeCN, 50 °C
N R2 + R
R3 146
10
R1
N
R3
R
N
OTf
F
R
R
R
147
R2
2
R1 N
R3
Me
N
Ph
N
N
N
Ph
45%
Scheme 7.29
et al. [47].
R1 N
N R2
148
R3
PMP
N
F
N
PMP
Boc
34%
30%
N R2
149
Ph
N
N
F
Ph
35%
Formal insertion of arynes into imidazolidines. Source: Based on Yang
287
288
7 Molecular Rearrangements Triggered by Arynes
of linear 1,2-ethylenediamines as byproducts. Mechanistically, the reaction proceeds
via initial N-arylation of imidazolidine 146. The resulting zwitterion 148 may be
in equilibrium with the ring-opened form 149, which cyclizes via intramolecular
nucleophilic addition of the phenyl anion to the iminium ion to afford benzodiazepine 147.
7.3.3
Formal Insertion of Arynes into Heteroatom–Heteroatom Bonds
Analogous to the C—N bonds of amides, the P—N bonds of phosphoryl amides 150
participate in the aryne insertion to afford (2-aminoaryl)phosphine oxides 151 in
moderate-to-good yields (Scheme 7.30) [48]. In this case, arynes 2 are generated
in situ from 2-silylaryl triflates 10 in the presence of KF and 18-crown-6, and the
addition of Cs2 CO3 facilitates the nucleophilic addition of phosphoryl amides 150
to arynes 2. Mechanistically, N-arylation of phosphoryl amide 150 with aryne 2 in
the presence of Cs2 CO3 generates aryl anion 153, which cyclizes via intramolecular
nucleophilic addition to the P=O bond to afford benzannulated four-membered ring
154. This intermediate undergoes fragmentation followed by protonation to afford
(2-aminoaryl)phosphine oxide 151.
O
Ar2P NHAr′ + R
150
Base
10
R
O
Ar2P NAr′
O
Ph2P
153
Scheme 7.30
et al. [48].
H
Ar2
P
N
O
Ar′
O
Ar2P
Br
63%
NHAr′
151
F
R
H
N
R
OTf
2
152
O
PAr 2
KF, 18-crown-6
Cs2CO3, THF, 80 °C
TMS
R
H
N
Cl
Ar = 4-MeC6H4, 70%
154
O
PAr 2
N
Ar′
O
Ph2P
O
O
PAr 2
R
155
H
N
NAr′
Br
O
45%
Formal insertion of arynes into phosphoryl amides. Source: Based on Shen
Similar aryne insertion can occur with the P—O bonds of organophosphorus acids
156, delivering (2-hydroxyaryl)phosphine oxides, (2-hydroxyaryl)phosphinates,
and (2-hydroxyaryl)phosphonates in moderate-to-good yields (Scheme 7.31a) [49].
Moreover, the aryne insertion is applicable to the S—N bonds of trifluoromethanesulfinamides bearing S=O bonds (Scheme 7.31b) [34], which might play roles
similar to the P=O bonds as shown above.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
(a)
O
R1 P OH +
R2
156
HN
O
S
TMS
TBAT, THF, 60 °C
OTf
O
PR1R2
OH
157
R1 = Ph, R2 = Me, 65%
R1 = Ph, R2 = OEt, 64%
R1 = R2 = OEt, 57%
10a
O
S
CF3
TMS
+
(b)
NHCOCF3
158
10a
TBAF, THF, rt
CF3
NH
OTf
NHCOCF3
159, 58%
Scheme 7.31 Formal insertion of arynes into organophosphorus acids and sulfinamides.
(a) Formal insertion of benzyne into organophosphorus acids. Source: Based on Qi et al. [49].
(b) Formal insertion of benzyne into a sulfinamide. Source: Based on Liu and Larock [34].
Without the aid of heteroatom–oxygen double bonds, certain heteroatom–
heteroatom σ-bonds can participate in the aryne insertion reactions. Obviously,
a four-membered ring is unlikely to be formed as a rearrangement precursor in
such aryne insertion reactions. In 2015, Chen and Wang disclosed the insertion of
arynes 2 (generated in situ from 2-silylaryl triflates 10 in the presence of KF and
18-crown-6) into the N—O bonds of N-hydroxyindolin-2-ones 160, delivering sterically hindered 2-aminophenols 161 in moderate-to-good yields (Scheme 7.32) [50].
Mechanistically, the reaction proceeds via the addition of N-hydroxyindolin-2-one
160 to aryne 2 followed by a [1,3]-rearrangement, which is possibly facilitated
by the introduction of the amide group to enhance the electrophilic nature of
nitrogen, in comparison to a hydroxyamine. The structural rigidity of cyclic amides
might impede the π–π stacking conformation required for the transition state of a
[3,3]-rearrangement.
A number of other heteroatom–heteroatom σ-bonds have been reported to
participate in the aryne insertion reactions, probably involving a similar
[1,3]-rearrangement (Scheme 7.33). The insertion of arynes into N—Si [51],
N—S [52], P—P [53], S—S [54], S—Sn [55], S—Bi [56], Se—Se [57], and F—Sn
bonds [58] affords a wide variety of 1,2-difunctionalized arenes, which are difficult
to be prepared by alternative methods.
7.3.4 Vicinal Carbon–Carbon/Carbon–Carbon Bond-Forming Reactions
of Arynes
In addition to formal insertion of arynes into σ-bonds, there are a number of other
methods toward vicinal formation of two σ-bonds for the 1,2-difunctionalization
289
290
7 Molecular Rearrangements Triggered by Arynes
R2
R2 R1
R1
N
160 OH
KF, 18-crown-6
DME, 40 °C
TMS
O + R
10
O
N
OH
OTf
R
F
R
R2
R1
2
161
[1,3]
N
O
O
H 162
R
O
N
N
O
N
Scheme 7.32
Wang [50].
O
OH
OH
OH
45%
O
54%
N
Me
82%, 7:1 rs
Formal insertion of arynes into N–O bonds. Source: Based on Chen and
of arynes involving molecular rearrangements. In 2018, Li, Chen, and coworkers reported the reaction of arynes 2 (generated in situ from 2-silylaryl triflates
10 in the presence of CsF) with β-(2-isocyanophenyloxy)acrylates 179 (or analogues), delivering 1,2-disubstituted arenes 180 bearing a benzoxazole ring
and an alkenyl group in good yields (Scheme 7.34) [59]. Mechanistically, this
domino reaction proceeds via the nucleophilic addition of the isocyano group
of β-(2-isocyanophenylox)yacrylate 179 (or its analogue) to aryne 2, affording
zwitterion 181. Intramolecular Michael addition of the aryl anion to the activated carbon–carbon double bond takes place to afford intermediate 182, which
undergoes ring opening via C—O bond cleavage followed by cyclization to afford
1,2-disubstituted arene 180. An alternative pathway involves first formation of
the benzoxazole moiety from zwitterion 181. Then, the resulting intermediate 184
undergoes [1,4]-migration of the alkenyl group via intermediacy of a five-membered
ring to afford the final product 180.
Taking advantage of the nucleophilic addition of isocyanides to arynes, Biju and
coworkers have developed a three-component reaction of isocyanides 186, arynes 2
(generated in situ from 2-silylaryl triflates 10 in the presence of CsF), and carbon
dioxide, delivering N-substituted phthalimides 187 in moderate-to-good yields
(Scheme 7.35) [60]. Mechanistically, the nucleophilic addition of isocyanide 186 to
aryne 2 generates zwitterion 188, which undergoes a stepwise [3+2] cycloaddition
with carbon dioxide leading to the formation of imino isobenzofuranone 190.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
KF, 18-crown-6
THF, 0 °C
TMS
(a)
Et2N SiMe2Ph +
163
(b)
NEt2
OTf
10a
164, 65%
TMS
Me
+
PhS N
Ph
165
CsF, DME, 25 °C
OTf
10a
Ph2P PPh2 +
167
10a
F3CS SCF3 +
169
10a
PhS SnBu3
+
171
S
(f)
BiAr2
10a
+
10a
10a
F SnBu3 +
177
SCF3
170 , 71%
10a
KF, 18-crown-6
THF, 0 °C
SnBu3
SPh
172, 54%
KF, 18-crown-6
THF, 0 °C
CsF, MeCN, rt
Me
BiAr2
S
OTf
SePh
SePh
176, 76%
OTf
TMS
(h)
SCF3
174, Ar = 4-MeC6H4, 79%
PhSe SePh +
175
o
CsF, DME, 85 C
OTf
TMS
(g)
PPh2
OTf
TMS
Me
173
PPh2
168, 65%
OTf
TMS
(e)
TBAT, MS
DCE, 60 °C
OTf
TMS
(d)
Me
N
Ph
SPh
166, 59%
TMS
(c)
SiMe2Ph
KF, 18-crown-6
DME, 0 °C
SnBu3
F
178, 97%
Scheme 7.33 Formal insertion of arynes into various heteroatom–heteroatom bonds. (a)
Formal insertion of benzyne into a N—Si bond. Source: Based on Yoshida et al. [51a];
Yoshida et al. [51b]. (b) Formal insertion of benzyne into a N—S bond. Source: Based on
Gaykar et al. [52]. (c) Formal insertion of benzyne into a P—P bond. Source: Based on
Okugawa et al. [53]. (d) Formal insertion of benzyne into a S—S bond. Source: Based on
Mesgar and Daugulis [54]. (e) Formal insertion of benzyne into a S—Sn bond. Source: Based
on Yoshida et al. [55]. (f) Formal insertion of benzyne into a S—Bi bond. Source: Based on
Chen and Murafuji [56]. (g) Formal insertion of benzyne into a Se—Se bond. Source: Based
on Toledo et al. [57]. (h) Formal insertion of benzyne into a F—Sn bond. Source: Based on
Yoshida et al. [58].
291
292
7 Molecular Rearrangements Triggered by Arynes
EWG
O
EWG
R1
TMS
CsF, MeCN, 80 °C
+ R
NC
180
F
R
O
N
EWG
EWG
O
2
R
N
Path a
C
O
R1
EWG
R1
R1
R
N
Path b
N
183
EWG
O
R1
R
182
EWG
181
R
N
OTf
10
179
O
R1
R
184
R1
R
O
180
N 185
MeO2C
EWG
O
N
EWG = CO2Me, 71%
EWG = COMe, 72%
EWG = SO2Ph, 82%
MeO2C
X
O
O
N
X = F, 66%
X = Cl, 64%
X = CO2Me, 80%
OMe
N
OMe
72%
Scheme 7.34 Reaction of arynes with β-(2-isocyanophenyloxy)acrylates (or analogues).
Source: Based on Su et al. [59].
A fluoride-induced rearrangement transforms this intermediate to N-substituted
phthalimide 187 via intermediacy of acylfluoride 191.
In 2019, Yennam and coworkers disclosed the reaction of 2-arylidene-1,3indandiones 192 (R = electron-rich or neutral group) with benzyne (2a) (generated in situ from 2-silylaryl triflate 10a in the presence of CsF) under aerobic
conditions, delivering dibenzo[a,c]anthracene-9,14-diones 193 in moderate yields
(Scheme 7.36) [61]. Mechanistically, the reaction proceeds via [4+2]-cycloaddition
between 2-arylidene-1,3-indandione 192 and benzyne (2a), and the resulting spirocycle 194 undergoes intramolecular nucleophilic addition to the carbonyl group to
form the cyclopropane ring in strained tricyclic alcohol 195, which upon retro-aldol
reaction and air oxidation affords dibenzo[a,c]anthracene-9,14-dione 193.
7.3.5 Vicinal Carbon–Carbon/Carbon–Heteroatom Bond-Forming
Reactions of Arynes
The charge-accelerated aza-Claisen rearrangement constitutes one powerful protocol for the introduction of vicinal carbon–carbon and carbon–heteroatom bonds into
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
O
TMS
R1 NC +
186
+ CO2
R
10
R
N
OTf
187
F
2
R1
N
R
O
C
N R1
R
O
F
R
188
CsF, MeCN, 30 °C
R
O
O
189
1
N R
R1
O
O
O
O
Me
O
191
O
N
76%
tBu
O
O
Me
O
R1
O
N tBu
O
O
R = tBu, 76%
R = Cy, 64%
R = 4-MeOC6H4, 44%
N
F
R
O F
N tBu
N R
O
O
190
–
38%
81%
Scheme 7.35 Three-component reaction of arynes, isocyanides, and carbon dioxide.
Source: Based on Kaicharla et al. [60].
O
O
TMS
+
O
192
10a
R
CsF, MeCN, 80 °C
OTf
O
F
193
R = H, 42%
R = Me, 54%
R = OMe, 56%
O2
2a
O
R
OH
R
R
H
O
194
O
195
Scheme 7.36 Reaction of benzyne with 2-arylidene-1,3-indandiones. Source: Based on
Payili et al. [61].
arynes. In 2009, Greaney and coworkers disclosed the aryne-triggered aza-Claisen
rearrangement of tertiary allylic amines 196, delivering 2-allylanilines 197 in
moderate-to-excellent yields (Scheme 7.37) [62]. This reaction avoids high reaction
temperature or the use of stoichiometric amounts of Lewis acids as required for
conventional aza-Claisen rearrangements. Mechanistically, the reaction is initiated
by the nucleophilic addition of tertiary allylic amine 196 to aryne 2 (generated in
293
294
7 Molecular Rearrangements Triggered by Arynes
situ from 2-silylaryl triflate 10 in the presence of CsF), generating zwitterion 198,
which is protonated by the solvent to afford quaternary ammonium salt 199. This
salt undergoes an aza-Claisen rearrangement to afford 2-allylaniline 197. Notably,
the tertiary allylic amines can be prepared in situ from secondary allylic amines and
arynes prior to the aryne-triggered aza-Claisen rearrangement [63]. Greaney and
coworkers further applied the aryne-triggered aza-Claisen rearrangement of tertiary
allylic amines to the construction of unsaturated nine- and ten-membered cyclic
amines through ring expansion of five- and six-membered cyclic amines bearing
a vinyl group at the amine α-C position [62]. Later, Saito and coworkers extended
the ring expansion to 2-vinylazetidines, delivering 1-benzazocine derivatives in
moderate-to-good yields [64].
R1
N
196
TMS
R2
+ R
10
R
R1 R2
N
R
2
SolH
CsF, PhMe/MeCN, 110 °C
OTf
197
62%
R1
SolH
[3,3]
199
Me
N
Ph
91%
Sol
H
R1 R2
N
Sol
198
O
N
R2
F
R
N
R
R
200
N
R2
R1
N
79%
N
Me
41%
Scheme 7.37 Aryne-triggered aza-Claisen rearrangement of tertiary allylic amines. Source:
Based on Cant et al. [62].
The aryne-triggered propargyl Claisen rearrangement was recently reported by
Palakodety and coworkers (Scheme 7.38) [65]. 3-Alkynyl-3-hydroxyindolin-2-ones
201 and 2-silylaryl triflates 10 were treated with CsF, 18-crown-6, Cs2 CO3 , and
molecular sieves, and the reaction afforded 3-benzofuranylindolin-2-ones 202 in
moderate-to-good yields. Mechanistically, deprotonation of propargylic alcohol
201 by the base generates propargyloxide 203, which undergoes nucleophilic
addition to aryne 2 to afford aryl anion 204. This intermediate participates in a
propargyl Claisen rearrangement to afford allene 205, which undergoes 5-exo-dig
cyclization followed by protonation to afford 3-benzofuranylindolin-2-one 202.
Another type of [3,3]-sigmatropic rearrangement might occur in the reaction of
arynes with N-hydroxyindoles (Scheme 7.39) [50]. In sharp contrast to the aryne
insertion reaction of N-hydroxyindolin-2-ones involving a [1,3]-rearrangement
(Scheme 7.32) [50], this reaction afforded C3-arylated indoles in moderate yields
via a [3,3]-sigmatropic rearrangement.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
R
R2
R2
HO
CsF, 18-crown-6
Cs2CO3, MS, MeCN, rt
TMS
R1
+ R
O
N
201 Me
10
R
Base
O
N
202 Me
F
+
R
R2
O
H
R2
R2
•
R1
O
N
203 Me
[3,3]
O
R
R2
O
R1
R1
OTf
R
2
O
O
O
R1
N
204 Me
R1
O
O
N
206 Me
N
205 Me
F
MeO
Me(H2C)5
O
O
I
O
O
Br
O
O
N
Me
O
N
Me
56%
Me(H2C)5
F
N
Me
65%
65%
O
N
Me
51%
Scheme 7.38 Aryne-triggered propargyl Claisen rearrangement. Source: Based on
Kalvacherla et al. [65].
O
Me
OH
TMS
Me +
MeO2C
207
Scheme 7.39
Wang [50].
N
OH
10a
OTf
COMe
CsF, MeCN, rt
Me
MeO2C
N
208, 50%
Reaction of arynes with N-hydroxyindoles. Source: Based on Chen and
Cycloaddition or formal cycloaddition of arynes followed by rearrangements
constitutes another class of protocols for the introduction of vicinal carbon–carbon
and carbon–heteroatom bonds into arynes. In 2013, Studer and coworkers
reported the reaction of arynes 2 (generated in situ from 2-silylaryl triflates 10
in the presence of CsF) with nitrosoarenes 209, delivering carbazoles 210 in
moderate-to-good yields (Scheme 7.40) [66]. Mechanistically, the reaction proceeds
via the [2+2]-cycloaddition between nitrosoarene 209 and aryne 2, and the resulting benzannulated four-membered ring 211 undergoes ring opening via N—O
bond cleavage to afford o-quinone derivative 212. This intermediate cyclizes via
295
296
7 Molecular Rearrangements Triggered by Arynes
intramolecular addition to the carbonyl group to afford intermediate 213. The C—O
bond of intermediate 213 is cleaved by a nucleophile, and subsequent protonation
eventually affords carbazole 210.
N
TMS
O +
R
R1
209
H
N
CsF, MeCN, rt
10
210
F
N
H
R
R
2
214
R1
N
O
R
R1
N
N
R
R1
R
O
212
211
H
N
tBu
H
N
OMe
Nu
H
N
Scheme 7.40
et al. [66].
62%
OH
213
R1
H
N
F
Br
45%
R1
R
OTf
47%
F
30%
Reaction of arynes with nitrosoarenes. Source: Based on Chakrabarty
In 2016, Hoye and coworkers disclosed the reaction of aromatic thioamides
215 with aryne 218 (generated in situ by the hexadehydro-Diels–Alder cycloisomerization of triyne 216), delivering structurally diverse dihydrobenzothiazines
217 in a regio- and diastereoselective manner (Scheme 7.41) [67]. It is postulated
that the reaction proceeds via the initial [2+2] cycloaddition between thioamide
215 and aryne 218 followed by ring opening of the resulting benzothietene 219
via C—S bond cleavage to form o-thiolatoaryliminium 221. This intermediate
undergoes intramolecular [1,3]-hydrogen migration to give iminium zwitterion
222, which cyclizes via the addition of the thiolate anion to the iminium ion to
afford dihydrobenzothiazine 217.
In addition to [2+2] cycloaddition, [3+2] cycloaddition occurs prior to a variety of rearrangements in the vicinal carbon–carbon and carbon–heteroatom
bond-forming reactions of arynes. In 1974, Yamazaki and coworkers disclosed
the reaction of benzyne (2a) (generated from benzenediazonium-2-carboxylate
(224)) with diazo compounds 224, delivering 1-acyl-3-phenylindazole 225 in varied
yields (Scheme 7.42) [68]. Mechanistically, the reaction proceeds via initial [3+2]
cycloaddition between diazo compound 223 and benzyne (2a). The resulting adduct
226 undergoes [1,3]-migration and/or successive [1,2]-migrations of the acyl group
to afford indazole 225.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
TMS
O
Ar
Me
O
S
TMS
C6H6, 90 °C
R2 +
N
R1
215
S
Me
216
Ar
217
TMS
O
Me
TMS
O
R2
N
R1
Me
S
218
TMS
O
Ar
220
N
R2
R1
Ph
N
R1
Me
S
S
Ph
H
N
2
R
R1
Ar
221
O
Me
N
Ph
S
R2
TMS
O
TMS
Me
S
Me
N
Me
iPr
N
O2N
48%
Scheme 7.41
Me
S
TMS
O
TMS
O
Me
S
219
R2
TMS
O
Me
Ar
N
R1
Ar
222
72%
71%
Reaction of arynes with thioamides. Source: Based on Palani et al. [67].
Ph
N2
Ph
223
CO2
R +
O
224
N2
[1,3]
R
Ph
2a
N
N
226
Scheme 7.42
et al. [68].
N
CH2Cl2
N
R
O
[1,2]
225
R = Ph, 60–90%
R = 4-MeOC6H4, 14%
Ph
R
O [1,2]
N
N
227
O
Reaction of benzyne with diazo compounds. Source: Based on Yamazaki
297
298
7 Molecular Rearrangements Triggered by Arynes
In 2006, Larock and coworkers disclosed the reaction of arynes 2 (generated in
situ from 2-silylaryl triflates 10 in the presence of CsF) with pyridine N-oxides 228 in
a regioselective manner, delivering 3-(2-hydroxyphenyl)pyridines 229 in good yields
(Scheme 7.43) [69]. Mechanistically, the reaction proceeds via [3+2] cycloaddition
between aryne 2 and pyridine N-oxide 228, and the resulting oxazolopyridine
230 undergoes a simultaneous rearrangement to form the cyclopropane ring of
intermediate 231. This intermediate opens up via C—C bond cleavage to afford
3-(2-hydroxyphenyl)pyridine 229. 2-Substituted quinoline N-oxides and acridine
N-oxides can undergo a similar rearrangement reaction with arynes to afford
3-(2-hydroxyaryl)quinolines and 4-arylacridines, respectively [70]. The reaction
of 3-silylarynes (generated from 2,6-disilylaryl triflates) with pyridine N-oxides
results in the regioselective incorporation of a hydroxy group on its C2 position,
and subsequent one-pot triflation/tosylation allows the preparation of 2,3-aryne
precursors [71].
R
TMS
R1
CsF, MeCN, rt
N O + R
228
10
OTf
R1
OH
229
N
F
R
R1
R
2
R
R1
N
O
N
O
230
231
Me
+
Me
N
Scheme 7.43
et al. [69].
OH
N
81% (6.7:1)
OH
Me
OH
N
52%
N
OH
90%
Reaction of arynes with pyridine N-oxides. Source: Based on Raminelli
Stepwise formation of five-membered rings as rearrangement precursors also
contributes to the vicinal incorporation of carbon–carbon and carbon–heteroatom
bonds into arynes. In 2018, Shamsabadi and Chudasama disclosed the reaction
of arynes 2 with acyl hydrazides 232, delivering 2-hydrazobenzophenones 233 in
moderate-to-good yields (Scheme 7.44) [72]. Mechanistically, nucleophilic addition
of deprotonated acyl hydrazide 234 to aryne 2 affords aryl anion 235, which
cyclizes via intramolecular nucleophilic addition to the carbonyl group to afford
2,3-dihydro-1H-indazole 236. This intermediate participates in fragmentation
followed by protonation to afford 2-hydrazobenzophenone 233.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
R1
O
R1
H
N
N
CO2iPr + R
i
CO2 Pr
232
TMS
R1
N
233 HN CO iPr
2
F
R
2
O
iPr
N
CO2
CO2iPr
234
R1
H
R
R1
O
O
N
O
CO2iPr
R
OTf
10
R
Base
TBAT, PhMe, 50 °C
N
CO2iPr
N
CO2iPr
235
R1
N N
CO2iPr
iPrO C
2
236
R
237
N
N
O
CO2iPr
CO2iPr
CO2Me
I
O2N
OMe
N
HN
O
CO2iPr
CO2iPr
74%
N
HN
O
CO2iPr
CO2iPr
68%
N
HN
O
CO2iPr
CO2iPr
72%
N
HN
O
CO2iPr
CO2iPr
48%
Scheme 7.44 Reaction of arynes with acyl hydrazides. Source: Based on Shamsabadi and
Chudasama [72].
In 2016, Voskressensky and coworkers disclosed the reaction of arynes 2
(generated in situ from 2-silylaryl triflates 10 in the presence of CsF) with
1-aroyl-3,4-dihydroisoquinolines 238, delivering indoloisoquinolinones 239 in
good-to-excellent yields (Scheme 7.45) [73]. Mechanistically, nucleophilic addition
of dihydroisoquinoline 238 to aryne 2 generates zwitterion 240, which cyclizes via
intramolecular nucleophilic addition of the aryl anion to the carbonyl group to form
cyclic iminium 241. [1,2]-migration of the aryl group to the iminium carbon affords
indoloisoquinolinone 239.
In 2016, Greaney and coworkers disclosed the reaction of arynes 2 (generated
in situ from 2-silylaryl triflates 10 in the presence of KF and 18-crown-6) with
aryl sulfonamides 242, delivering sterically hindered 2-amino biaryls 243 in
moderate-to-good yields (Scheme 7.46) [74]. Mechanistically, nucleophilic addition
of deprotonated aryl sulfonamide 244 to aryne 2 generates aryl anion 245. This
intermediate undergoes sequential Smiles-type ipso substitution via σ-complex 246,
extrusion of sulfur dioxide, and protonation to afford 2-amino biaryl 243.
The aryne-triggered Smiles rearrangement has also been taken advantage
of in multicomponent reactions. In 2015, Biju and coworkers disclosed the
three-component reaction of arynes 2 (generated in situ from 2-silylaryl triflates 10
in the presence of KF and 18-crown-6), tertiary aromatic amines 248, and carbonyl
compounds 249, delivering 2-aminobenzyl aryl ethers 250 in moderate-to-good
299
300
7 Molecular Rearrangements Triggered by Arynes
R1
N
R1
TMS
O
238
R2
R2
OTf
10
N
CsF, MeCN, rt
+ R
R
O
239
F
R
2
R1
O
N
R
R2
240
R2
R
O
241
Me
Me
N
EtO
N
EtO
R1
N
Ph
EtO
O
OMe
Me
O
EtO
OMe
90%
Me
Me
N
Ph
O
69%
94%
Scheme 7.45 Reaction of arynes with 1-aroyl-3,4-dihydroisoquinolines. Source: Based on
Varlamov et al. [73].
R
SO2NHR1
TMS
KF, 18-crown-6, THF, 65 °C
EWG + R
242
base
10
R
SO2NR
1
2
NHR1
OTf
EWG
F
O R1
O S N
H
1
O R
O S N
+
R
- SO2
EWG
244
EWG
MeO
245
R
EWG
243
NR1
R
246
EWG
247
Cl
N
NHPh
O 2N
63%
Scheme 7.46
[74].
Br
Cl
88%
NHPh
N
NHPh
43%
S
NHPh
73%
Reaction of arynes with aryl sulfonamides. Source: Based on Holden et al.
7.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes
yields (Scheme 7.47) [75]. Mechanistically, the reaction proceeds via the nucleophilic addition of tertiary aromatic amine 248 to aryne 2, and the resulting aryl
anion 251 undergoes nucleophilic addition to carbonyl compound 249 to afford
zwitterion 252. An intramolecular nucleophilic aromatic substitution reaction
occurs in zwitterion 252 to afford 2-aminobenzyl aryl ether 250 via σ-complex 253.
Later, Okuma and coworkers reported that cyclic tertiary aromatic amines, such
as indolines and tetrahydroquinolines, can participate in the three-component
reaction with arynes and aldehydes to afford medium-sized dibenzannulated
heterocycles such as dibenzo[1,5]oxazonines and dibenzo[1,5]oxazecines [76].
R3
R2
N
TMS
R1
248
O
+
+ R
10
OTf
KF, 18-crown-6
THF, –10 °C- rt
R4
R5
R3
N
R
249
R
R3 R2
N
R
251
R4
R5 249
NMe2
R1
R
O
R4
2
R3 R
N
R3 R2
N
R1
R
O
R5
252
O
OPh
NMe2
OPh
O
Br
63%
R5 253
NMe2
CO2Et
CN
R1
O
R4
NMe2
O
R1
R4 R5
250
F
2
R2
O
CN
80%
N
Me
CN
48%
72%
Scheme 7.47 Three-component reaction of arynes, tertiary aromatic amines, and carbonyl
compounds. Source: Based on Bhojgude et al. [75].
Biju and coworkers further developed the three-component reaction of arynes 2
(generated in situ from 2-silylaryl triflates 10 in the presence of KF and 18-crown-6),
tertiary aromatic amines 248, and carbon dioxide (Scheme 7.48) [77]. When the
tertiary aromatic amine partners possess an electron-withdrawing group on the
aromatic ring, the reaction affords aryl 2-aminobenzoates 254 via an aryl migration.
Otherwise, the reaction affords alkyl 2-aminobenzoates 255 via an alkyl migration.
Mechanistically, the reaction proceeds via the nucleophilic addition of tertiary
aromatic amine 248 to aryne 2, and the resulting aryl anion 251 undergoes nucleophilic addition to carbon dioxide to afford zwitterion 256. When the R1 group on
the aromatic ring is an electron-withdrawing group, zwitterion 256 undergoes
intramolecular nucleophilic aromatic substitution to afford aryl 2-aminobenzoate
254 via σ-complex 257. Otherwise, zwitterion 256 undergoes O-alkylation to afford
alkyl 2-aminobenzoate 255.
301
302
R3
7 Molecular Rearrangements Triggered by Arynes
R2
N
TMS
R1
KF, 18-crown-6, THF
+ CO2
+ R
248
–10 °C
OTf
10
R3
N
F
R
2
R3
R
R2
N
251
O C O
O-alkylation
255
R1
O
O
O
R1
R
R1
O
O
R2
255
O-arylation
R3 R
N
R
O
Me
N
Me
O
257
Br
N
O
CHO
65%
R1
O
256
CO2Et
75%
R2
O
2
R3 R2
N
R
Me
N
Me
O
R3
N
O
254
R1
R
–10 to 60 °C
O
86%
Me
OMe
Ph
N
Me
OBn
O
82%
Scheme 7.48 Three-component reaction of arynes, tertiary aromatic amines, and carbon
dioxide. Source: Based on Bhojgude et al. [77].
7.3.6 Vicinal Carbon–Heteroatom/Carbon–Heteroatom Bond-Forming
Reactions of Arynes
Cycloaddition between arynes and heteroatom–heteroatom bonds followed
by rearrangements constitutes an important strategy for the formation of vicinal carbon–heteroatom and carbon–heteroatom bonds with arynes. In 2017,
Li and Studer reported the oxythiolation of arynes 2 (generated in situ from
2-silylaryl triflates 10 in the presence of CsF) with aryl vinyl sulfoxides 258,
delivering 2-sulfanylaryl vinyl ethers 259 with complete stereospecificity in
moderate-to-good yields (Scheme 7.49) [78]. The use of water as an additive suppresses fluoride-mediated disproportionation of the sulfoxide to the corresponding
sulfide and sulfone. Mechanistically, the reaction proceeds via a concerted [2+2]
cycloaddition between aryl vinyl sulfoxide 258 and aryne 2, and the resulting
benzannulated four-membered ring 260 undergoes ring opening via S—O bond
cleavage to afford zwitterion 261. The sulfur to oxygen migration of the vinyl
group proceeds via intramolecular oxa-Michael addition followed by elimination,
affording 2-sulfanylaryl vinyl ether 259.
7.4 Rearrangements Involved in the 1,2,3-Trifunctionalization of Arynes
R1
O
S
R3
CsF, H2O
MeCN, 55 °C
TMS
R4
+ R
R2 258
10
SR1
R
O
OTf
259
R3
R2
F
R4
R
2
O
R
S
R1
R2
260
R3
R4
O R3
R4
R
261
S
R1
R2
O R2 R3
R
262
S
R1
R4
SPh
SPh
O
63%
Scheme 7.49
Studer [78].
SPh
CONEt2
O
CO2Me
O
46%
CO2Me
SiEt3
80%
Reaction of arynes with vinyl sulfoxides. Source: Based on Li and
In the absence of a vinyl group, the aryl group of an aryl sulfoxide undergoes
sulfur to oxygen migration in a similar reaction pathway when treated with an
aryne generated from the corresponding 2-silylaryl triflate under appropriate conditions. In 2017, Hosoya and coworkers disclosed the oxythiolation of arynes with
diaryl sulfoxides, delivering 2-sulfanylaryl aryl ethers in moderate-to-good yields
(Scheme 7.50a) [79]. Notably, the more electron-deficient aryl group prefers to participate in the sulfur to oxygen migration in the reaction of an unsymmetrical diaryl
sulfoxide. Moreover, Hosoya and coworkers observed similar sulfur to nitrogen
migration of the aryl group in the thioamination of arynes with sulfilimines,
delivering 2-sulfanylanilines in moderate-to-good yields (Scheme 7.50b) [80].
In 2014, Hosoya and coworkers disclosed the reaction of 3-triflyloxybenzyne (2c)
(generated from 1,3-bis(triflyloxy)-2-iodobenzene (268) in the presence of a Grignard
reagent) with nucleophiles 267 such as triphenylphosphine and diphenyl sulfide,
delivering zwitterionic triflones 269 in good yields (Scheme 7.51) [81]. The reaction
proceeds via initial regioselective nucleophilic addition to 3-triflyloxybenzyne (2c)
at the site distal from the triflyloxy group. The resulting ortho-triflyloxyaryl anion
270 undergoes a thia-Fries rearrangement to afford triflone 269.
7.4 Rearrangements Involved in the
1,2,3-Trifunctionalization of Arynes
1,2,3-Trifunctionalization of arynes involving rearrangements is powerful for
the regioselective synthesis of polysubstituted arenes. In 2016, Li and coworkers disclosed the three-component reaction of arynes 2 (generated in situ from
303
304
7 Molecular Rearrangements Triggered by Arynes
OMe
S
O
S
Cl
OMe
TMS
+
(a)
Me
KF, 18-crown-6
dioxane, 80 °C
Me
O
Cl
263
10b
OTf
264, 86%
OMe
SPh
Ph
(b)
NH
S
NO2
OMe
TMS
+
265
10b
KF, 18-crown-6
THF, 60 °C
NH
NO2
OTf
266, 60%
Scheme 7.50 Reaction of arynes with diaryl sulfoxides or sulfilimines. (a) Reaction of
3-methoxybenzyne with a diaryl sulfoxide. Source: Based on Matsuzawa et al. [79].
(b) Reaction of 3-methoxybenzyne with a sulfilimine. Source: Based on Yoshida et al. [80].
OTf
Nu +
267
O
TMSCH2MgCl
Et2O, –30 °C
I
SO2CF3 269
Nu = PPh3, 77%
Nu = SPh2, 76%
Nu
OTf
268
O
S
CF3
O
O
OTf
Nu (267)
2c
Scheme 7.51
270
Nu
Synthesis of triflones. Source: Based on Yoshida et al. [81].
2-silylaryl triflates 10 in the presence of CsF), allyl aryl sulfoxides 271, and alkyl
bromides 272, delivering 1,2,3-trifunctionalized arenes 273 in moderate-to-good
yields (Scheme 7.52) [82]. The 1,2,3-trifunctionalization of arynes 2 with aryl allyl
sulfoxides 271 was achieved through formation of C—S, C—O, and C—C bonds
on three consecutive positions of the aromatic ring. Mechanistically, the reaction
proceeds via a formal [2+2] cycloaddition between allyl aryl sulfoxide 271 and
aryne 2, and the resulting benzannulated four-membered ring 274 undergoes the
sulfur to oxygen migration of the ally group to afford ylide 275. This intermediate
undergoes an oxonium Claisen rearrangement to afford intermediate 276. Opening
of the four-membered ring via S—O bond cleavage affords phenoxide 277, which is
alkylated with alkyl bromide 272 to afford 1,2,3-trifunctionalized arene 273.
7.5 Rearrangements Involved in the Multicomponent Reactions with Two or More Aryne Molecules
R3
R1
R3
O
S
271
R2
CsF, MeCN
50 or 80 °C
TMS
R4 + R
OTf
10
+ R5 Br
272
R
O
S
1
R
274
R4
R
R2
273
Br
272
R3
275
R4
R2
R3
R3
OR5
R5
R
R4
R2
R
F
2
R4
O
S
R1
[3,3]
- H+
R3
R4
R2
O
S
R
276
SR1
R2
O
R
R1
277
SR1
CO2Et
CO2Et
O
CO2Et
O
O
Me
Me
O
Me
S
S
75%
S
S
64%
OMe
65%
S
62%
Scheme 7.52 Three-component reaction of arynes, allyl sulfoxides, and alkyl bromides.
Source: Based on Li et al. [82].
7.5 Rearrangements Involved in the Multicomponent
Reactions with Two or More Aryne Molecules
A variety of active intermediates are generated during the reactions involving
aryne-triggered rearrangements, and they might be trapped by the highly electrophilic arynes. To date, two or three aryne molecules have been reported to
participate in a number of multicomponent reactions involving rearrangements.
These multicomponent reactions with two or three aryne molecules provide
convenient access to complex organic molecules.
7.5.1
Three-Component Reactions with Two Aryne Molecules
In the aryne insertion into certain active methylene compounds, the rearrangement
intermediates can be trapped by one extra aryne molecule to afford diarylmethanes.
In 2007, Kunai and coworkers disclosed the coupling of two molar amounts of
arynes 2 (generated in situ from 2-silylaryl triflates 10 in the presence of KF
and 18-crown-6) with nitriles 278 bearing an electron-withdrawing group at the
α-position, delivering functionalized diarylmethanes 279 in moderate-to-good yields
(Scheme 7.53) [83]. Mechanistically, initial nucleophilic addition of deprotonated
nitrile 280 to aryne 2 affords aryl anion 281. Subsequent intramolecular nucleophilic
substitution at the cyano moiety generates benzyl anion 282, which undergoes
305
306
7 Molecular Rearrangements Triggered by Arynes
nucleophilic addition to another molecule of aryne 2 followed by protonation to
afford diarylmethane 279.
NC
278
+ R
10
base
R
EWG
NC
R
R
OTf
F
+
279
H
N
CN
2
EWG
R
280
EWG
CN
2
R
281
Ts
CN
R
283
CN
Ts
MeO
75%
EWG
R
282
CN
CN
EWG
CN
KF, 18-crown-6
THF, 0 °C or rt
TMS
EWG
OMe
55%
49%
Scheme 7.53 Three-component reaction of nitriles with two aryne molecules. Source:
Based on Yoshida et al. [83].
In 2017, Gogoi and coworkers disclosed the three-component reaction of
4-hydroxycoumarins 284 with two aryne molecules (generated in situ from
2-silylaryl triflates 10 in the presence of CsF), delivering 3-substituted isocoumarins
285 in moderate-to-good yields (Scheme 7.54) [84]. Mechanistically, a formal
[2+2] cycloaddition between the deprotonated form of 4-hydroxycoumarin 284
and aryne 2 affords benzannulated cyclobutoxide 286, which undergoes ring
opening via C—O bond cleavage and adds to another molecule of aryne 2 to afford
benzocyclobutanone 287. This intermediate opens up via C—C bond cleavage to
afford ketene 288, which undergoes ring closure to afford isocoumarin 285.
In 2011, Biswas and Greaney disclosed the three-component reaction of thioureas
289 with two aryne molecules (generated in situ from 2-silylaryl triflates 10 in the
presence of CsF), involving aryne insertion and S-arylation (Scheme 7.55) [85].
The aryne inserts into the thiourea C=S bond, in contrast to C—N bond insertion for
related ureas. A range of amidine products 290 were obtained in moderate-to-good
yields. Mechanistically, the reaction proceeds via the initial nucleophilic addition
of thiourea 289 as a sulfur nucleophile to aryne 2, and the resulting zwitterion 291
cyclizes via intramolecular nucleophilic addition of the aryl anion to the C=N bond
to generate benzannulated four-membered ring 292. This intermediate collapses
via C—S bond cleavage to give thiophenol 293, which undergoes S-arylation via
nucleophilic addition to a second molecule of aryne 2 to afford amidine 290.
In 2017, Yao and coworkers disclosed the three-component reaction of oximes
294 with two aryne molecules (generated in situ from 2-silylaryl triflates 10 in
7.5 Rearrangements Involved in the Multicomponent Reactions with Two or More Aryne Molecules
O
OH
O
TMS
CsF, MeCN, 80 °C
+ R
R1
O
284
Base
O
O
OTf
10
R
R1
R
F
285
R
2
O
R
R1
R1
R
O
O •
O
O
O
OO
286
R
O
287
R
288
R
+
H
2
R
R1
O
O
O
O
O
O
O
O
Br
O
MeO
OPh
71%
OPh
87%
O
O
57%
Scheme 7.54 Three-component reaction of 4-hydroxycoumarins with two aryne
molecules. Source: Based on Neog et al. [84].
S
R2
N
R2
R1
N
H
289
TMS
CsF, MeCN/PhMe, 90 °C
+ R
F
R
R2
2
R2
N
R1
N
R2 H
2
R N N
H
S
S
R
S
R
R1
R2
BnN
NMe2
SPh
N
NR1
SH
292
PhN
R2
N
R
293
PhN
NMe2
290
2
R
291
N
NR1
R
OTf
10
R2
R2
N
N(iPr)
SPh
2
MeO
NMe2
S
SPh
OMe
60%
65%
55%
80%
Scheme 7.55 Three-component reaction of thioureas with two aryne molecules. Source:
Based on Biswas and Greaney [85].
307
308
7 Molecular Rearrangements Triggered by Arynes
the presence of CsF), delivering structurally diverse dihydrobenzo[d]oxazoles 295
in moderate-to-excellent yields (Scheme 7.56) [86]. Mechanistically, the reaction
proceeds via the nucleophilic addition of the nitrogen of oxime 294 to aryne 2.
The aryl anion in the resulting zwitterion 296 abstracts a proton from the hydroxyl
group to generate nitrone 297. [3+2] cycloaddition between nitrone 297 and a
second molecule of aryne 2 affords dihydrobenzo[d]isoxazole 298. Thermal N—O
bond cleavage, either by a radical fission (Path a) or by an ionic fission (Path b),
followed by rebonding affords spiro aziridine 300. This intermediate undergoes
ring opening via C—C bond cleavage to generate iminium 301, which cyclizes
via intramolecular addition of the phenoxide anion to the iminium ion to afford
dihydrobenzo[d]oxazole 295.
R1
N
OH
TMS
CsF, MeCN, 80 °C
+ R
R1 R2
294
295
F
R
N
296
R1
R1
N
R1
301
R
R
N
N
O
O
R1
R2
298
R1 R2
297
Path a
O
R2
R
300
Path b
R
R
R
O
R
2
R2
R2
N
R
OH
N
R
OTf
10
O
R2
R
N
R1
R
O
R2
299
R
MeO2C
I
Me
O
O
Me
Ph
O
Ph
N
N
MeO
Me
O
N
OMe
Ph
91%
86%
83%
Scheme 7.56 Three-component reaction of oximes with two aryne molecules. Source:
Based on Yao et al. [86].
7.5.2
Four-Component Reactions with Three Benzyne Molecules
In 2007, Xie and Zhang disclosed the four-component reaction of N-substituted
imidazoles 302 with three benzyne molecules (generated in situ from 2-silylaryl
7.6 Conclusions
triflate 10a in the presence of CsF), delivering 9-anthracenylamines 303 in
moderate-to-good yields (Scheme 7.57) [87]. Mechanistically, the reaction proceeds
via multiple cycloadditions and a final nucleophilic addition. Initial Diels–Alder
reaction of N-substituted imidazole 302 with benzyne (2a) leads to the formation of
nitrogen-bridged isoquinoline 304. Elimination of HCN from bridged isoquinoline
304 via a retro Diels–Alder reaction affords isoindole 305, which undergoes a
second Diels–Alder reaction with a second molecule of benzyne (2a) to give
nitrogen-bridged anthracene 306. Finally, nucleophilic addition of intermediate
306 to a third molecule of benzyne (2a) followed by ring opening via C—N bond
cleavage affords 9-anthracenylamine 303.
R2
R1
N
N
TMS
CsF, MeCN, 50 °C
R2 +
302
10a
R1
F
2a
R1
N
R2
304
OTf
H
- HCN
N
2a
N R1
305
R2
N
Ph 303
R1
N H
2a
R2
306
Me
N
N
Ph
55%
MeO
57%
Ph
N
Me
Ph
70%
Scheme 7.57 Four-component reaction of imidazoles with three benzyne molecules.
Source: Based on Xie and Zhang [87].
7.6
Conclusions
The highly electrophilic nature of arynes enables them to be added by various
nucleophiles and unsaturated systems to form active intermediates such as zwitterions and strained cycles, which are ready to serve as versatile precursors for
a number of molecular rearrangements such as the Stevens rearrangement, the
aza-Claisen rearrangement, and the Smiles rearrangement. The scope for the
aryne-triggered rearrangements has recently been expanded dramatically due to
the in situ generation of arynes from 2-silylaryl triflates under mild conditions as
developed by Kobayashi and coworkers [2]. The aryne-triggered rearrangements
309
310
7 Molecular Rearrangements Triggered by Arynes
proceed under transition-metal-free conditions and enable a variety of synthetically
useful operations, including skeletal construction, functional group transposition,
ring formation, ring expansion, ring contraction, and chirality transfer. They provide convenient protocols for the formation of one, two, and three carbon–carbon
and carbon–heteroatom bonds with arynes, delivering structural diverse organic
compounds that might otherwise be difficult to access. Nevertheless, it deserves
more efforts to explore the synthetic potentials of arynes in molecular rearrangements. It is highly desirable to develop new convenient methods for the generation
of structurally diverse arynes, particularly those functionalized, as well as find new
reaction modes of arynes, thereby diversifying the applications of aryne-triggered
rearrangements in chemical synthesis. It is reasonable to believe that more
fascinating outcomes will be disclosed in future.
References
1 For reviews, see: (a) Idiris, F.I.M. and Jones, C.R. (2017). Org. Biomol. Chem. 15:
9044–9056. (b) Goetz, A.E., Shah, T.K., and Garg, N.K. (2015). Chem. Commun.
51: 34–45. (c) Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112: 3550–3577.
(d) Holden, C. and Greaney, M.F. (2014). Angew. Chem. Int. Ed. 126: 5854–5857.
Angew. Chem. Int. Ed., 2014, 53, 5746-5749. (e) Diamond, O.J. and Marder, T.B.
(2017). Org. Chem. Front. 4: 891–910.
2 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett.: 1211–1214.
3 For a review, see: Roy, T. and Biju, A.T. (2018). Chem. Commun. 54: 2580–2594.
4 Wittig, G. and Merkle, W. (1943). Ber. Dtsch. Chem. Ges. 76: 109–120.
5 Wittig, G. and Benz, E. (1959). Chem. Ber. 92: 1999–2013.
6 Lepley, R., Giumanini, A.G., Giumanini, A.B., and Khan, W.A. (1966). J. Org.
Chem. 31: 2051–2055.
7 Sato, Y., Toyo’oka, T., Aoyama, T., and Shirai, H. (1975). J. Chem. Soc., Chem.
Commun.: 640–641.
8 Roy, T., Thangaraj, M., Kaicharla, T. et al. (2016). Org. Lett. 18: 5428–5431.
9 Pan, X. and Liu, Z. (2018). Org. Chem. Front. 5: 1798–1810.
10 Roy, T., Gaykar, R.N., Bhattacharjeec, S., and Biju, A.T. (2019). Chem. Commun.
55: 3004–3007.
11 Zhang, J., Chen, Z.-X., Du, T. et al. (2016). Org. Lett. 18: 4872–4875.
12 Moss, S.G., Pocock, I.A., and Sweeney, J.B. (2017). Chem. Eur. J. 23: 101–104.
13 Pan, X., Ma, Y., and Liu, Z. (2018). Org. Biomol. Chem. 16: 7393–7399.
14 Zhou, M.-G., Dai, R.-H., and Tian, S.-K. (2018). Chem. Commun. 54: 6036–6039.
15 Guo, J.-Y., Zhong, C.-H., He, Z.-Y., and Tian, S.-K. (2018). Asian J. Org. Chem. 7:
119–122.
16 Bhunia, A., Roy, T., Pachfule, P. et al. (2013). Angew. Chem. Int. Ed. 125:
10224–10227. Angew. Chem. Int. Ed., 2013, 52, 10040-10043.
17 Xu, X.-B., Lin, Z.-H., Liu, Y. et al. (2017). Org. Biomol. Chem. 15: 2716–2720.
18 Thangaraj, M., Gaykar, R.N., Roy, T., and Biju, A.T. (2017). J. Org. Chem. 82:
4470–4476.
References
19 Tan, J., Zheng, T., Xu, K., and Liu, C. (2017). Org. Biomol. Chem. 15: 4946–4950.
20 Danheiser, R.L. and Helgason, A.L. (1994). J. Am. Chem. Soc. 116: 9471–9479.
21 Shair, M.D., Yoon, T., and Danishefsky, S.J. (1995). Angew. Chem., Int. Ed. 34:
1721–1723.
22 Meyers, A.I. and Pansegrau, P.D. (1984). Tetrahedron Lett. 25: 2941–2944.
23 Tambar, U.K. and Stoltz, B.M. (2005). J. Am. Chem. Soc. 127: 5340–5341.
24 Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Chem. Commun.:
3292–3294.
25 Samineni, R., Srihari, P., and Mehta, G. (2016). Org. Lett. 18: 2832–2835.
26 Okuma, K., Tanabe, Y., Fukami, T., and Ishibashi, Y. (2018). Heteroat. Chem 29:
e21444.
27 Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Tetrahedron Lett.
46: 6729–6731.
28 Hu, J.-H. and Zheng, H.-J. (2019). Synth. Commun. 49: 558–562.
29 Liu, Y.-L., Liang, Y., Pi, S.-F., and Li, J.-H. (2009). J. Org. Chem. 74: 5691–5694.
30 Zhang, T., Huang, X., Xue, J., and Sun, S. (2009). Tetrahedron Lett. 50:
1290–1294.
31 Ahire, M.M., Khan, R., and Mhaske, S.B. (2017). Org. Lett. 19: 2134–2137.
32 (a) Yoshida, H., Kishida, T., Watanabe, M., and Ohshita, J. (2008). Chem. Commun.: 5963–5965. (b) Yoshida, H., Ito, Y., Yoshikawa, Y. et al. (2011). Chem.
Commun. 47: 8664–8666. (c) Rao, B., Tang, J., Wei, Y., and Zeng, X. (2016).
Chem. Asian J. 11: 991–995. (d) Rao, B., Tang, J., and Zeng, X. (2016). Org. Lett.
18: 1678–1681.
33 Kranthikumar, R., Chegondi, R., and Chandrasekhar, S. (2016). J. Org. Chem. 81:
2451–2459.
34 Liu, Z. and Larock, R.C. (2005). J. Am. Chem. Soc. 127: 13112–13113.
35 Pintori, D.G. and Greaney, M.F. (2010). Org. Lett. 12: 168–171.
36 Schwan, J., Kleoff, M., Hartmayer, B. et al. (2018). Org. Lett. 20: 7661–7664.
37 (a) Yoshida, H., Shirakawa, E., Honda, Y., and Hiyama, T. (2002). Angew. Chem.
Int. Ed. 114: 3381–3383. Angew. Chem. Int. Ed., 2002, 41, 3247-3249. (b) Saito, N.,
Nakamura, K., Shibano, S. et al. (2013). Org. Lett. 15: 386–389. (c) Kaneko, H.,
Ikaw, T., Yamamoto, Y. et al. (2018). Synlett 29: 943–948.
38 Rao, B. and Zeng, X. (2014). Org. Lett. 16: 314–317.
39 Yoshioka, E., Kohtani, S., and Miyabe, H. (2010). Org. Lett. 12: 1956–1959.
40 Dubrovskiy, A.V. and Larock, R.C. (2013). Tetrahedron 69: 2789–2798.
41 Dhokale, R.A. and Mhaske, S.B. (2017). J. Org. Chem. 82: 4875–4882.
42 Yoshida, H., Mimura, Y., Ohshita, J., and Kunai, A. (2007). Chem. Commun.:
2405–2407.
43 Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Chem. Lett. 34:
1538–1539.
44 Zhao, X., Huang, Y., Qing, F.-L., and Xu, X.-H. (2017). RSC Adv. 7: 47–50.
45 (a) Ahire, M.M., Thoke, M.B., and Mhaske, S.B. (2018). Org. Lett. 20: 848–851.
(b) Li, Z., Jian, H., Wang, W. et al. (2018). Chin. J. Org. Chem. 38: 2045–2053.
46 Łaczkowski, K.Z., García, D., Peña, D. et al. (2011). Org. Lett. 13: 960–963.
47 Yang, Y., Xu, Y., and Jones, C.R. (2019). Eur. J. Org. Chem.: 5196–5200.
311
312
7 Molecular Rearrangements Triggered by Arynes
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
Shen, C., Yang, G., and Zhang, W. (2013). Org. Lett. 15: 5722–5725.
Qi, N., Zhang, N., Allu, S.R. et al. (2016). Org. Lett. 18: 6204–6207.
Chen, Z. and Wang, Q. (2015). Org. Lett. 17: 6130–6133.
(a) Yoshida, H., Minabe, T., Ohshita, J., and Kunai, A. (2005). Chem. Commun.:
3454–3456. (b) Yoshida, S., Nakamura, Y., Uchida, K. et al. (2016). Org. Lett. 18:
6212–6215.
Gaykar, R.N., Bhattacharjee, S., and Biju, A.T. (2019). Org. Lett. 21: 737–740.
Okugawa, Y., Hayashi, Y., Kawauchi, S. et al. (2018). Org. Lett. 20: 3670–3673.
Mesgar, M. and Daugulis, O. (2017). Org. Lett. 19: 4247–4250.
Yoshida, H., Terayama, T., Ohshita, J., and Kunai, A. (2004). Chem. Commun.:
1980–1981.
Chen, J. and Murafuji, T. (2011). Organometallics 30: 4532–4538.
Toledo, F.T., Marques, H., Comasseto, J.V., and Raminelli, C. (2007). Tetrahedron
Lett. 48: 8125–8127.
Yoshida, H., Yoshida, R., and Takaki, K. (2013). Angew. Chem. Int. Ed. 125:
8791–8794. Angew. Chem. Int. Ed. 2013, 52, 8629–8632.
Su, S., Li, J., Sun, M. et al. (2018). Chem. Commun. 54: 9611–9614.
Kaicharla, T., Thangaraj, M., and Biju, A.T. (2014). Org. Lett. 16: 1728–1731.
Payili, N., Rekula, S.R., Aitha, A. et al. (2019). Org. Biomol. Chem. 17: 9442–9446.
Cant, A.A., Bertrand, G.H.V., Henderson, J.L. et al. (2009). Angew. Chem. Int.
Ed. 121: 5301–5304; Angew. Chem. Int. Ed., 2009, 48, 5199-5202. For corrections,
see: Cant, A.A., Bertrand, G.H.V., Henderson, J.L., Roberts, L., and Greaney, M.F.
(2012) Angew. Chem. Int. Ed., 124, 10360-10360; Angew. Chem. Int. Ed., 2012, 51,
10214–10214.
Mangina, N.S.V.M.R., Guduru, R., and Karunakar, G.V. (2018). Org. Biomol.
Chem. 16: 2134–2142.
Aoki, T., Koya, S., Yamasaki, R., and Saito, S. (2012). Org. Lett. 14: 4506–4509.
Kalvacherla, B., Batthula, S., Balasubramanian, S., and Palakodety, R.K. (2018).
Org. Lett. 20: 3824–3828.
Chakrabarty, S., Chatterjee, I., Tebben, L., and Studer, A. (2013). Angew. Chem.
Int. Ed. 125: 3041–3044. Angew. Chem. Int. Ed., 2013, 52, 2968–2971.
Palani, V., Chen, J., and Hoye, T.R. (2016). Org. Lett. 18: 6312–6315.
Yamazaki, T., Baum, G., and Shechter, H. (1974). Tetrahedron Lett. 15:
4421–4424.
Raminelli, C., Liu, Z., and Larock, R.C. (2006). J. Org. Chem. 71: 4689–4691.
Dhiman, A.K., Kumar, R., Kumar, R., and Sharma, U. (2017). J. Org. Chem. 82:
12307–12317.
Lv, C., Wan, C., Liu, S. et al. (2018). Org. Lett. 20: 1919–1923.
Shamsabadi, A. and Chudasama, V. (2018). Chem. Commun. 54: 11180–11183.
Varlamov, A.V., Guranova, N.I., Novikov, R.A. et al. (2016). RSC Adv. 6:
12642–12646.
Holden, C.M., Sohel, S.M.A., and Greaney, M.F. (2016). Angew. Chem. Int. Ed.
128: 2496–2499. Angew. Chem. Int. Ed., 2016, 55, 2450–2453.
Bhojgude, S.S., Baviskar, D.R., Gonnade, R.G., and Biju, A.T. (2015). Org. Lett. 17:
6270–6273.
References
76 Okuma, K., Kinoshita, H., Nagahora, N., and Shioji, K. (2016). Eur. J. Org.
Chem.: 2264–2267.
77 Bhojgude, S.S., Roy, T., Gonnade, R.G., and Biju, A.T. (2016). Org. Lett. 18:
5424–5427.
78 Li, Y. and Studer, A. (2017). Org. Lett. 19: 666–669.
79 Matsuzawa, T., Uchida, K., Yoshida, S., and Hosoya, T. (2017). Org. Lett. 19:
5521–5524.
80 Yoshida, S., Yano, T., Misawa, Y. et al. (2015). J. Am. Chem. Soc. 137:
14071–14074.
81 Yoshida, S., Uchida, K., Igawa, K. et al. (2014). Chem. Commun. 50:
15059–15062.
82 Li, Y., Qiu, D., Gu, R. et al. (2016). J. Am. Chem. Soc. 138: 10814–10817.
83 Yoshida, H., Watanabe, M., Morishita, T. et al. (2007). Chem. Commun.:
1505–1507.
84 Neog, K., Dutta, D., Das, B., and Gogoi, P. (2017). Org. Lett. 19: 730–733.
85 Biswas, K. and Greaney, M.F. (2011). Org. Lett. 13: 4946–4949.
86 Yao, T., Ren, B., Wang, B., and Zhao, Y. (2017). Org. Lett. 19: 3135–3138.
87 Xie, C. and Zhang, Y. (2007). Org. Lett. 9: 781–784.
313
315
8
New Strategies in Recent Aryne Chemistry
Yang Li
Chongqing University, School of Chemistry and Chemical Engineering, 174 Shazheng Street, Chongqing
400030, P.R. China
8.1 Introduction
Since the first experimental confirmation of benzyne intermediate by Roberts in
1953 [1], the chemistry of aryne has attracted tremendous attention in the past over
60 years. By the time Hoffman published the first, and also the only, seminal monograph on aryne chemistry in 1967 [2], several characteristic reaction modes of arynes
had become well known, i.e. pericyclic reactions and nucleophilic reactions. The
development of aryne chemistry, however, slowed down in the next few decades.
Until the end of 1990s, along with the growing utilization of mild aryne generation protocols particularly by Kobayashi’s method [3] and, recently, by intramolecular hexadehydro-Diels–Alder (HDDA) aryne formation strategy [4–6], both reaction
efficiency and the chance to discover new types of transformations have been greatly
promoted. Several novel aryne reaction modes, such as transition-metal-catalyzed
reactions, insertion reactions, and multicomponent reactions, emerged in the past
two decades. Consequently, aryne chemistry stepped into a renaissance era.
This chapter will focus on some of the aspects that, at least in part, can be seen as
interesting recent advances in aryne chemistry mainly in the past two decades. The
contents of this chapter will include three topics: new aryne generation methods,
aryne regioselectivity, and aryne multifunctionalization.
8.2 New Aryne Generation Methods
Along with the advance of aryne chemistry, efforts in searching for mild and
efficient aryne generation methods have never stopped. Because arynes possess
extremely high activity, they have to be generated and consumed in situ. In this
context, conditions for both aryne generation and subsequent reactions should
match with each other well. Therefore, only when sufficiently efficient and, particularly, mild aryne generation methods are employed will they promote the rapid
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
316
8 New Strategies in Recent Aryne Chemistry
development of aryne chemistry in terms of enhanced reaction efficiency, better
selectivity, more functional group tolerance, and broader synthetic applications.
Although Kobayashi aryne generation method has become the most prevailing
one within the past two decades, it remains desirable to find alternative protocols
that are effective toward some unreachable transformations by current methods.
Consequently, new aryne generation approaches emerged in the past two decades.
In general, there are two principal strategies toward generation of aryne intermediates from judiciously designed precursors (Scheme 8.1): (i) strategy I:
ortho-deprotonative elimination with strong bases by concomitantly kicking
out a leaving group (LG); (ii) strategy II: simultaneous removal of two vicinal
substituents on arene ring, one of which serves as an accepting group (AG) and
the other LG. A distinct difference between these two strategies is that in strategy I
ortho-deprotonation of mono-substituted aryne precursors usually requires strong
bases; while the “push–pull” activating mode through a combination of AG and
LG in strategy II could provide versatile aryne generation means under much
milder conditions. Nevertheless, strategy I remains attractive simply because of
atom-economical consideration. Although both strategies have been utilized since
the early era of aryne chemistry, in the past two decades, new methods appeared
through constant modification on both the structures and activating conditions of
aryne precursors. Notably, an outstanding HDDA aryne generation strategy was
recently developed by Hoye, which then led to a rapid and intensive investigation
on this protocol [4–6]. Because this generation method and its applications will be
covered in chapter 10, it will not be discussed in this section.
LG
Deprotonative
elimination
H
Activation with
strong bases
Elimination of vicinal
AG and LG groups
LG: leaving group
LG = Cl, Br, F, OTf, I+Ar, etc.
Scheme 8.1
8.2.1
LG
AG
AG: accepting group
AG = SiMe3, halide , B(OR)2
LG = OTf, OTs, I+Ar
Two general aryne generation strategies.
Revisiting ortho-Deprotonative Elimination Protocols
Although the earliest method to generate benzyne is through dehydrohalogenation
of halobenzenes, its application has been hampered by both harsh conditions
unavoidable from strongly basic activating reagents and, even worse, undesired
nucleophilic attack by those noninnocent bases. As a result, this aryne generation
protocol has its inherent drawbacks: limited functional group tolerance and competing side reactions from activating reagents. Despite these unfavorable characters,
this deprotonative elimination strategy has not only been attractive with respect to
atom-economical consideration, but also owns its merit on ready accessibility of
functionalized aryne precursors from either cheap aryl halides or aryl triflates. In
8.2 New Aryne Generation Methods
this context, people have been motivated to search for alternates of conventional
generation conditions in an aim to achieving deprotonative elimination under mild
conditions with high tolerance to various functional groups and reaction modes. To
this end, modifications by both employing non-nucleophilic bases and enhancing
the leaving ability of LGs on aryne precursors have been explored.
In 1973, Olofson and coworkers first disclosed that lithium 2,2,6,6-tetramethylpiperidide (LiTMP) could be utilized as a bulky base to efficiently generate aryne
from chlorobenzene, at which moment nucleophilic attack on aryne by TMP
anion was prevented due to its bulky size (Scheme 8.2) [7]. In this study, however,
only phenylethyn-1-ide and benzenethiolate were used as nucleophiles. In 2011,
Daugulis and coworkers revisited this aryne generation protocol and applied it in
arylation of heteroaromatic compounds, in which the C—H bonds on heterocycles
could be deprotonated by another equivalent of LiTMP (Scheme 8.3a) [8]. Moreover,
the employment of both lithium dicyclohexylamide and lithium diisopropylamide
(LDA) afforded the arylation product in slightly lower yields. They reasoned that the
success of this transformation was ensured by both the bulkiness and low solubility
of LiTMP in solvent. Later on, this generation protocol was further extended to
the preparation of a broad spectrum of functionalized polyaryls [10]. In 2012, the
Daugulis group applied this protocol in ortho-arylation of anilines as well, whereas
no N-arylation product was detected (Scheme 8.3b) [9]. In marked contrast, anilines
have been known to be efficient N-nucleophiles in aryne reactions with either
Kobayashi’s or Suzuki’s precursors. Moreover, an efficient preparation of helicenes
and 2-arylphenol was demonstrated (Scheme 8.3c) [11]. A divergent synthesis of
both types of compounds was discovered by simply varying the base: when LiTMP
was used, helicenes were found to be the only products; whereas 2-arylphenols
could be obtained in the presence of t-BuONa and AgOAc.
OMe
OMe
OMe
Cl
Bases
Li
Ph
Ph
Bases:
LiN(i-Pr)2
LiN(i-Pr)Cy
LiNCy2
LiTMP
14%
18%
46%
80%
Scheme 8.2 Olofson’s early study on PhCl-LiTMP system. Source: Based on Olofson and
Dougherty [7].
The strategy by using sufficiently bulky base to prevent undesired side reactions
was further examined by Daugulis and coworkers in 2018, where a more hindered
amide salt, namely lithium diadamantylamide (LDAM), was prepared and employed
as activating reagent to generate aryne intermediates from either aryl halides or
aryl triflates (Scheme 8.4) [12]. Unwanted nucleophilic addition by LDAM was suppressed, the base of which was also proven to be superior over LiTMP with higher
reaction yields. Furthermore, they exhibited that the aryne intermediates generated
317
318
8 New Strategies in Recent Aryne Chemistry
S
LiTMP
Cl
LiTMP
Li
Pentane
–THF
Ph
S
S
(a)
Cl
Ph
NH2
LiTMP
C6H12/Et2O
Ph
NH2
R
R
Ph
NH2
NH2
Ph
NHMe
Ph
(b)
72%
OH
R
85%
62%
Cl
t-BuONa
+ Phenols
Ph AgOAc, dioxane
135–155 °C
N
H
70%
LiTMP
Pentane/THF
LiTMP
Phenols
O
O
O
O
O
(c)
Scheme 8.3 Study on PhCl-LiTMP system. (a) C—H bond arylation of heterocycles. Source:
Based on Truong and Daugulis [8], (b) ortho-arylation of anilines. Source: Based on Truong
and Daugulis [9], and (c) reactions with phenols.
under these conditions could insert into Si—P, Si—S, Si—N, and C—C σ-bonds
with high functional group tolerance. These examples demonstrated that, under
certain circumstances, base-promoted dehydrohalogenation protocol could be efficiently utilized in a broad spectrum of transformations as long as undesired side
reactions by activating reagents can be prevented.
Beyond the solutions by increasing steric congestion on activating bases to
suppress side reactions, Uchiyama and coworkers developed another approach
8.2 New Aryne Generation Methods
X
LDAM
TMS-Y
R
R
TMS
R
Y
X = Cl, Br, OTf
Li
N
TMS
R
TMS
R
PAr2
With TMS-PAr2
LDAM
Scheme 8.4
TMS
R
SEt
With TMS-SEt
NRR′
With TMS-NRR′
LDAM as bulky base for aryne generation. Source: Based on Mesgar et al. [12].
to circumvent nucleophilic side reactions. In 2002, they found that lithium
di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2 Zn(TMP)Li) could serve as an
efficient activating reagent for both halobenzene and phenyl triflate (Scheme 8.5)
[13, 14]. Particularly, this generation method avoided the employment of strong
bases, making it compatible to a broad scope of functional groups, such as ester,
cyano, and amide. Their computational study revealed that the key steps involve a
regio- and chemoselective deprotonative zincation and the preferential coordination
of dialkylzinc moiety to halogen reduces the activation energy for elimination [14].
FG
FG
H
Br
Me2Zn(TMP)Li
THF
Li+
ZnMe2
FG
Br
FG = CN, CONR2, CO2tBu, Cl, F, OMe, etc.
Scheme 8.5
Uchiyama’s conditions. Source: Uchiyama et al. [13]; Uchiyama et al. [14].
With a desire to meet the demands on better leaving ability, ready availability,
and/or convenient preparation, people have also searched for alternative LGs other
than halides. In this context, triflyloxy (OTf) group was chosen to replace halogens,
despite the fact that thia-Fries rearrangement might be a competing side reaction
after ortho-deprotonation [15]. In 1999, Wickham and Scott first reported a benzyne generation protocol using PhOTf and LDA (Scheme 8.6a) [16]. Unfortunately,
this study solely afforded N-arylated product on diisopropylamine. This drawback
was then solved by Wang and coworkers in 2018, who utilized LiZnEt2 (TMP) as an
activating reagent to accomplish an efficient deprotonative zincation-elimination on
PhOTf (Scheme 8.6b) [17]. Both benzyne Diels–Alder cycloaddition reaction and
insertion into the N—CO σ-bond of urea were examined, affording the corresponding products in high yields. Moreover, in Daugulis’ study with LDAM base, they also
found that the OTf group has almost the same departure tendency with chloride [12].
Meanwhile, LGs with comparable or even better leaving ability with respect to
halogens or OTf were pursued. In a study carried out by Okuyama and Ochiai,
they revealed that the leaving ability of an aryliodonio group is million times better
319
320
8 New Strategies in Recent Aryne Chemistry
OTf
R
LDA
N
R
R
67–98%
(a)
Ph
Ph
OTf Et2Zn(TMP)Li
O
R
R
Ph
O
R
O
Ph
NMe
MeN
O
NMe
R
(b)
N
Me
Scheme 8.6 Aryne generation via elimination of HOTf. (a) Elimination of HOTf with LDA by
Wickman and Scott. Source: Based on Wickham et al. [16], and (b) mild elimination of HOTf
with E2 Zn(TMP)Li by Wang. Source: Based on Cho and Wang [17].
than that of the OTf group [18], making diaryliodonium salts superior candidates
as aryne precursors over aryl halides or aryl triflates. Although the idea by using
diaryliodonium salts as aryne precursors was first demonstrated by Akiyama and
coworkers in 1974, only limited examples were shown in this study with low
reaction efficiency [19]. In 2016, Stuart and coworkers re-examined this approach
and developed a distinct and efficient aryne generation protocol from readily
prepared aryl(mesityl)iodonium tosylate, which could be trapped by furan, benzyl
azide, and amine nucleophiles (Scheme 8.7a) [20, 21]. This study unambiguously
disclosed the superior leaving ability of hypervalent iodine moiety by showing the
inertness of other potential LGs, such as fluoride, chloride, bromide, and triflate
on the same molecules. Particularly, a regioselective deprotonation behavior was
disclosed in this transformation as well. Using this aryne generation protocol, Han,
Wang and coworkers subsequently reported a direct arylation of tertiary amines
(Scheme 8.7b) [22].
8.2.2
Arynes from ortho-Difunctionalized Precursors
As the most investigated as well as successfully utilized strategy, aryne generation
via elimination of ortho-difunctionalized arenes has received continuous attention.
A prominent advantage of this strategy over deprotonative elimination one is that
the generation conditions could avoid the utilization of strong bases. Particularly,
the “push–pull” activating mode of this strategy would make aryne generation conditions sufficiently mild by concomitantly meeting the requirements for both the
8.2 New Aryne Generation Methods
O
I
LiHMDS
Mes
R
OTs
I
R
R
or t-BuONa
OTs
O
Bn
N
N
N
N
Mes
Deprotonation site
Me
Me
Br
Br
X
X = Cl, Br, I, SF5, CN, NO2
78% (3.9 : 1)
63% (3.8 : 1)
(a)
I
R
Mes
OTs
R1
N
R3
R2
R2
N
LiHMDS
Toluene, 110 °C
R
R3
(b)
Scheme 8.7 Aryne generation via elimination of aryliodonio group. (a) Staurt’s method.
Source: Sundalam et al. [20]; Stuart [21], and (b) arylation with teritary amines. Source:
Based on Zhang et al. [22].
employment of less harsh, non-nucleophilic bases and high tolerance with respect
to various functional groups as well as reaction modes. To this end, an outstanding
example is o-siylphenyl triflate, commonly known as Kobayashi’s benzyne precursor, which employs fluoride-induced generation conditions by concomitant removal
of a TMS and an OTf group. The giant success of this generation method in the
past two decades stimulated people to further explore variations of aryne generation strategies. Consequently, modifications on either AGs or LGs have been scrutinized in the past decades. As shown in Scheme 8.1, the prevailingly investigated AGs
include TMS, halogens (I or Br), and boronic acid/ester, and those frequently utilized
LGs are OTf, OTs, bromide, and aryliodonio group. Here in this section, some of the
efforts other than Kobayashi’s conditions will be summarized.
Beside Kobayashi aryne precursor, presumably the most successfully utilized
aryne precursors in the past three decades are o-haloaryl sulfonates. In 1991, Suzuki
and coworkers reported the first example by using o-iodoaryl triflates as aryne
precursors (Scheme 8.8a) [23]. n-BuLi was used in iodine–lithium exchange and
a consequent departure of the OTf group could afford aryne intermediates, those
of which were then trapped by furan through Diels–Alder reactions. Similar to
Kobayashi’s method, this protocol takes the advantage of the excellent leaving
ability of the OTf group, which was subsequently proven by Snowden to be a better
LG over fluoride, chloride, and OTs [26]. Equipped with this generation method,
Suzuki and coworkers discovered a convenient [2+2] cycloaddition of arynes with
ketene silyl acetals (KSAs) (Scheme 8.8b) [24, 25]. Distinctively, the presence of
alkoxy groups on the 3-position of benzyne promised an excellent regioselective
control by discriminating the two carbons on aryne triple bond. Notably, in our
previous study, we found that o-silylaryl triflates were not as efficient as o-iodoaryl
triflate in [2+2] cycloaddition with KSAs [27]. Later on, this generation protocol
321
322
8 New Strategies in Recent Aryne Chemistry
found widespread applications both in different aryne transformations [28–33] and
in natural product synthesis [34–36].
OR
O
I
OMe
OR
n-BuLi
OH
R = Me, MOM, Bn
74–82%
(a)
OBn
OBn
I
OTf
(b)
R′O
R″
OMe
O
THF, –78 °C
10 min
OTf
OR
OMe
OSiR3
R″
n-BuLi
THF, –78 °C
10 min
OR′
OSiR3
R″
R″
OBn
aq HF
O
R″
MeCN, 0 °C
R″
54–94%
Scheme 8.8 Suzuki’s o-iodoaryl triflate as aryne precursor. (a) o-iodoaryl triflate as
benzyne precursar. Source: Matsumoto et al. [23], and (b) [2+2] cycloaddition with
o-iodoaryl triflate. Source: Hosoya et al. [24]; Hosoya et al. [25].
Encouraged by Suzuki’s success on o-iodoaryl triflates, variations of this aryne
generation protocol were subsequently reported. First, the activating reagents were
investigated. In 2015, Hosoya and coworkers found that trimethylsilylmethyl Grignard reagent (TMSCH2 MgCl) could serve as a mild activating reagent to generate
arynes from o-iodoaryl triflates [37]. Distinctively, Suzuki and coworkers also disclosed that alkynyllithium was able to activate o-iodophenyl triflate in a catalytic
fashion (Scheme 8.15) [38].
Moreover, the OTf group was found to be replaced by other sulfonates with
unequal leaving abilities. This modification was based on the expectation that
under certain circumstances the diminished departure tendency and/or enhanced
stability toward side reactions, such as thia-Fries rearrangement [15], of those LGs
could adjust the aryne generation rate and make certain transformations accessible.
Indeed, Knochel and coworkers demonstrated that by altering the LGs on o-iodoaryl
sulfonates, both reaction efficiency and functional group tolerance in Diels–Alder
reaction varied significantly (Scheme 8.9) [39–41]. Notably, isopropylmagnesium
chloride (i-PrMgCl) was found to be able to serve as a mild activating reagent to
efficiently produce arynes from various o-iodoaryl sulfonates. In marked contrast,
o-iodoaryl triflate with OTf as the LG was found to be ineffective under this reaction
condition (Scheme 8.9).
Within the past two decades, modifications on either silyl-based or OTf-based
difunctionalized aryne precursors have also been examined. As shown in
Scheme 8.10a, the silyl-based difunctionalized aryne precursors were reported
by the groups of Kitamura et al. [42], Akai and coworkers [43], Novák and coworkers [44], Jiang, Wang and coworkers [45], and Daugulis and coworker [46], all of
which take the advantage of fluoride-induced mild generation conditions. On the
other hand, when OTf group was selected as the LG, the AG side has also been
8.2 New Aryne Generation Methods
OR
O
I
O
i-PrMgCl
–78 to –10 °C
CO2Me
CO2Me
CO2Me
R = Tf, 0%
Ms, 72%
Ts, 90%
4-ClC6H4SO2, 93%
2,5-Cl2C6H3SO2, 87%
3,5-(CF3)2C6H3SO2, 78%
Scheme 8.9 Knochel’s aryne precursors. Source: Sapountzis et al. [39]; Lin et al. [40];
Lin et al. [41].
explored by Hosoya and coworkers, in which boronic ester [47], arylsulfoxide
[48], and diarylphosphinyl groups [49] were found to be effective alternative AGs
(Scheme 8.10b). Harsh activating conditions, however, were usually needed to
generate arynes from these precursors. Beside aforementioned achievements,
photoinduced aryne generation methods have also been recently discovered
independently by the groups of Schnarr and coworkers [50] and Shi and coworkers
[51], which would expand aryne chemistry through the utilization of UV-light as
activating condition (Scheme 8.10c).
TMS
TMS
TMS
TMS
SHMe2
I(Ph)OTf
OSO2C4F9
OSO2lm
OSO2F
Br (I)
Novák and
coauthors [44]
Jiang, Wang and
coauthors [45]
Daugulis and
coauthor [46]
Kitamura et al. [42]
Akai and
coauthors [43]
(a)
Bpin
OTf
S(O)p-Tol
Activation with
t-BuLi or s-BuLi
Hosoya and
coauthors [47]
OTf
Activation with
PhMgBr
Hosoya and
coauthors [48]
N
(c)
N
Ac
N
Me
OTf
Activation with
PhMgBr
Hosoya and
coauthors [49]
(b)
CO2H
P(O)Ar2
O
hv
hv
–CO2, –N2, –AcNHMe
–2CO2
Schnarr and
coauthors [50]
O
O
O
Shi and
coauthors [51]
Scheme 8.10 Other ortho-difunctionalized aryne precursors. (a) Silyl-based
difunctionalized aryne precursors, (b) OTf-based difunctionalized aryne precursors, and
(c) photoinduced generation of benzyne.
8.2.3
Catalytic Aryne Generation Methods
The employment of stoichiometric and frequently excess amount of activating
reagents might not be compatible with certain aryne transformations, especially
under the circumstances that those activating reagents are not inert to arynes or
323
324
8 New Strategies in Recent Aryne Chemistry
to substrates. In this context, Hoye’s HDDA aryne strategy provides an excellent
example, which could avoid both the generation of departed residues from AG and
LG and the necessary for activating reagents. Thus, strategies that could produce
aryne intermediates under catalytic activation conditions are highly desirable and
would be one of the pursuits in aryne chemistry.
In 2006, Hu and coworkers reported a Pd-associated aryne generation strategy from either 1-chloro-2-halobenzenes or 2-haloaryl tosylates with hindered
Grignard reagents and revealed a distinct Pd-catalyzed annulative domino process (Scheme 8.11) [52]. In this study, they first disclosed that, in the absence
of phosphine or NHC ligands, various palladium catalysts could promote the
formation of Pd(II)ClX associated benzyne from 1-chloro-2-halobenzenes via a
sequential oxidative addition of Pd(0) and β-chloro elimination. A subsequent
carbopalladation with hindered Grignard reagents was followed by intramolecular
C—H bond activation and reductive elimination, giving rise to substituted fluorenes
(Scheme 8.11). Furthermore, 2-haloaryl tosylates could participate in the same
transformation with palladium catalyst as well. Their in-depth mechanistic study
revealed that these transformations proceeded through the generation of Pd-aryne
species.
Cl/OTs
R′
X
Me
Me
3 mol% Pd(OAc)2
BrMg
Me
R
R′
X = l, Br, Cl
C–H activation
cross-coupling
Pd(0)
Cl/OTs
Pd
PdX
Cl/OTs ArM
X
Transmetalation
Scheme 8.11
R
THF, 60 °C
65–95%
Pd
Cl/OTs
PdII
Ar
Ar
Carbopalladation
Pd-catalyzed aryne generation by Hu. Source: Based on Dong and Hu [52].
In 2008, Kim and coworkers reported a Pd-mediated aryne generation protocol
from methyl 2-bromobenzoates, the generated aryne of which was then trapped in
[2+2+2] cyclotrimerization reaction (Scheme 8.12) [53]. A plausible mechanism was
proposed: oxidative addition of Pd(0) species with aryl bromide was followed by a
δ-carbon elimination-decarboxylation to afford Pd-aryne complex, which then participated in a Pd-catalyzed [2+2+2] cyclotrimerization to furnish triphenylenes.
Greaney and coworkers also investigated different approaches toward catalytic
aryne generation. In 2010, they reported a method to produce arynes from benzoic acids via a sequential Pd-catalyzed ortho C—H bond activation to form a
cyclopalladated complex and a decarboxylation to produce Pd-aryne complex.
Subsequent Pd-catalyzed [2+2+2] cyclotrimerization gave rise to triphenylenes
as well (Scheme 8.13) [54]. Later on, inspired by Wenger and Bennett’s work on
aryne generation with stoichiometric amount of either Pd(0) or Ni(0) species [55],
8.2 New Aryne Generation Methods
5 mol% Pd(OAc)2, 10 mol% PPh3
CO2R K2CO3 (2.0 equiv), TBAC (1.0 equiv)
R′
DMF, 110 °C
Br
Pd(0)
O
O
R′
R
R
–CO2
Pd
Br
PdBr
[2+2+2]
–Pd(0)
Scheme 8.12 Pd-mediated aryne generation from methyl 2-bromobenzoates. Source:
Based on Kim et al. [53].
10 mol% Pd(OAc)2, 10 mol% phen
Cu(OAc)2 (0.75 equiv), K2HPO4 (2.0 equiv)
O
OH
PdX2-L
TBAB (1.0 equiv), sulfolane
4 A MS, 150 °C
–HX
[2+2+2]
O
Scheme 8.13
et al. [54].
L
–CO2
O
Pd
L
L
Pd
PdL2
L
Pd-mediated aryne generation from benzoic acids. Source: Based on Cant
Greaney and coworkers developed a Pd-catalyzed aryne generation protocol from
(2-bromoaryl)boronic esters (Scheme 8.14) [56]. t-BuOK was found to be an efficient
base to activate boronic ester group in this transformation. After careful inspection
R
Bpin
R
5 mol% Pd(dba)2, 5 mol% DPEphos
t-BuOK (1.1 equiv)
R
Pd(0)
Ot-Bu
Bpin K+
Bpin
R
R
PdBr
R
Toluene, 100 °C
Br
PdBr
[2+2+2] –Pd(0)
–t-BuOBpin
–KBr
L
R
Pd
L
Scheme 8.14 Pd-mediated aryne generation from o-bromoaryl boronic esters. Source:
Based on García-López and Greaney [56].
325
326
8 New Strategies in Recent Aryne Chemistry
on the product ratio by using unsymmetrically substituted aryne precursors, they
ruled out the possibility of Suzuki–Miyaura coupling mechanism and suggested
that the reaction underwent through an aryne pathway. Moreover, competing
experiment with 2,5-dimethylfuran gave no observation of aryne Diels–Alder
cycloadduct, indicating that no free aryne was generated in the reaction system.
In 2012, Hamura, Suzuki and coworkers reported an unprecedented catalytic
generation of arynes via alkynyllithium catalysis [38]. As shown in Scheme 8.15,
this transformation initiated with metal–halogen exchange between o-iodophenyl
triflate and alkynyllithium. After the generation of benzyne, another alkynyllithium
acted as a nucleophile to attack it and produce aryllithium intermediate, which
could undergo the second metal–halogen exchange with the previously generated
iodoalkyne species to afford iodoarene product by simultaneously releasing alkynyllithium for next catalytic cycle. In this transformation, alkynyllithium served as
both nucleophile and aryne-generating catalyst. Particularly, other C-nucleophiles
could be also utilized in this transformation in the presence of catalytic amount of
alkynyllithium [38].
I
OTf
Li
R
I
R
R
Li
Catalyst
R
OTf
I
Li
–LiOTf
Li
Scheme 8.15
et al. [38].
R
Li
Nucleophile
R
Alkynyllithium-catalyzed aryne generation. Source: Based on Hamura
Although the aforementioned aryne generation protocols might not be a complete
coverage in this research area and some of them might find no more future applications as well, we still want to reiterate that, in view of the future exploration on
new types of aryne reactions, certain generation protocols might become feasible
when those popular ones fail. Therefore, when people plan to study a new aryne
transformation, they should keep in mind that consideration on examining different
aryne generation methods might be an indispensable part of the project.
8.3 Aryne Regioselectivity
Aryne regioselectivity has long been accompanying with the advances of aryne
chemistry. When an unsymmetrically substituted benzyne participates in a reaction,
a mixture of regioisomers will be conceived. This lack of regioselectivity situation,
8.3 Aryne Regioselectivity
however, could be detrimental to an aryne reaction and, in some cases, results
in inseparable regioisomers. In this context, both verifying the origin of aryne
regioselectivity and paving ways to solve this problem would greatly promote the
rapid advance of related fields with respect to developing highly efficient and
practical aryne transformations in unambiguous regioselective control.
A conventional approach to access high regioselective aryne reactions was through
intramolecular transformation, which has been broadly applied in natural product synthesis [34–36]. This strategy, however, has its limitation, because extra steps
are needed for both the preparation of aryne precursors and the removal of the
unwanted linkers after aryne reactions. On the other hand, highly efficient regioselective tuning factors in intermolecular aryne transformations have not been systematically explored until recently. Therefore, it is desirable to discuss new strategies
on aryne regioselective control as a topic in this chapter, especially in view of the
recent achievements in this field. As shown in Scheme 8.16, there are currently
three means that could manipulate regioselectivity in an intermolecular aryne transformation: steric effect, electronic effect, and ring strain. In the past decade, new
strategies equipped with easily removable or convertible tuning groups were developed by different research groups, making solutions to reach high regioselective
control in aryne transformations more and more convenient.
(a) steric repulsion:
R
Disfavored
Favored
Scheme 8.16
8.3.1
(c) regioselectivity
via ring-strain:
(b) electronic effects:
EDG
EWG
Favored
Favored
Favored
Regioselective controls in intermolecular aryne reactions.
Steric Effect
One of the earliest approaches to realize aryne regioselective control is through steric
repulsion, which requires the introduction of a bulky group on the 3-position of a
benzyne intermediate (Scheme 8.16). For instance, a 3-tert-butylbenzyne usually
exhibits high regioselectivity in different reactions and favors less sterically congested products.
In 2011, Kazmaier and coworkers reported an aryne insertion reaction into
Sn—H bond [57]. In this work, the product ratio of two substrates was prominently
affected by the bulkiness of the substituents on the 3-position of benzyne. As shown
in Scheme 8.17a, when aryne intermediate possesses a 3-methyl group, the ratio of
regioisomers is about 2 : 1. In contrast, when a 3-tert-butylbenzyne was utilized,
only meta-selective product was obtained. In a study carried out by Garg and
Houk, they examined nucleophilic addition on 3-tert-butylbenzyne and found that
all three nucleophiles gave rise to solely meta-selective products (Scheme 8.17b)
[58]. Unfortunately, this 3-tert-butylbenzyne protocol is not a practical solution
327
328
8 New Strategies in Recent Aryne Chemistry
for aryne regioselectivity, because both the removal and further elaboration on
the tert-butyl group will be problematic. Apparently, ideal candidates for this
steric repulsion-driven regioselective control are those that both possess sufficient
bulkiness and could be readily removable or convertible.
KF, 18-c-6
hydroquinone (10 mol%)
TMS
+ Bu3SnH
R
THF, rt
OTf
Me
SnBu3
R
H
t-Bu
Me
t-Bu
SnBu3
Me
SnBu3
t-Bu
SnBu3 Me
SnBu3 t-Bu
30% (100 : 0)
81% (68 : 32)
(a)
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
O
Nu
O
NHPh
66%
Nu
(b)
NHBn
61%
t-Bu
50%
Scheme 8.17 Steric effect by 3-alkyl groups on arynes. (a) Kazmaier’s study and (b)
Garg–Houk’s study. Source: Based on Bronner et al. [58].
In 2005, Schlosser observed that a trimethylsilyl (TMS) group on the 3-position
of an aryne intermediate can well tune the regioselectivity in a [4+2] cycloaddition with 2-(trimethylsilyl)furan (Scheme 8.18). In the absence of this TMS group,
however, 3-fluorobenzyne gave rise to a 2 : 1 mixture of cycloadducts with an opposite regioselective control [59]. This study disclosed a potential of silyl groups as
sterically congested tuning factors in regioselective aryne transformations.
TMS
O
TMS
TMS
F
O
TMS
O
O
F
TMS
Single isomer
Scheme 8.18
F
25%
62%
F
F
TMS
O
TMS
2 : 1 ratio
TMS as sterically congested group by Schlosser.
Later on, Akai and coworkers reported a similar property of silyl as sterically
congested groups in [4+2] cycloaddition reactions with 2-substituted furans [60].
As shown in Scheme 8.19, the presence of both phenyl and tert-butyl groups on
the 3-position of benzyne had almost no regioselective control in this Diels–Alder
reaction. Interestingly, when TMS group was employed, the isomeric ratio raised
8.3 Aryne Regioselectivity
to 39 : 1 with preferential formation of anti-adduct. Distinctively, a bulkier
tert-butyldimethylsilyl (TBDMS) group could further enhance the product ratio up
to more than 50 : 1. Moreover, the TBDMS group in cycloadducts was found to be
readily converted to aryl groups via palladium-catalyzed Hiyama cross-coupling
reactions, exhibiting the versatility of this silyl-based regioselective control protocol
in practical synthesis. Subsequently, this silyl-based aryne strategy was successfully
utilized by the groups of Akai-Ikawa [43, 61], Du Bois [62], and Hosoya [63].
O
R
R
t-Bu
R
O
O
R′
R′
R′
t-Bu
anti-adduct
R = t-Bu, R′ = t-Bu
R = TMS, R′ = Me
R = TBDMS, R′ = Me
Scheme 8.19
Yield
53%
63%
69%
t-Bu
syn-adduct
anti : syn
1.7 : 1
39 : 1
>50 : 1
Silyl as sterically congested group by Akai.
Further exploration on steric effect imposed by 3-silyl group on benzyne revealed
that the structure of an arynophile has an indispensable impact on the regioselective
outcome as well. As shown in Scheme 8.20, in a study carried out by Garg and Houk
on nucleophilic addition with 3-triethylsilylbenzyne, they disclosed that if a nucleophile is not bulky enough, significant amount of ortho-substituted product could be
obtained along with meta-substituted product. When a nucleophile possesses sufficient steric bulkiness, meta-position is favored [58].
TES
TES
TES
Nu
Nu
Nu
meta-product
BnNH2
82%
meta: ortho = 1 : 2
p-TolSH
91%
meta: ortho = 4 : 1
H2N
52%
only isomer
ortho-product
CO2H
SH
CO2Me
77%
meta: ortho = 10 : 1
Scheme 8.20
O
TES
t-Bu
53%
meta: ortho = 1 : 3
Garg-Houk’s study on silyl group as bulky group.
Beside silyl groups as distinct steric congesting groups, boronic esters were found
to be efficient steric tuning factors as well. In 2010, Akai and coworkers discovered
that a 3-borylbenzyne could reach regioselective [4+2] cycloaddition reactions
329
330
8 New Strategies in Recent Aryne Chemistry
with 2-substituted furan (Scheme 8.21) [30, 64]. Depending on the size of the
2-substituent on furan ring, ratios of regioisomers varied with preferential formation of less hindered cycloadducts. In view of enormous applications of boronic
acids/esters in Suzuki–Miyaura cross-coupling transformations, the products in
this approach could be readily converted to diverse molecular architectures.
Bpin
O
Bpin
R
Bpin R
O
Me
Me
anti-a
R = Me
R = t-Bu
R = TMS
R = CO2Me
Yield
85%
>99%
91%
57%
R
O
Me
syn-b
anti-a: syn-b
88 : 12
94 : 6
>98 : 2
93 : 7
Scheme 8.21 Boronic ester as sterically congested group by Akai. Source: Ikawa et al. [30];
Takagi et al. [64].
8.3.2
Electronic Effect
In comparison with steric factors, electronic effect has been found to be a more
versatile way to reach high regioselective control. A variety of approaches
have been developed by utilizing both inductively electron-donating (ED) and
electron-withdrawing (EW) substituents on aryne ring. Early experimental observations have indicated that a 3-substituted inductively EW group on benzyne ring
could lead to preferential meta-selective products in nucleophilic reactions as
well as other transformations using polar arynophiles (Scheme 8.16b). Later on,
an opposite regioselective outcome was observed when an inductive ED group
presents on the 3-position of a benzyne (Scheme 8.16b). Recently, the groups of
Garg and Houk established a powerful and practical aryne distortion/interaction
model to explain and predict aryne regioselectivity [65–69]. This model divides the
activation energy of a bimolecular process into two components: a distortion energy
that allows the reactants to reach the transition state geometry; a second energy
accounts for the interaction between two distorted species. Moreover, this aryne
distortion model could also be well utilized to explain and predict the regioselective
outcomes in the chemistry of indolynes, pyridynes, and other heterocyclic arynes
(hetarynes) [65, 66, 68–74]. Distinctively, their experimental results were highly
consistent with this aryne distortion model.
Scheme 8.22 lists some geometry optimization of commonly substituted benzynes
and hetarynes using density functional theory (DFT) calculations DFT methods
[58, 67, 75]. Based on this aryne distortion model, the larger the internal angle
is on the triple bond carbon, the more electrophilic site is on an aryne species
in either nucleophilic or other polar transformations. Moreover, the difference
between two internal angles is closely related to the degree of regioselectivity.
8.3 Aryne Regioselectivity
When the internal angle difference is larger than 4∘ , distinct regioisomeric
ratios would be obtained [66, 67, 69], which has also been confirmed by many
experimental results.
F
OMe
EWG
Favored
EDG
Favored
Cl
118°
121°
122°
135°
135°
132°
132°
(ref 67)
(ref 67)
SiEt3
124°
130°
(ref 67)
(ref 67)
HN
B(dan) = B
HN
131°
122°
125°
(ref 67)
B(dan)
124°
(ref 58)
(ref 75)
123°
130°
129°
I
120°
134°
(a)
Br
N
H
N
H
135°
N
N
H
4,5-indolyne
5,6-indolyne
6,7-indolyne
(ref 70)
(ref 70)
(ref 70)
125.3°
104°
130°
127°
124.7°
151°
O
4,5-benzofuranyne 2,3-pyridyne
(ref 74)
N
3,4-pyridyne
(ref 66)
(ref 73)
(b)
Scheme 8.22 Geometry-optimized substituted benzynes and hetarynes. (a) Substituted
arynes and (b) Heterocyclic arynes.
Prior to the establishment of this aryne distortion model, there have been already
many experimental examples that could realize decent regioselectivities through
electronic effects. For instance, electron-withdrawing groups (EWGs), such as
methoxy and halogens, are traditionally used as tuning factors in many transformations. In 1993, Suzuki and coworkers first disclosed that 3-silyl substituents on
benzyne exhibited remarkable ED inductive effect (Scheme 8.23) [76]. Thus, in
1,3-dipolar reactions with nitrones, 3-silylbenzynes could afford [3+2] cycloadducts
in excellent regioselective control. The aryne generation conditions in this study,
however, required n-BuLi as the activating reagent. In 2011, Akai and coworkers
found that upon activation with Kobayashi’s method, 3-trimethylsilylbenzyne
could be achieved. Meanwhile, its reaction with primary amines produced products
through nucleophilic addition preferentially on the ortho-position of the silyl
group (Scheme 8.24a) [77]. Their theoretical study revealed that a silicate-like
complex might be formed, which further increases the ED inductive effect, despite
R
Me
OTf n-BuLi
THF
Br –78 °C
R
Ph
O–
N+
R
t-Bu
N
Me
Me
R = TMS
R = TBDMS
Scheme 8.23
et al. [76].
R
Ph
O
5%
12%
O
t-Bu
N
t-Bu
Me
Ph
89%
82%
Silyl groups as ED inductive groups by Suzuki. Source: Based on Matsumoto
331
332
8 New Strategies in Recent Aryne Chemistry
the fact that the steric demand of this complex might be larger than the corresponding neutral one. In 2013, the same group demonstrated that 3-borylbenzynes
could conduct regioselective nucleophilic addition reactions with amines as well
(Scheme 8.24b) [75]. In this study, they found that under the conditions of CsF
and 18-c-6 in THF/HMPA (1 : 1) at 0 ∘ C TMS group was removed and boronic
ester groups remained intact, which could generate 3-borylbenzyne in highly
chemoselective manner. Further inspection on the boronic ester groups revealed
that 1,8-diaminonaphthalene (dan) protected 3-borylbenzyne could afford the
maximum ortho to meta ratio of the amination products.
TMS
TMS
OTf
Me
TMS
B(dan)
OTf
TMS
HN
B(dan) = B
HN
(b)
THF, –40 °C
R=H
R = Me
R = Bn
(a)
TMS
RNH2, TBAF
H2NR
CsF, 18-c-6
THF-HMPA
(1 : 1), 0 °C
F
NHR
NHR
Me
meta-product
Yield
63%
62%
73%
Me Si
Me
Me
Me
ortho-product
NH2R
meta: ortho
1.0 : 12
1.0 : 6.2
1.0 : 7.3
B(dan)
B(dan)
131°
124°
R = n-Bu
R = allyl
R = Bn
NHR
meta-product
Yield
99%
87%
90%
B(dan)
NHR
ortho-product
meta: ortho
1.0 : 14
1.0 : 20
1.0 : 12
Scheme 8.24 Ikawa-Akai’s work on 3-silyl- and 3-borylbenzynes. (a) nucleophilic reaction
with 3-trimethylsilylbenzyne. Source: Based on Ikawa et al. [77]; (b) nucleophilic reaction
with 3-borylbenzyne. Source: Based on Takagi et al. [75].
It is now known that both 3-boryl and 3-silyl groups are EDGs, both of which
also possess certain degree of steric congestion. Interestingly, under certain circumstances, one effect dominates and in other cases the other could become the major
one. In a study carried out by Tokiwa, Akai, and coworkers, they reported their observation on regiocomplementary [3+2] cycloaddition reactions by using either 3-borylor 3-silylbenzynes [78]. As shown in Scheme 8.25, they found that in aryne [3+2]
cycloaddition reactions with 1,3-dipoles, cycloadducts with opposite regioselectivity were obtained from either 3-boryl- or 3-silylbenzynes. When 3-borylbenzyne was
employed, the regioisomeric ratios of cycloadducts with azides were predominantly
affected by its inductively ED effect [75]. In contrast, the regioselectivity in [3+2]
cycloaddition between azides and 3-silylbenzyne was dominated by the steric repulsion of the silyl group [60]. These phenomena were also unambiguously explained
by their DFT calculations [78].
In the past decade, the groups of Garg and Houk have systematically investigated
a variety of hetarynes, including indolines, pyridynes, and benzofuranyne, which
8.3 Aryne Regioselectivity
N
R 3
R = TMS
TMS
N
N
N
R
distal-Adduct
major isomer
TMS
Me
Steric effect
Electronic effect
Me
N
Bpin
N
N
Scheme 8.25
N
N
N
CO2Et
78%
(3.3 : 1)
Me
CO2Et
N
Bpin
N
Me
t-Bu
Me
R
N
N
N
t-Bu
TMS
N
80%
(10 : 1)
Bpin
proximal-Adduct
major isomer
N
Me
N
R 3
R = Bpin
R
N
67%
Only isomer
Me
N
74%
Only isomer
Regiocomplementary [3+2] cycloaddition reactions by Tokiwa-Akai.
led to many outstanding applications in natural product total syntheses. Here, we
only want to briefly mention some intriguing aspect related to aryne regioselective
control in their study. With the assistance of aryne distortion model, Garg, Houk,
and coworkers could easily predict the regioselective preference when different
substituents are present on the proximal position of an aryne triple bond. More
distinctively, they could intentionally manipulate the regioisomeric ratios on some
hetaryne species through the incorporation of inductively EW groups on designated
positions.
In their study on 4,5-indolyne, Garg and coworkers demonstrated that by incorporating a bromo group on its 6-position, the original geometry of 4,5-indolyne
changed and the regioselective preference upon nucleophilic attack was reversed
(Scheme 8.26) [72]. In the absence of 6-bromo group, 4,5-indolyne favored
C5 nucleophilic addition product; whereas on 6-bromo-4,5-indolyne various
nucleophiles attacked its C4-position preferentially. Encouraged by these experimental observations, they commenced a distinct total synthesis of indolactam
V, the key step of which involved a regioselective C4-nucleophilic addition on
6-bromo-4,5-indolyne intermediate.
Subsequently, Garg and coworkers reported another outstanding example by
using inductively EW tuning factors to enhance and/or alter the regioselectivity
on 3,4-pyridyne [73]. As shown in Scheme 8.27a, their DFT calculation indicated
that a simple 3,4-pyridyne has similar internal angles (125.3∘ and 124.7∘ ) on its
triple bond, which means that there is lack of regioselective control upon reaction
with arynophiles. Interestingly, by incorporating EWGs on either 5- or 2-positions
of 3,4-pyridyne, the internal angles of both aryne carbons changed markedly
(Scheme 8.27a). When an EWG was on 5-position, C3-carbon became the more
electrophilic site over C4-carbon. In contrast, the C4-position of 2-substituted
3,4-pyridyne is more electrophilic. Next, they examined these DFT calculated
structures in various aryne reactions. As shown in Scheme 8.27b, in the absence
of substituents on 3,4-pyridyne, there was almost no regioselective control in both
333
334
8 New Strategies in Recent Aryne Chemistry
Favored
site
Favored
site
125°
130°
129°
124°
N
H
4,5-indolyne
N
H
6-bromo-4,5-indolyne
Br
Nu
4
5
Nu
Nu
i-Pr
N
H
X
X
N
H
X
N
H
C4 product
Me
N
OH
O
4
C5 product
H
N
Nucleophiles:
N
H
Indolactam V
CO2H
H2NPh
Scheme 8.26
et al. [72].
NH2
O
t-Bu
X = H, C4: C5 = 1 : 6
X = Br, C4: C5 = 13 : 1
X = H, C4: C5 = 1 : 8
X = H, C4: C5 = 1 : 6
X = Br, C4: C5 = 20 : 1 X = Br, C4: C5 = 14 : 1
Reversing regioselectivity on 4,5-indolyne. Source: Based on Bronner
125.3°
N
4
4
X
124.7°
3
3
N
X
2-substituted
3,4-pyridyne
N
5-substituted
3,4-pyridyne
3,4-pyridyne
C3
C4
X
129.8° 119.8°
Cl
129.1° 120.6°
Br
OSO2NMe2 130.5° 118.8°
(a)
X
C3
C4
Cl
121.8° 127.6°
Br
122.1° 127.2°
OSO2NMe2 120.3° 128.9°
O
N
O
N
Me
N
N
N
O
N
2.1 : 1
N Me
68%
HNMePh
Ph
MeN
Ph
NMe
77%
N
N
N
N
1.9 : 1
O
Me
N
O
Br
N
N
N Me
Br
72%
HNMePh
N
MeN
Ph
Ph
NMe
Br
Br
77%
N
N
N
Only isomer
1 : 5.8
O
N
N
O
N
OSO2NMe2
Only isomer
Me
N
N Me
79%
HNMePh
N
OSO2NMe2
MeN
Ph
Ph
NMe
64%
N
OSO2NMe2
N
OSO2NMe2
12 : 1
(b)
Scheme 8.27 Manipulating regioselectivity on 3,4-pyridyne. (a) internal angels of
substituted 3,4-pyridynes; (b) Garg’s study on regioselective 3,4-pyridyne chemistry.
8.3 Aryne Regioselectivity
nucleophilic addition and C—N σ-bond insertion reaction. Distinctively, both 5and 2-substituted 3,4-pyridynes could afford products with much higher regioselectivity in the same reactions. Particularly, as shown in their DFT calculation, the
regioselective preferences of both 5- and 2-substituted 3,4-pyridynes were opposite
to each other.
8.3.3
Regioselectivity on Small Ring-Fused Arynes
Another factor that could tune aryne regioselectivity was through ring strain on
small ring-fused arynes, which is uncommon with respect to aryne regioselectivity.
This tuning factor was accidentally discovered by Suzuki and coworkers, when they
studied the [2+2] cycloaddition of a four-membered ring-fused aryne precursor
(Scheme 8.28a) [79]. Two regioisomers were obtained in 31 : 1 ratio. Although
they first speculated that steric repulsion might be responsible for this regioselective outcome, it was then ruled out by employing different ring-fused aryne
precursors (Scheme 8.28b). Particularly, high regioselectivity was observed when
a four-membered ring was fused onto the 3,4-positions of a benzyne intermediate.
In marked contrast, both five- and six-membered ring-fused benzyne precursors
afforded the products in low regioisomeric ratios (Scheme 8.28b). To elucidate the
origin of these regioselective observations, they reasoned that, according to the
work by Finnegan [80] and Streitwieser [81], the bridgehead carbon rehybridizes
and uses orbital with more p character to bind with the four-membered ring. The
consequence of this rehybridization makes the meta-position of the strained ring
more electrophilic.
O
EtO
O
OTf
OSiR3
(a)
EtO
n
OSiR3
OTf
OSiR3
OEt
75%
(22 : 1)
O
OSiR3
OEt
OEt
OSiR3
ratio = 31 : 1
n
n-BuLi
THF, –78°C
I
Scheme 8.28
et al. [79].
O
O
n-BuLi
THF, –78°C
73%
SiR3 = Sit-BuMe2
I
(b)
O
n
OSiR3
OEt
OSiR3
OEt
51%
(2.3 : 1)
OEt
OSiR3
OSiR3
OEt
43%
(5.7 : 1)
Suzuki’s study on small ring-fused arynes. Source: Based on Hamura
335
336
8 New Strategies in Recent Aryne Chemistry
Soon after the discovery of regioselective control by fused four-membered ring
on benzyne, Suzuki and coworkers quickly utilized this protocol in a series of
outstanding syntheses of hexasubstituted benzenes, those of which were otherwise
difficult to access via other methods [82–84]. These works will be covered in detail
in next section. In view of the growing application of 4,5-indolyne and HDDA aryne
chemistry recently developed by Garg-Houk and Hoye, respectively, a question is
whether the origin of regioselectivity in some of these aryne intermediates might
come from fused ring on arynes as well.
8.4 Recent Advances in Aryne Multifunctionalization
The merit of aryne transformations resides in ready assembly of various vicinal
difunctionalized arenes. A massive number of aromatic compounds, however,
contain more than two substituents or polycyclic frameworks. Consequently,
convenient preparation of polysubstituted arenes through aryne intermediates
not only belongs to a natural extension of current difunctionalization strategies,
but also occupies an essential portion of aryne chemistry. To break the vicinal
difunctionalization restriction on conventional aryne intermediates, Hart and
others began their investigation on benzdiyne and benztriyne equivalents in 1980s
(Scheme 8.29) [85]. Unfortunately, the synthetic applications of these early studies
have been hampered by harsh aryne generation conditions, i.e. n-BuLi or LDA,
resulting in both low reaction efficiency and limited reaction modes. Along with the
growing applications of both Kobayashi aryne precursors and Suzuki’s o-iodoaryl
triflate in the past two decades, breakthroughs in the chemistry of benzdiyne
and benztriyne with respect to versatile and intriguing applications were recently
unraveled.
2
1
1,2-benzdiyne
Scheme 8.29
8.4.1
3
1
1,3-benzdiyne
3
4
1
1,4-benzdiyne
5
1
1,3,5-benztriyne
Benzdiynes and benztriynes. Source: Based on Shi et al. [85].
1,2-Benzdiyne
1,2-Benzdiyne is constituted by 1,2-benzyne and 2,3-benzyne, which can be
sequentially generated either in cascade or in stepwise fashion (Scheme 8.30a).
Particularly, its C2-carbon is involved in both aryne transformations, which is
the key factor to allow a successive generation of two aryne intermediates in
1,2-benzdiyne processes. Although this strategy was first demonstrated by Hart
in 1980s, 1,2,3-trihalobenzenes were employed at the moment as 1,2-benzdiyne
equivalents (Scheme 8.30b) [86, 87]. In addition, only Grignard reagents with
either aryl or alkenyl/alkynyl groups could serve as both the activating reagents
8.4 Recent Advances in Aryne Multifunctionalization
and double nucleophiles, limiting the application of this early 1,2-benzdiyne
investigation. Although efforts have been then tried to find alternative arynophiles,
this protocol was still largely restricted by its harsh aryne generation conditions.
Recently, new 1,2-benzdiyne reagent by employing Kobayashi’s generation method
was prepared by Li and coworkers (Scheme 8.30c) [88, 89]. The uniqueness of this
reagent is its ability to incorporate three different chemical bonds on a benzene ring
in domino processes under mild conditions, both breaking the difunctionalization
restriction of conventional aryne chemistry and possessing step-economical advantage. Along with in-depth investigation on this domino 1,2-benzdiyne as well as
other 1,2-benzdiyne processes, more and more synthetic applications were recently
disclosed.
LG
2
2
1
1,2-benzdiyne
I
Excess RMgBr
X
–LG
Nu
1,2-aryne
2,3-aryne
R
R
RMgBr
then E
E
R
R
X
X = Cl or Br
E = –H, –I, –CONHAr
Grignard ragents: activating reagents and nucleophiles
(b)
OTf
TMS
“F” or carbonate salts
Y
OTf
OTf
TPBT
X
Nu
–OTf
(c)
2
Nu
1
LG
(a)
X
3
LG
AG
1,2-aryne i
Nu
2,3-aryne ii
Nu
Scheme 8.30 1,2-benzdiyne process and equivalents. (a) General scheme of 1,2-benzdiyne
process, (b) Hart’s 1,2-benzdiyne equivalents (1980s). Source: Du et al. [86]; Du and Hart
[87], and (c) TPBT reagent. Source: Qiu et al. [88]; Shi et al. [89].
In 2015, Li and coworkers prepared 2-(trimethylsilyl)-1,3-phenylene bis
(trifluoromethanesulfonate) (TPBT) as a domino aryne precursor, which is
constituted by two OTf groups and one TMS group on 1,2,3-positions of an arene
ring [88, 89]. As shown in Scheme 8.30c, this modification allows a ready generation
of 3-triflyloxybenzyne i [90, 91], in which the meta-position of the OTf group is
more electrophilic due to the EW inductive effect of the OTf group. At this stage, a
nucleophile will preferentially attack this meta-position with concomitant departure of the OTf group to generate 2,3-aryne intermediate ii, the process of which is
similar to SN 2′ mechanism but on aromatic ring. Another interesting property of
TPBT reagent as 1,2-benzdiyne equivalent is that no fluoride salt is necessary as the
337
338
8 New Strategies in Recent Aryne Chemistry
activating reagent; instead, carbonates, such as K2 CO3 or Cs2 CO3 , were found to be
efficient activating reagents.
With this TPBT reagent in hand, Li and coworkers first examined its reaction with
protected thiobenzamides (Scheme 8.31a) [89]. 2,4-Disubstituted benzothiazole
2 was readily obtained with a concomitant formation of C—S, C—N, and C—C
bonds on three consecutive positions of a benzene ring. As shown in Scheme 8.31b,
this domino process involves a first S-nucleophilic addition to 3-triflyloxybenzyne
i and intramolecular N-nucleophilic attack to the in situ generated 2,3-aryne iii.
After an intramolecular 1,3-carbonyl group migration, a C—C bond was formed
on the C3-position of the benzene ring. Alternatively, when carbonyl groups
contain α-proton, 1,5-hydrogen abstraction took place to produce difunctionalized
product 1.
H
O
OTf
HN
R
S
i
N
R′
R′
R
O
R
S
1
R′ = Me, PhCH2
Ph2CH, Me2CH
N
S
iii
O
N
R = Me
Ph
Ph
S
Intramolecular
H-abtraction
R = t-Bu
Intramolecular
migration
t-Bu
R
H
O
N
R
O
(a)
Ph
N
Ph
(b)
2
Ph
S
N
S
2
R′ = t-Bu, Ad
Ph, PhMe2C
O
N
S
S
1
Scheme 8.31 Reaction of TPBT with protected thiobenzamides. (a) reaction between TPBT
and protected thiobenzamides; (b) proposed mechanism. Source: Based on Shi et al. [89].
Subsequently, Li and coworkers demonstrated that when sulfamides were
employed with SO2 group as both the bridge and the electron-tuning factor, they
could serve as dual nucleophile in domino aryne process. Diverse sulfamides
with either N-aromatic or N-aliphatic substituents could all produce the corresponding vicinal diaminobenzenes (Scheme 8.32a) [92]. Alternatively, when TPBT
reagent was treated with sulfonyl protected anilines, the second N-nucleophile
attacked the 3-position of 2,3-aryne intermediate, resulting in 1,3-diaminobenzenes
(Scheme 8.32b) [93]. Notably, by simply altering the reaction conditions, i.e. using
toluene as the solvent and K2 CO3 as the activating reagent, C2-protonation could
be prohibited. Instead, an intramolecular thia-Fries rearrangement of a Tf group
took place, affording 1,2,3-trisubstituted 1,3-diaminobenzenes (Scheme 8.32b) [93].
Further investigation by Li and coworkers revealed that this domino aryne
process could accommodate two reaction modes, such as nucleophilic addition
and ene reaction. They speculated that the strong nucleophilic property of the
sulfonamide anion would prefer a nucleophilic attack to 1,2-aryne intermediate;
whereas a subsequent intramolecular ene reaction could become more kinetically
favored than competing intermolecular nucleophilic reaction after the formation of
2,3-aryne. However, an accurate management on the reactivity difference between
N-nucleophile and ene arynophile was required for the success of this design.
8.4 Recent Advances in Aryne Multifunctionalization
OTf
R
R1NHSO2NHR2
MeCN, 80 °C
i
(a)
NTf
CsF
RNHTf
N
Tf
R
R
OTf
R
R1
N O
S
N O
R2
OTf
K2CO3/18-c-6
TMS
R
22–85%
Ar
K2CO3/18-c-6
ArNHTf
OTf
MeCN, rt
NH
Tf
PhMe, 100 °C
N
Tf
i
50–87%
Ar
60–83%
(b)
Scheme 8.32 Diamination reactions with TPBT reagent. (a) vicinal diamination with TPBT.
Source: Li et al. [92]; (b) reactions with sulfonyl protected anilines; Source: Based on Qiu
et al. [93].
To this end, a domino aryne nucleophilic-ene reaction cascade was developed,
in which a N-nucleophile and an olefin were connected together with a linker
(Scheme 8.33) [94]. Notably, a second-generation domino aryne precursor TTPM
was developed by simply replacing one of the OTf groups on TPBT reagent with
OTs, which could generate 1,2-aryne iv preferentially. By using TTPM as domino
aryne precursor, a significant enhancement in reaction efficiency was achieved.
This result was reasoned by the fact that the retarded departure tendency of the
OTs group might be able to better match with the low reactivity in ene reaction,
which typically requires higher activation energy than other pericyclic reactions,
i.e. Diels–Alder reaction.
OTs
TMS
R
+
R
OTf
TTPM
iv
R1
R2
OTs
R3
HN
PG
R2'
Nu-ene
cascade
R
O
Ph
H
N
R
N
Ts
up to 77%
Scheme 8.33
N
Ts
64%
N H
Ts
53%
R1
R3
N
PG
OBn
O
HN
H2N
. MeSO3H
N
Ms
Ibutamoren mesylate
Domino aryne nucleophilic-ene cascade. Source: Based on Xu et al. [94].
Very recently, Hoye and coworkers reported an outstanding process by merging
1,2-benzdiyne chemistry with their HDDA aryne process in a highly efficient cas-
339
340
8 New Strategies in Recent Aryne Chemistry
cade (Scheme 8.34) [95]. Upon activation of TTPM, 1,2-aryne iv will be formed. A
nucleophilic addition with 1,3-diyne substrate, followed by a concomitant departure
of the OTs group, could give 2,3-aryne intermediate v. An intramolecular HDDA
reaction was then took place to afford naphthyne intermediate vi. By trapping this
intermediate with various arynophiles, either intramolecularly or intermolecularly,
diverse polysubstituted naphthalenes could be achieved. A distinct property of this
transformation was the combination of three aryne intermediates, namely 1,2-aryne
iv, 2,3-aryne v, and naphthyne vi, into a highly efficient and sequential generation
pathway.
R
R
OTs
K2CO3
18-c-6
TMS
T2
PhCl, 130 °C
OTf
TTPM
TfN
TfHN
v
N
Tf
Scheme 8.34
et al. [95].
vi
H
TBS
TfN
81%
T2
TfN
NTs
O
TfN
T1
T1
HDDA
TfN
51%
75%
Naphthyne from 1,2-benzdiyne-HDDA cascade. Source: Based on Xiao
To explore other transformation possibilities of 1,2-benzdiyne, Li and coworkers also demonstrated that the four-membered ring of [2+2] cycloadduct 3 of
1,2-aryne i with ketene silyl acetyls (KSAs) could be opened in a highly selective
manner, in which the Csp2—Csp3 bond on the four-membered ring of compound
3 was cleaved with its Csp3—Csp3 bond intact (Scheme 8.35a) [27]. 2,3-Aryne
intermediate vii was then generated, and those four chemical bonds between OTf
and OTBS groups on benzocyclobutenol scaffold constitute a Grob fragmentation
system. Further investigation on this transformation disclosed that sterically
congested groups, i.e. gem-dimethyl and gem-dimethoxy groups, on the benzylic
position of benzocyclobutenol could efficiently enhance the regioselectivity of the
following transformations. This Grob fragmentation protocol allowed the syntheses
of several drug molecules, such as Niraparab (anti-ovarian cancer medicine) and
pain relievers Carprofen and Fenoprofen. Later on, Hosoya and coworkers reported
a similar aryne generation method via Grob fragmentation process. In this work,
they used aryllithium as the nucleophile to attack benzocyclobutenones, followed
by a selective ring-opening step to give 2,3-aryne, which was then trapped by
arynophiles in high efficiency (Scheme 8.35b) [96].
Other than Kobayashi’s method, Hosoya and coworkers demonstrated that
3-triflyloxybenzyne could be generated from iodophenyl 2,6-bis(triflate) using
Suzuki’s conditions as well, which could in turn insert into the N—Si σ-bond of
8.4 Recent Advances in Aryne Multifunctionalization
R1O
OTBS
OTf
OTf
R2
–TBSF
–OTf–
R3
3 Grob fragmentation
i
N
OMe
Bn
N
OMe
CO2Me
(a)
OTf
R
R
R′Li
PhMe
–78 °C
O
(b)
N
NH
R
Niraparib
O
R′
OMe
O
O
Ph
Ph
82%
OR1
OMe
N
Ph
83%
R3
N
Grob fragmentation
O
O
NH2
O
R
Ph
O
R2
vii
Arynophiles
R′
R
Y
OR1
R = Me, 91%
OMe, 60%
OTf
O
R3
Arynophiles
CO2Me
R R
R = Me, 83%
OMe, 70%
R = Me, 73%
OMe, 54%
R2
N N
N
CO2Me
R
O
CsF
OR1
R2
[2+2]
cycloaddition
R
X
OTBS
R3
40%
Scheme 8.35 Aryne trifunctionalization through Grob fragmentation. (a) Li’s study. Source:
Based on Shi et al. [27]; (b) Hosoya’s study; Source: Based on Uchida et al. [96].
N-silylamines in excellent regioselectivity (Scheme 8.36a) [97]. Consequently, the
isolated products could be activated to produce 2,3-aryne and trapped by various
arynophiles in good yields and high regioselectivity. The overall process offered a
convenient way to access 1,2,3-trisubstituted arenes containing amino moieties.
Very recently, the same group developed a similar two-step protocol. The 1,2-aryne
species could insert into S—Si σ-bonds in regiospecific manner (Scheme 8.36b)
[98]. After a subsequent generation of 2,3-aryne intermediate, it was trapped by
various arynophiles.
In 2018, Li and coworkers demonstrated an uncommon 1,2-benzdiyne process.
After redesigning the constitution of 1,2-benzdiyne equivalent, they proposed a
composition of two AGs and one LG as 1,2-benzdiyne precursor [99]. As shown
in Scheme 8.37, after the formation of 3-(trimethylsilyl)benzyne viii, it reacted
with pyridine N-oxide to generate a C—OH bond and a C-pyridine carbon bond in
highly regioselective manner. Due to a strong ED inductive effect of the TMS group,
the incoming oxygen selectively attacked its ortho-position. Through a one-pot
protection of this OH group with either Tf or Ts group, new sets of Kobayashi
precursors 4 were readily prepared with pyridinyl groups on their 3-position. These
aryne precursors were then activated and examined with various arynophiles,
affording the desired products in both good yields and excellent regioselectivity.
341
342
8 New Strategies in Recent Aryne Chemistry
OTf
OTf
TMSCH2MgCl
I
R
TMSNR′R″
R1
R
NR′R″
NRR′
2,3-aryne
1,2-aryne
O
N
N
Me
84%
OTf
I
R
O
N
N
N
68%
TMSSR′
TMS
R
R2
R
SPh
Ph
O
80%
R1
CsF
SR′
SPh Me
NHPh
Me
85%
OTf
TMSCH2MgCl
Me
90%
(b)
Me
O
N
N
Bn
76%
OTf
SPh
O
OMe
OMe
Ph
(a)
NR′R″
R′, R″ = alkyl, aryl
OTf
N
R2
R
OTf
O
CsF
TMS
SR′
SPh
CO2Et
N t-Bu
O
86%
(87 : 13)
O
O
78%
Scheme 8.36 1,2-Benzdiyne processes through σ-bond insertion of N—Si and S—Si bonds.
(a) insert into N—Si 𝜎-bond. Source: Based on Yoshida et al. [97]; (b) insert into S—Si
𝜎-bond. Source: Based on Nakamura et al. [98].
8.4.2
1,3-Benzdiyne
1,3-Benzdiynes are composed of two pairs of aryne precursors on 1,2- and
3,4-positions of the same benzene ring, respectively, which could be able to incorporate up to four substituents on a benzene ring. Early study by Hart and coworkers
using polyhalobenzenes as 1,3-benzdiyne equivalents received only low reaction
efficiency with limited application [100, 101]. Beside the low efficiency caused
by harsh generation conditions, there remain other obstacles on 1,3-benzdiyne
chemistry. Because two aryne intermediates are independent of each other, both
the regioselective control and the reaction modes on these twofold aryne scaffolds
are difficult to manipulate. In this context, recent efforts have been tried toward
breaking these restrictions. Through properly tuning the generation of two arynes
in stepwise manner, a wide range of reaction modes could be accommodated.
8.4 Recent Advances in Aryne Multifunctionalization
N
TMS
3
TMS
O
2
″F″
One-pot
X
1
2,3-aryne
N
O
N
Me
O
Bn
OMe
N
N N
78%
Scheme 8.37
X
Trisubstituted
arenes
N
N
Me
Y
X
4
X = pyr
viii
3-Silylbenzyne
Z
2
OTf(Ts)
65%
N
N
OMe
53%
60%
3-Silylbenzyne as 1,2-benzdiyne equivalent.
Moreover, a judiciously designed reaction sequence could help enhance the
regioselectivity as well.
In 2003, Suzuki and coworkers found that [2+2] cycloaddition of 5 with KSAs
was highly regioselective to produce benzocyclobutenol 6 due to EW inductive effect
of oxygen on 3-position (Scheme 8.38) [79]. This benzocyclobutenol was then converted to a 3,4-aryne precursor 7. Upon activation, 3,4-aryne ix was generated and
the following reactions were highly regioselective as well due to the presence of fused
four-membered ring on the proximal position of 3,4-aryne ix. This work was probably the first example to demonstrate that by properly designing the structure of
aryne precursors and reaction modes, 1,3-benzdiyne process could be realized in
high efficiency with exclusive regioselective manner.
OSiR3
OTBS
I
5
OTf
EtO
n-BuLi
THF, –78 °C
[2+2]
OTBS
OTBS
OSiR3
2
OEt
1
6
OSiR3
Steps
OTf
3
I
O
EtO
O
4
7
n-BuLi
THF, –78 °C
[2+2]
O
EtO OSiR
3
O
O
71%
(31 :1)
O
1,2-aryne
Scheme 8.38
3,4-aryne ix
Suzuki’s 1,3-benzdiyne strategy. Source: Based on Hamura et al. [79].
In 2016, Ikawa, Akai and coworkers designed a new 1,3-benzdiyne equivalent 8
(Scheme 8.39) [102]. A unique property of this compound is that TMS will be first
activated by fluoride over TBS group. Consequently, 1,2-aryne x could be generated
preferentially. Distinctively, the regioselective control with respect to 1,2-aryne x was
manipulated by the strong inductively ED effect of the 3-TBS group. After accomplishing highly regioselective cycloaddition reactions on 1,2-aryne x, they further
343
344
8 New Strategies in Recent Aryne Chemistry
realized a time-dependent sequential generation of 1,2- and 3,4-arynes by adding
two types of arynophiles at different reaction stages, affording unsymmetrical bisannulated products.
TBS
TfO
OTf
R1
R2
Arynophile I
TfO
R4
R
Arynophile II
R1
CsF, MeCN, rt
18–24 h
2
CsF, MeCN, rt
TMS
30 min
8
R3
TBS
TBS
R4
R2
3
R
R1
R2
TfO
R1
3,4-aryne
1,2-aryne x
Me
Bn
N
N
N
O
Bn N
N N
O
Me
N
t-Bu
70% in two steps
(76 : 24 isomers)
49% in two steps
(87 : 13 isomers)
Scheme 8.39
Mes
Bn N
N N
O
41% in two steps
(>98 : 2 isomers)
Ikawa-Akai’s 1,3-benzdiyne strategy. Source: Based on Ikawa et al. [102].
In 2018, Kitamura and coworkers developed an unprecedented hybrid
1,3-benzdiyne equivalent 9, in which phenyliodonio and OTf groups were utilized as LGs (Scheme 8.40) [103]. This design was based on the fact that the
TMS
I(p-An)OTf
OTf
9
TMS
R1
R2
Arynophile I
R3
R2
R1
Arynophile II
OTf
CsF, MeCN
0 °C, 10 min
R4
R2
R1
R3
45 °C, 15 h
R4
TMS
R2
OTf
R1
TMS
1,2-aryne xi
O
Me
Me
Me
O
3,4-aryne
O
Me
Ph
Ph
Me
N N
Bn N
Me
O
Ph
Me
72%
Scheme 8.40
et al. [103].
Me
Ph
74%
51%
Kitamura’s hybrid 1,3-benzdiyne equivalent. Source: Based on Kitamura
8.4 Recent Advances in Aryne Multifunctionalization
phenyliodonio group has a much higher leaving ability than that of the OTf
group [18], allowing a chemoselective formation of 1,2-aryne xi via preferential
extrusion of the phenyliodonio group under mild conditions. With this hybrid
1,3-benzdiyne equivalent in hand, a one-pot double cycloaddition process with
different arynophiles was conducted through convenient temperature control,
affording angular polycyclic aromatic compounds in high yields.
8.4.3
1,4-Benzdiyne
The utilization of 1,4-benzdiyne equivalents can be traced back to the early stage
of benzdiyne chemistry in 1980s, at which moment Hart pioneered a study in this
field [104–107]. Unfortunately, unlike both 1,2-benzdiyne and 1,3-benzdiyne, there
is almost no way to control the regioselectivity in 1,4-benzdiyne processes, because
two aryne intermediates, namely 1,2- and 4,5-arynes, are apart from each other on
a benzene ring. However, this drawback does not prevent its synthetic applications.
Indeed, not only solutions on regioselective control were discovered in some cases,
but also a rich and unprecedented utilization of 1,4-benzdiyne strategy in constructing polycyclic aromatic hydrocarbons (PAHs), i.e. “nanographene” frameworks, has
been developed in recent years.
In 2006, Suzuki and coworkers prepared a novel 1,4-benzdiyne equivalent,
namely bis(sulfonyloxy)diiodobenzene (10), with an OTf and an OTs group as
LGs (Scheme 8.41a) [28]. This design could differentiate the generation of two
arynes based on the fact that OTf group has a better leaving tendency than OTs
group, producing 1,2-aryne xii preferentially. In addition, a methoxy group was
intentionally positioned on C3-position between two arynes, which could serve
as a key factor for regioselective control through its inductively EW effect. With
this 1,4-benzdiyne equivalent 10 in hand, they also developed a one-pot process to
generate two aryne intermediates in stepwise fashion by simply varying the reaction
temperature from −95 ∘ C to above −78 ∘ C. Consequently, different arynophiles
were able to react with sequentially generated arynes, namely 1,2- and 4,5-arynes,
in highly selective manner, affording various polycyclic products. Later on, they
also applied 1,4-benzdiyne equivalent 10 in a temperature-dependent double
nucleophilic–iodination reaction with different alkynyllithium in a one-pot fashion,
giving rise to asymmetrically bis(alkyn)ylated product 11 (Scheme 8.41b) [38].
Very recently, Suzuki and coworkers employed 1,4-benzdiyne strategy in a total
synthesis of actinorhodin, which is a dimeric natural product (Scheme 8.42) [108].
In this synthesis, they first designed and prepared a 1,4-benzdiyne equivalent 12
with o-iodoaryl tosylate and o-silylaryl triflate as two sets of aryne precursors.
Upon activation with n-BuLi, the o-iodoaryl tosylate side could be first converted
to 1,2-aryne intermediate xiii, which was then trapped by excess amount of
furan. Next, the activation of o-silylaryl triflate with KF and 18-crown-6 in dilute
THF at room temperature allowed the formation of 4,5-aryne xiv, which then
participated in an insertion reaction into the C—C σ-bond of methyl acetoacetate
to afford 13. The regioselectivities in both aryne reactions were well tuned by a
benzyloxy group on C3-position. After several-step manipulation, monomer 14
345
346
8 New Strategies in Recent Aryne Chemistry
OMe
I
I
TsO
n-BuLi, –95 °C
n-BuLi, –78 °C
Arynophile 1
Arynophile 2
OMe
OTf
10
OMe
OMe
I
TsO
1,2-aryne xii
TBSO
EtO
OMe Ph
4,5-aryne
OMe
N t-Bu
O
OTBS
OEt
TBSO
EtO
OMe OMe
O
(a)
68%
OMe
OMe
I
TsO
Li
I
10
OH
58%
68%
OTf
TMS Li
Et2O
–78 to –50 °C
I
TIPS
I
Et2O, 0 °C
TIPS
(b)
11, 63%
TMS
Scheme 8.41 1,4-Benzdiyne from bis(sulfonyloxy)diiodobenzene 10. Source: Based on
Hamura et al. [28]; Hamura et al. [38].
OBn
TsO
I
12
OTf
n-BuLi, furan
TMS
THF, –78 °C
91%
O
CO2Me
Me
OBn
KF, 18-c-6
OTf
O
TMS
THF (0.02 M), rt
53%
OBn
OBn
O
CO2Me
O
13
OBn
OTf
O
TMS
1,2-aryne xiii
O
Steps
4,5-aryne xiv
OH
OH
OH O
HO2C
O
OBn
Steps
O
O
O
OH
CO2H
OH O
OMe
14
Actinorhodin
Scheme 8.42 Total synthesis of actinorhodin via 1,4-benzdiyne equivalent 12. Source:
Based on Ninomiya et al. [108].
was prepared. With this monomer in hand, subsequent dimerization, followed by
further transformations, completed the synthesis of actinorhodin.
A significant contribution of 1,4-benzdiyne chemistry is its ready assembly of
PAHs. In 2003, Wudl and coworkers first prepared 1,4-bis(trimethylsilyl)phenyl
2,5-bis(triflate) (15) as 1,4-benzdiyne equivalent, which could be activated through
8.4 Recent Advances in Aryne Multifunctionalization
Kobayashi’s method under mild conditions (Scheme 8.43a). A “twistacene” with a
seven linear polyacene core was readily prepared from 15 and pyrano-diphenylcyclopentadienone through double [4+2] cycloadditions (Scheme 8.43a) [109]. In 2016,
same double [4+2] cycloaddition strategy of compound 15 was employed by
Sygula and coworkers to prepare bis-corannulenoanthracene from isocorannulenofuran (Scheme 8.43b) [110]. Recently, Pérez, Martín, and coworkers could use
1,4-benzdiyne equivalent 15 to link either two C60 or one C60 with few-layered
graphene (FLG) unit as well (Scheme 8.43c) [111].
(a)
(b)
Ph
Ph
Ph
Ph
Ph
O
O
Ph
TMS
TfO
TBAF, DCM
TMS
(c)
15
OTf
CsF, MeCN-DCM
C60
TBAF, PhCl
OTf
TMS
Scheme 8.43 1,4-bis(trimethylsilyl)phenyl 2,5-bis(triflate) 15 as 1,4-benzdiyne equivalent.
(a) Wudl’s study. Source: Based on Duong et al. [109]; (b) Sygula’s study. Source:
Kumarasinghe et al. [110]; (c) Pérez-Martín’s study. Source: Based on Garcia et al. [111].
Nanographene frameworks could also be prepared using 1,4-benzdiyne precursor
15. In 2012, Peña and coworkers synthesized compound 16 via [4+2] cycloaddition
of compound 15 with cyclopentadienone and applied it in Palladium(0)-catalyzed
[2+2+2] cyclotrimerization, affording clover-shaped hexabenzotrianthrycene 17
(Scheme 8.44a) [112]. Subsequently, they could employ the same protocol to prepare
nanographene 19 from Pd-catalyzed [2+2+2] cyclotrimerization of aryne precursor
18 with a total of 22 aromatic rings (Scheme 8.44b) [113]. Both studies employed
a strategy by preparing 4,5-aryne precursor with polycyclic aromatic skeletons via
347
348
8 New Strategies in Recent Aryne Chemistry
[4+2] cycloaddition of 1,2-aryne intermediate, which then underwent Pd-catalyzed
[2+2+2] cyclotrimerization to afford nanographene frameworks.
(a)
(b)
Ph
TMS
TMS
OTf
OTf
Ph
16
18
CsF
Pd(0)
22%
CsF
Pd(0)
46%
Ph
Ph
Ph
Ph
Ph
Ph
17
19
Scheme 8.44 Nanographenes from 1,4-benzdiyne strategy. Source: Based on Alonso et al.
[112]; Schuler et al. [113].
Besides, Ikawa, Akai and coworkers investigated the reaction behavior of
1,4-benzdiyne equivalent 15 with different arynophiles, which led to the formation
of various unsymmetrical bisannulated products in a one-pot reaction sequence
(Scheme 8.45) [102]. Because two arynes are too far away with respect to each other,
regioselectivities in this study were generally not satisfied.
Moreover, along with the invention of hybrid 1,3-benzdiyne equivalent 9 using
both phenyliodonio and OTf groups as LGs (Scheme 8.40), Kitamura and coworkers
also prepared a hybrid 1,4-benzdiyne equivalent 20, which could generate 1,2-aryne
xv and 4,5-aryne xvi (Scheme 8.46) [103]. By employing temperature-dependent
activation strategy on this hybrid 1,4-benzdiyne equivalent, they developed a one-pot
double cycloaddition process with different arynophiles as well.
1,4-Benzdiyne strategy has also been utilized in natural product synthesis as
well. In 2006, Martin and coworkers reported a convergent synthesis of vineomcinone B2 methyl ester, in which a double intramolecular Diels–Alder reaction
of 1,4-benzdiyne equivalent 21 took place to assemble the core framework 22
(Scheme 8.47) [114]. 1,4-Benzdiyne equivalent 21 was prepared with two removable
silicon-containing linkers, which could guarantee regiospecific intramolecular
8.4 Recent Advances in Aryne Multifunctionalization
R1
R2
TMS Arynophile 1
TfO
TMS
CsF, MeCN
15–45 min
OTf
15
O
Me
R2
R4
R3
TMS Arynophile 2
R2
R3
R1
OTf
CsF, MeCN
3–11 h
R1
R4
OMe
N
N
N
N
Bn
N
Me
43% in two steps
(75 : 25 isomers)
Scheme 8.45
TMS
TfO(Ph)I
Br
H
N
MeO
Ph
N
N
N
CO2Et
55% in two steps
(76 : 24 isomers)
t-Bu
O
Br
Me
40% in two steps
(70 : 30 isomers)
Ikawa-Akai’s 1,4-benzdiyne strategy. Source: Based on Ikawa et al. [102].
OTf
R2
R1
Arynophile 1
R1
OTf
R4
R3
Arynophile 2
R1
R4
TMS
CsF, MeCN
0 °C, 10 min
R2
TMS
45 °C, 15 h
R2
R3
20
OTf
R1
R2
4,5-aryne xvi
TMS
1,2-aryne xv
Me
Me
Me
Ph
Ph
Me
O
O
Ph
90%
Me
Ph
O
O
O
Ph
Me
Me
90%
Scheme 8.46
et al. [103].
Me
Ph
85%
Kitamura’s hybrid 1,4-benzdiyne equivalent. Source: Based on Kitamura
double [4+2] cycloaddition reactions. After cleavage of the silicon-bridgehead
carbon bonds on cycloadduct 22, followed by further manipulations, vineomcinone
B2 methyl ester could then be efficiently prepared.
8.4.4
1,3,5-Benztriyne
Presumably one of the ultimate goals of aryne multifunctionalization strategy is to
reach hexasubstituted arenes that are otherwise challenging to access via traditional
methods. This proposal was first demonstrated in 1980s by Stoddart and coworkers, who employed both hexabromobenzene [115] and 1,2,4,5-tetrabromobenzene
[116] as equivalents of 1,3,5-benztriyne. These early efforts on benztriyne hexasubstitution, however, received little attention, presumably due to both unfriendly
aryne generation conditions and lack of strategic design on this triple-aryne process.
Until recently, 1,3,5-benztriyne chemistry was revisited by Suzuki and coworkers,
349
350
8 New Strategies in Recent Aryne Chemistry
O
R1
Me Si
Me
OH
O
Si
Br
n-BuLi
Br
Br
Br
O
O
OH O
Steps
O
O
Me
O H
R2
O
Me
Si Me
21
HO
R1
O
22
R2
OH
Me
Si
CO2Me
OH
Vineomycinone B2 methyl ester
O
Scheme 8.47 Total synthesis of Vineomcinone B2 methyl ester by Martin. Source: Based
on Chen et al. [114].
where they developed several novel strategies to generate three aryne intermediates, namely 1,2-, 3,4-, and 5,6-arynes, in both stepwise fashion and strictly ordered
sequence. In this context, a series of intriguing molecular frameworks could be readily synthesized.
In 2006, Suzuki and coworkers reported a novel preparation of tricyclobutabenzene (TCBB) 29 (Scheme 8.48) [82]. In this synthesis, three sequential [2+2]
cycloaddition reactions with ketene silyl acetals (KSAs) were realized in regioselective manner. Starting from aryne precursor 23, the proximal methoxy group on
1,2-aryne xvii ensured a regiospecific [2+2] cycloaddition to afford compound 24.
3,4-Aryne precursor 25 was then prepared after several-step manipulations. Upon
OTBS
OMe
EtO
OTf
i. n-BuLi, THF, –78 °C
Br
CH(OMe)2
ii. aq HF, MeCN, rt
[2+2]
OMe
23
OTf
OMe
O Steps
I
CH(OMe)2
OSiR3
O
O
O
OSiR3
O
EtO
O
n-BuLi
THF, –78 °C
[2+2]
O
25
24
EtO
O
O
O
26
O
Steps
CH(OMe)2
O
1,2-aryne xvii
O
3,4-aryne xviii
O
MeO
O
OMe
OMe
OMe
MeO
O
O
29
MeO
MeO
OSiR3
28
MeO
OSiR3
MeO
OMe
n-BuLi, Et2O, –78 °C
[2+2]
MeO
OMe
MeO
OMe
OMe
OMe
I
OTf
27
OMe
OMe
5,6-aryne xix
Scheme 8.48
Suzuki’s synthesis of tetraketone 29. Source: Based on Hamura et al. [82].
8.4 Recent Advances in Aryne Multifunctionalization
activation, the second [2+2] cycloaddition took place on 3,4-aryne intermediate
xviii. At this stage, the regioselective control was realized by proximally fused
four-membered ring, which led to a preferential formation of cycloadduct 26
[79]. After the preparation of compound 27, 5,6-aryne xix could be generated
and participate in the third [2+2] cycloaddition reaction to give cycloadduct 28.
Hydrolysis of ketene groups on compound 28 prepared compound tetraketone
29. It is worth noting that the overall route in this synthesis employed three pairs
of o-iodoaryl triflate as aryne precursors, demonstrating the power of this aryne
generation method in the construction of complex molecular framework.
In the same year, Suzuki and coworkers reported the syntheses of TCBBs 33 and 34
(Scheme 8.49) [83]. Once again, this synthetic route was accomplished through three
[2+2] cycloaddition reactions as the key steps on sequentially generated 1,2-aryne
xx, 3,4-aryne xxi, and 5,6-aryne xxii from their corresponding precursors 30, 31,
and 32, respectively. Although both the second and third [2+2] cycloaddition reactions did not give high regioselectivity, after universal conversion of three silyl ethers
to methyl ethers, dodecamethoxy-TCBB 33 could be obtained. Upon hydrolysis of
ketene groups with concentrated sulfuric acid, hexaoxo-TCBB 34 was achieved.
Later in 2010, Suzuki and coworkers reported an unprecedented synthesis
of hexaradialenes 38, starting from the same compound 30 (Scheme 8.50) [84].
After two regioselective [2+2] cycloadditions with KSAs, compound 35 was
obtained, which then underwent the third [2+2] cycloaddition via 5,6-aryne xxiii
to afford cycloadduct 36. With further manipulations, compound 37 was prepared.
Under elevated temperature, compound 37 could readily dearomatize to afford
hexaradialene 38.
8.4.5
Benzyne Insertion, C–H Functionalization Cascade
The successful employment of both benzdiyne and benztriyne equivalents as the
efficient synthons for the preparation of polysubstituted arenes expands the realm of
aryne chemistry from traditional vicinal disubstitution to multiple sites on a benzene
ring. The expense through these strategies, however, is the utilization of equally
substituted aryne equivalents as the starting materials, which requires increasing
number of steps in their preparation. Therefore, these strategies fall into lack of
functional group economy. In this regard, a better approach toward aryne multifunctionalization is to employ aryne precursors with less substituents. To this end,
a possible solution is to combine traditional aryne transformation with sequential
C–H functionalization in cascade processes.
In 2016, Li and coworkers reported an unprecedented cascade aryne trifunctionalization protocol by using simple benzyne (Scheme 8.51) [117]. They found that a
three-component reaction involving simple benzyne, aryl allyl sulfoxide, and ethyl
bromoacetate could afford 1,2,3-trisubstituted arenes with concomitant formation
of C—S, C—O, and C—C bonds on the consecutive positions of a benzene ring.
This cascade process was proposed to proceed through a benzyne insertion into
sulfoxide bond, an intramolecular S to O allyl migration, and an oxonium Claisen
rearrangement sequence. Overall, it was highly efficient and can accommodate
351
MeO
OTBS
TBSO
OTBS
MeO
I
BnO
OTf
30
OMe
n-BuLi, Et2O
BnO
[2+2]
OTBS
Br
Steps
OMe
OMe
BnO
OMe
OTBS
OTs
Br
31
BnO
MeO
MeO
OTBS
OMe
TBSO
OMe [2+2]
BnO
OMe
BnO
Br
1,2-aryne xx
OTBS
OMe
OMe
OMe
OMe
OTBS
OMe
OMe
OMe
Br
Steps
3,4-aryne xxi
MeO
MeO
O
O
O
O
O
O
34
Scheme 8.49
conc. H2SO4
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
OMe
33
MeO
MeO
[2+2]
TBSO
Then steps
MeO
MeO
OMe
OTBS
TBSO
OMe
OMe
OMe
5,6-aryne xxii
Suzuki’s synthesis of TCBBs 33 and 34. Source: Based on Hamura et al. [83].
TsO
OMe
OTBS
OMe
OMe
OMe
Br
32
8.4 Recent Advances in Aryne Multifunctionalization
MeO
OTBS
I
BnO
OTf
TsO
30
Br
35
Double [2+2]
MeO
OTMS
MeO
OMe
MeO
OMe
OMe
OMe
OMe
MeO
[2+2]
OAr
Steps
OMe
OMe
MeO
MeO
O
OMe
OAr
ArO
37
36
Toluene
100–110 °C
OMe
OMe
ArO
5,6-aryne xxiii
OAr
OAr
Scheme 8.50
et al. [84].
38
Suzuki’s synthesis of hexaredialene 38. Source: Based on Shinozaki
various substrates on both sulfoxides and aryne rings. Up to five substituted arenes
could be readily prepared in high yields and excellent selectivity. This work was also
the first example of arene trisubstitution from traditional Kobayashi benzyne precursor, revealing a great potential for further exploration toward atom-economical
aryne multifunctionalization solutions.
Ar
Ar
H
STol
OR
S
R2
O
S
R3
R1
CH2CO2Et, 87%
CH2COPh, 70%
R = allyl, 62%
cinnamyl, 63%
Bn, 71%
R′X
MeCN, 50 °C
R3
STol
O
R′
R1
R2
Br
STol
CO2Et
Me
64%
Scheme 8.51
et al. [117].
O
O
CO2Et
82%
Aryne trifunctionalization from simple benzynes. Source: Based on Li
From these examples, people can easily recognize that the chemistry of benzdiyne
and benztriyne possesses two advantages. The first one is to readily prepare multifunctionalized arenes via these polyaryne equivalents, some of which are otherwise
challenging through other methods. The other advantage of polyaryne chemistry is
the convenient and diverse preparation of various polycyclic aromatic hydrocarbons
or nanographenes, making it an interesting expansion in materials science–related
new research direction. Consequently, more intriguing and useful transformations
should be unraveled using benzdiyne and benztriyne strategies.
353
354
8 New Strategies in Recent Aryne Chemistry
8.5 Conclusions
Along with the employment of mild aryne generation conditions, such as
Kobayashi’s method and HDDA aryne strategy, people have witnessed a rapid
advance in aryne chemistry in the past two decades. Many new aryne reaction
modes were discovered as well, those of which include transition metal-catalyzed
reactions, insertion reaction, and multicomponent reactions. Although certain
fields in aryne chemistry remain underdeveloped, they may become new research
spotlights in due time. This chapter covers some of the aspects in aryne chemistry
that might be underestimated for some reason. Despite the fact that aryne generation strategies have been long accompanying with the development of aryne
chemistry, they will continue to play an essential role in the future, because the
generation step is indispensable in any aryne transformation. The aryne regioselectivity is normally a “silent” topic, in which there is no systematic summary on
it yet. However, regioselectivity stays in an important position in aryne chemistry,
not only in reaction efficiency consideration, but also for the sake of more practical
synthetic applications. The last one, aryne multifunctionalization, is an expansion
of traditional aryne difunctionalization strategies. On one hand, the development
of this subfield could provide convenient access to multisubstituted arenes that
would be otherwise challenging to reach with respect to atom- and step-economical
consideration; on the other hand, recent intensive studies in this subfield unraveled
its promising potential on ready preparation of polycyclic aromatic hydrocarbons,
which is closely related to materials science. Therefore, advances of these three
topics in the past two decades can be seen as new strategies in recent aryne
chemistry. Hopefully, along with the continuous exploration on these subfields of
benzyne chemistry, more breakthroughs could be unraveled.
References
1 Roberts, J.D., Simmons, H.E. Jr., Carlsmith, L.A., and Vaughan, C.W. (1953).
J. Am. Chem. Soc. 75: 3290–3291.
2 Hoffmann, R.W. (1967). Dehydrobenzene and Cycloalkynes. New York: Academic
Press.
3 Himeshima, Y., Sonoda, T., and Kobayashi, H. (1983). Chem. Lett.: 1211–1214.
4 Hoye, T.R., Baire, B., Niu, D. et al. (2012). Nature 490: 208–212.
5 Niu, D., Willoughby, P.H., Woods, B.P. et al. (2013). Nature 501: 531–534.
6 Niu, D. and Hoye, T.R. (2014). Nat. Chem. 6: 34–40.
7 Olofson, R.A. and Dougherty, C.M. (1973). J. Am. Chem. Soc. 95: 582–584.
8 Truong, T. and Daugulis, O. (2011). J. Am. Chem. Soc. 133: 4243–4245.
9 Truong, T. and Daugulis, O. (2012). Org. Lett. 14: 5964–5967.
10 Truong, T., Mesgar, M., Le, K.K.A., and Daugulis, O. (2014). J. Am. Chem. Soc.
136: 8568–8576.
11 Truong, T. and Daugulis, O. (2013). Chem. Sci. 4: 531–535.
References
12 Mesgar, M., Nguyen-Le, J., and Daugulis, O. (2018). J. Am. Chem. Soc. 140:
13703–13710.
13 Uchiyama, M., Miyoshi, T., Kajihara, Y. et al. (2002). J. Am. Chem. Soc. 124:
8514–8515.
14 Uchiyama, M., Kobayashi, Y., Furuyama, T. et al. (2008). J. Am. Chem. Soc. 130:
472–480.
15 Hall, C., Henderson, J.L., Ernouf, G., and Greaney, M.F. (2013). Chem. Commun. 49: 7602–7604.
16 Wickham, P.P., Hazen, K.H., Guo, H. et al. (1991). J. Org. Chem. 56: 2045–2050.
17 Cho, S. and Wang, Q. (2018). Tetrahedron 74: 3325–3328.
18 Okuyama, T., Takino, T., Sueda, T., and Ochiai, M. (1995). J. Am. Chem. Soc.
117: 3360–3367.
19 Akiyama, T., Imasaki, Y., and Kawanisi, M. (1974). Chem. Lett. 3: 229–230.
20 Sundalam, S.K., Nilova, A., Seidl, T.L., and Stuart, D.R. (2016). Angew. Chem.
Int. Ed. 55: 8431–8434.
21 Stuart, D.R. (2017). Synlett 28: 275–279.
22 Zhang, Z., Wu, X., Han, J. et al. (2018). Tetrahedron Lett. 59: 1737–1741.
23 Matsumoto, T., Hosoya, T., Katsuki, M., and Suzuki, K. (1991). Tetrahedron Lett.
32: 6735–6736.
24 Hosoya, T., Hasegawa, T., Kuriyama, Y. et al. (1995). Synlett 2: 177–179.
25 Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K. (1995). Tetrahedron Lett.
36: 3377–3380.
26 Ganta, A. and Snowden, T.S. (2007). Synlett 14: 2227–2231.
27 Shi, J., Xu, H., Qiu, D. et al. (2017). J. Am. Chem. Soc. 139: 623–626.
28 Hamura, T., Arisawa, T., Matsumoto, T., and Suzuki, K. (2006). Angew. Chem.
Int. Ed. 45: 6842–6844.
29 Ganta, A. and Snowden, T.S. (2008). Org. Lett. 10: 5103–5106.
30 Ikawa, T., Takagi, A., Kurita, Y. et al. (2010). Angew. Chem. Int. Ed. 49:
5563–5566.
31 Aikawa, H., Takahira, Y., and Yamaguchi, M. (2011). Chem. Commun. 47:
1479–1481.
32 Niu, W.-X., Yang, E.-Q., Shi, Z.-F. et al. (2012). Org. Chem. 77: 1422–1434.
33 Li, Y., Chakrabarty, S., Mück-Lichtenfeld, C., and Studer, A. (2016). Angew.
Chem. Int. Ed. 55: 802–806.
34 Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112: 3550–3577.
35 Gampe, C.M. and Carreira, E.M. (2012). Angew. Chem. Int. Ed. 51: 3766–3778.
36 Takikawa, H., Nishii, A., Sakai, T., and Suzuki, K. (2018). Chem. Soc. Rev. 47:
8030–8056.
37 Yoshida, S., Uchida, K., and Hosoya, T. (2015). Chem. Lett. 44: 691–693.
38 Hamura, T., Chuda, Y., Nakatsuji, Y., and Suzuki, K. (2012). Angew. Chem. Int.
Ed. 51: 3368–3372.
39 Sapountzis, I., Lin, W., Fischer, M., and Knochel, P. (2004). Angew. Chem. Int.
Ed. 43: 4364–4366.
40 Lin, W.W., Sapountzis, I., and Knochel, P. (2005). Angew. Chem. Int. Ed. 44:
4258–4261.
355
356
8 New Strategies in Recent Aryne Chemistry
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
Lin, W., Chen, L., and Knochel, P. (2007). Tetrahedron 63: 2787–2797.
Kitamura, T., Aoki, Y., Isshiki, S. et al. (2006). Tetrahedron Lett. 47: 1709–1712.
Ikawa, T., Nishiyama, T., Nosaki, T. et al. (2011). Org. Lett. 13: 1730–1733.
Kovács, S., Csincsi, Á.I., Nagy, T.Z. et al. (2012). Org. Lett. 14: 2022–2025.
Chen, Q., Yu, H., Xu, Z. et al. (2015). J. Org. Chem. 80: 6890–6896.
Mesgar, M. and Daugulis, O. (2016). Org. Lett. 18: 3910–3913.
Sumida, Y., Kato, T., and Hosoya, T. (2013). Org. Lett. 15: 2806–2809.
Yoshida, S., Uchida, K., and Hosoya, T. (2014). Chem. Lett. 43: 116–118.
Nishiyama, Y., Kamada, S., Yoshida, S., and Hosoya, T. (2018). Chem. Lett. 47:
1216–1219.
Gann, A.W., Amoroso, J.W., Einck, V.J. et al. (2014). Org. Lett. 16: 2003–2005.
Chang, D., Zhu, D., and Shi, L. (2015). J. Org. Chem. 80: 5928–5933.
Dong, C.-G. and Hu, Q.-S. (2006). Org. Lett. 8: 5057–5060.
Kim, H.S., Gowrisankar, S., Kim, E.S., and Kim, J.N. (2008). Tetrahedron Lett.
49: 6569–6572.
Cant, A.A., Roberts, L., and Greaney, M.F. (2010). Chem. Commun. 46:
8671–8673.
Retbøll, M., Edwards, A.J., Rae, A.D. et al. (2002). J. Am. Chem. Soc. 124:
8348–8360.
García-López, J.-A. and Greaney, M.F. (2014). Org. Lett. 16: 2338–2341.
Lakshmi, B.V., Wefelscheid, U.K., and Kazmaier, U. (2011). Synlett 2011:
345–348.
Bronner, S.M., Mackey, J.L., Houk, K.N., and Garg, N.K. (2012). J. Am. Chem.
Soc. 134: 13966–13969.
Masson, E. and Schlosser, M. (2005). Eur. J. Org. Chem. 2005: 4401–4405.
Akai, S., Ikawa, T., Takayanagi, S.-I. et al. (2008). Angew. Chem. Int. Ed. 47:
7673–7676.
Ikawa, T., Masuda, S., Nakajima, H., and Akai, S. (2017). J. Org. Chem. 82:
4242–4253.
Devlin, A.S. and Du Bois, J. (2013). Chem. Sci. 4: 1059–1063.
Yoshida, S. and Hosoya, T. (2013). Chem. Lett. 42: 583–585.
Takagi, A., Ikawa, T., Kurita, Y. et al. (2013). Tetrahedron 69: 4338–4352.
Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). Synlett 2011: 2599–2604.
Goetz, A.E., Bronner, S.M., Cisneros, J.D. et al. (2012). Angew. Chem. Int. Ed.
51: 2758–2762.
Medina, J.M., Mackey, J.L., Garg, N.K., and Houk, K.N. (2014). J. Am. Chem.
Soc. 136: 15798–15805.
Goetz, A.E. and Garg, N.K. (2014). J. Org. Chem. 79: 846–851.
Picazo, E., Houk, K.N., and Garg, N.K. (2015). Tetrahedron Lett. 56: 3511–3514.
Cheong, P.H.-Y., Paton, R.S., Bronner, S.M. et al. (2010). J. Am. Chem. Soc. 132:
1267–1269.
Im, G.-Y.J., Bronner, S.M., Goetz, A.E. et al. (2010). J. Am. Chem. Soc. 132:
17933–17944.
Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). J. Am. Chem. Soc. 133:
3832–3835.
References
73 Goetz, A.E. and Garg, N.K. (2013). Nat. Chem. 5: 54–60.
74 Shah, T.K., Medina, J.M., and Garg, N.K. (2016). J. Am. Chem. Soc. 138:
4948–4954.
75 Takagi, A., Ikawa, T., Saito, K. et al. (2013). Org. Biomol. Chem. 11: 8145–8150.
76 Matsumoto, T., Sohma, T., Hatazaki, S., and Suzuki, K. (1993). Synlett 1993:
843–846.
77 Ikawa, T., Nishiyama, T., Shigeta, T. et al. (2011). Angew. Chem. Int. Ed. 50:
5674–5677.
78 Ikawa, T., Takagi, A., Goto, M. et al. (2013). J. Org. Chem. 78: 2965–2983.
79 Hamura, T., Ibusuki, Y., Sato, K. et al. (2003). Org. Lett. 5: 3551–3554.
80 Finnegan, R.A. (1965). J. Org. Chem. 30: 1333–1335.
81 Streitwieser, A. Jr., Ziegler, G.R., Mowery, P.C. et al. (1968). J. Am. Chem. Soc.
90: 1357–1358.
82 Hamura, T., Ibusuki, Y., Uekusa, H. et al. (2006). J. Am. Chem. Soc. 128:
3534–3535.
83 Hamura, T., Ibusuki, Y., Uekusa, H. et al. (2006). J. Am. Chem. Soc. 128:
10032–10033.
84 Shinozaki, S., Hamura, T., Ibusuki, Y. et al. (2010). Angew. Chem. Int. Ed. 49:
3026–3029.
85 Shi, J., Li, Y., and Li, Y. (2017). Chem. Soc. Rev. 46: 1707–1719.
86 Du, C.-J.F., Hart, H., and Ng, K.-K.D. (1986). J. Org. Chem. 51: 3162–3165.
87 Du, C.-J.F. and Hart, H. (1987). J. Org. Chem. 52: 4311–4314.
88 Qiu, D., Shi, J., and Li, Y. (2015). Synlett 26: 2194–2198.
89 Shi, J., Qiu, D., Wang, J. et al. (2015). J. Am. Chem. Soc. 137: 5670–5673.
90 Yoshida, S., Uchida, K., Igawa, K. et al. (2014). Chem. Commun. 50:
15059–15062.
91 Ikawa, T., Kaneko, H., Masuda, S. et al. (2015). Org. Biomol. Chem. 13: 520–526.
92 Li, L., Qiu, D., Shi, J., and Li, Y. (2016). Org. Lett. 18: 3726–3729.
93 Qiu, D., He, J., Yue, X. et al. (2016). Org. Lett. 18: 3130–3133.
94 Xu, H., He, J., Shi, J. et al. (2018). J. Am. Chem. Soc. 140: 3555–3559.
95 Xiao, X. and Hoye, T.R. (2019). J. Am. Chem. Soc. 141: 9813–9818.
96 Uchida, K., Yoshida, S., and Hosoya, T. (2017). Org. Lett. 19: 1184–1187.
97 Yoshida, S., Nakamura, Y., Uchida, K. et al. (2016). Org. Lett. 18: 6212–6215.
98 Nakamura, Y., Miyata, Y., Uchida, K. et al. (2019). Org. Lett. 21: 5252–5258.
99 Lv, C., Wan, C., Liu, S. et al. (2018). Org. Lett. 20: 1919–1923.
100 Hart, H. and Shamouilian, S. (1981). J. Org. Chem. 46: 4874–4876.
101 Maurin, P., Ibrahim-Ouali, M., and Santelli, M. (2001). Tetrahedron Lett. 42:
8147–8149.
102 Ikawa, T., Masuda, S., Takagi, A., and Akai, S. (2016). Chem. Sci. 7: 5206–5211.
103 Kitamura, T., Gondo, K., and Oyamada, J. (2017). J. Am. Chem. Soc. 139:
8416–8419.
104 Hart, H., Lai, C.-Y., Nwokogu, G. et al. (1980). J. Am. Chem. Soc. 102:
6649–6651.
105 Hart, H., Shamouilian, S., and Takehira, Y. (1981). J. Org. Chem. 46: 4427–4432.
106 Hart, H., Harada, K., and Du, C.-J.F. (1985). J. Org. Chem. 50: 3104–3110.
357
358
8 New Strategies in Recent Aryne Chemistry
107 Bashir-Hashemi, A., Hart, H., and Ward, D.L. (1986). J. Am. Chem. Soc. 108:
6675–6679.
108 Ninomiya, M., Ando, Y., Kudo, F. et al. (2019). Angew. Chem. Int. Ed. 58:
4264–4270.
109 Duong, H.M., Bendikov, M., Steiger, D. et al. (2003). Org. Lett. 5: 4433–4436.
110 Kumarasinghe, K.G.U.R., Fronczek, F.R., Valle, H.U., and Sygula, A. (2016).
Org. Lett. 18: 3054–3057.
111 Garcia, D., Rodríguez-Pérez, L., Herranz, M.A. et al. (2016). Chem. Commun.
52: 6677–6680.
112 Alonso, J.M., Díaz-Álvarez, A.E., Criado, A. et al. (2012). Angew. Chem. Int. Ed.
51: 173–177.
113 Schuler, B., Collazos, S., Gross, L. et al. (2014). Angew. Chem. Int. Ed. 53:
9004–9006.
114 Chen, C.-L., Sparks, S.M., and Martin, S.F. (2006). J. Am. Chem. Soc. 128:
13696–13697.
115 Ashton, P.R., Isaacs, N.S., Kohnke, F.H. et al. (1989). Angew. Chem. Int. Ed. 28:
1261–1263.
116 Raymo, F., Kohnke, F.H., and Cardullo, F. (1992). Tetrahedron 48: 6827–6838.
117 Li, Y., Qiu, D., Gu, R. et al. (2016). J. Am. Chem. Soc. 138: 10814–10817.
359
9
Hetarynes, Cycloalkynes, and Related Intermediates
Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju
Indian Institute of Science, Department of Organic Chemistry, Gulmohar Marg, 560012, Bangalore, India
9.1 Introduction to Hetarynes
The term “hetarynes” has been suggested for ortho-dehydroaromatic compounds
with heteroatom in the ring. The studies of hetarynes are much older than conventional aryne, but the physical evidence for hetarynes is very inadequate. Several
challenges are associated with the generation of hetarynes and their use as intermediates for various synthetic targets. The journey of hetarynes started in 1902 invoking
the generation of 2,3-benzofuranyne as a reactive intermediate, reported by Stoermer
and Kahlert, although there was no direct evidence to prove the formation of aryne
intermediate at that time [1]. Hetarynes can be subdivided into two categories
depending upon the ring size of the hetaryne ring [2–6]. Five-membered hetarynes
are not well explored and difficult to generate due to the inherent strain present in
the five-membered ring. Thus, synthetic utility of five-membered hetarynes is very
limited. Compared to that, six-membered hetarynes are easy to generate and have
been used for complex synthetic targets. Among all the six-membered hetarynes,
pyridynes, and indolynes are most well studied. These arynes can be generated
in various positions of the ring as well. A discussion on challenges associated
with hetarynes, various types of hetarynes, methods of preparation, reactions of
hetarynes, applications in synthesis form the context of this hetaryne chapter.
9.2 Challenges in Hetarynes
The studies by Stoermer and Kahlert are already discussed in detail in Chapter 1.
The conclusive pieces of evidence for this intermediate were investigated by Robert
[7], Huisgen [8], and Wittig [9] to provide symmetry and reactivity of such species.
Further evidence from spectroscopic data in the gas phase [10], and argon matrixes
[11] has established that the benzyne intermediate exists.
Since hetaryne is an intermediate in a reaction, it cannot be observed freely. Only
from the product formation is it understandable whether the hetaryne intermediate is generated or not. But the same product can be generated from other pathways
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
360
9 Hetarynes, Cycloalkynes, and Related Intermediates
also (without the involvement of aryne). Various mechanisms can operate in nucleophilic substitution reactions rather than benzyne mechanism and can give the same
product. The elimination–addition (EA) mechanism is one of its kind (so-called
benzyne mechanism) (Scheme 9.1) [12–14]. In the EA mechanism, the first deprotonation from 1 takes place from ortho to the halogen. Elimination of halide would
generate the aryne intermediate 2. Nucleophilic addition can happen from both sides
to give ipso and cine products 3a and 3b.
Cl
–
H
NR2
–
NHR2
NR2
NR2
N
+
N
2
1
N
3a
N
3b
Scheme 9.1 Elimination–addition (EA) mechanism. Source: Sauer and Huisgen [12];
Huisgen and Sauer [13]; Kauffmann et al. [14].
The same product can also be obtained via the addition–elimination (AEn ) mechanism [12–14]. In this mechanism, nucleophile/strong base can attack at the C4
position, generating the adduct 4. Then, the expulsion of the leaving group can give
the product 3a (Scheme 9.2).
Cl
–
NR2
Cl
NR2
N
N
1
4
NR2
N
3a
Scheme 9.2 Addition–elimination (AEn ) mechanism. Source: Sauer and Huisgen [12];
Huisgen and Sauer [13]; Kauffmann et al. [14].
The abnormal addition–elimination (AEa ) mechanism also can operate for
nucleophilic substitution reaction, but this mechanism is very substrate sensitive
(Scheme 9.3) [14, 15]. In this case, nucleophilic addition can occur from cine
substitution to the leaving group on 5 to generate the intermediate 6. Leaving group
elimination from 6 produces the product 7.
Br
S
O2
5
H N
N
H
C2H5OH
S
O2
6
N
H
Br
S
O2
7
Scheme 9.3 Abnormal addition–elimination (AEa ) mechanism. Source: Kauffmann et al.
[14]; Bordwell et al. [15].
9.3 Different Types of Hetarynes
Except these three mechanisms, cine-substitution via trans-halogenation (BCHD),
cine-substitution via addition–substitution–elimination (ASE), or cine-substitution
via addition–ring-opening–elimination–ring-closure (ANRORC cine) also can
operate [3]. In another possibility, several mechanisms can operate simultaneously.
Thus, predicting the actual mechanism of the reaction is very difficult. However,
if the ratio of the isomers in the product obtained is not dependent on the nature
of the halogen in the starting precursor, it is valid to conclude that most probably
the EA mechanism is followed [2]. Cycloaddition with various conjugated dienes
is another indirect proof for the formation of aryne intermediate. But all aryne
precursors under definite conditions decompose to cationic, anionic, or radical
species, which may also react with a diene to give cycloaddition product [3, 16]. To
date, many heterocyclic arynes have been suggested as a reactive intermediate, but
in many cases, aryne was not involved as the intermediate [2–6].
9.3 Different Types of Hetarynes
Depending upon the ring size, hetarynes are generally two types. Hetarynes can
be generated in five-membered heterocycles. The first-discovered aryne from
3-bromobenzofuran 8 falls in this category (Scheme 9.4). 2,3-indolyne (9) and
2,3-benzothiophyne (10) are other examples [17]. Computational study by Garg and
coworkers suggests that the five-membered hetarynes generation (11–13) required
high energy, and thus synthetic application for this five-membered hetarynes is
very limited [18]. Hetarynes can be generated from thiophene also [19–21]. The
detailed studies of these hetarynes will be discussed in Sections 9.4–9.6.
O
2,3-Benzofuranyne
N
H
2,3-Indolyne
9
8
N
H
3,4-Pyrrolyne
2,3-Thiophyne
11
12
Scheme 9.4
S
S
2,3-Benzothiophyne
10
S
3,4-Thiophyne
13
5-Membered hetarynes.
Six-membered hetarynes are most well studied. Even pyridyne and indolyne are
already used for the synthesis of complex natural products [22–25]. Arynes
could be generated at different positions of pyridine and indole ring, thus
forming 2,3 or 3,4-pyridyne (14, 15) and 4,5/5,6 or 6,7-indolyne (16–18)
(Scheme 9.5) [6]. Computational study shows that 3,4-pyridyne 15 is more
361
362
9 Hetarynes, Cycloalkynes, and Related Intermediates
stable than 2,3-pyridyne 14 [26–29]. The idea of generating 1,2-pyridyne was not
successful in the solution phase, although the species was found in the gas-phase
study [30–32]. Although less explored, quinolynes (19, 20) are well known in
literature [33, 34]. 3,4-Dehydro-1,5-naphthyridine 20 and 4,5-dehydropyrimidine
21 could be generated in situ and can be trapped via nucleophilic addition or
cycloaddition reactions [35, 36]. Martens and Hertog reported the generation of
2,3-dehydropyridine-N-oxides 22 [37]. The method of generation of these arynes
will be discussed in Section 9.4.
2,3-Pyridyne
N
3,4-Pyridyne
N
H
4,5-Indolyne
14
15
16
N
N
H
5,6-Indolyne
N
H
6,7-Indolyne
N
3,4-Quinolyne
18
19
N
N
O
17
N
N
N
3,4-Dehydro-1,5naphthyridine
20
Scheme 9.5
4,5-Dehydropyrimidine
21
2,3-DehydropyridineN-oxide
22
6-Membered hetarynes.
9.4 Methods of Preparation
Due to high reactivity, aryne cannot be isolated, it must be generated in situ. The different groups tried different methodologies for various types of aryne generation. In
the early days, many groups claimed to generate aryne, but most claims are lacking
conclusive proof. Selected important methods are discussed in this section.
9.4.1
2,3-Benzofuranyne Generation
In 1902, Stoermer and Kahlert first proposed the existence of aryne intermediate
to explain the formation of 2-ethoxybenzofuran 24 from 3-bromobenzofuran 23 in
the presence of sodium ethoxide (Scheme 9.6) [1]. Notably, a possibility where the
starting precursor 3-bromobenzofuran contains some 2-bromobenzofuran as an
impurity, which can give the expected product via SN Ar route, was also suggested.
Indubitably, this is the starting point for all aryne reactions.
9.4 Methods of Preparation
Br
NaOEt
OEt
EtOH
O
O
23
24
O
8
Scheme 9.6
Kahlert [1].
9.4.2
2,3-Benzofuranyne from 3-bromobenzofuran. Source: Based on Stoermer and
2,3-Indolyne Generation
Conway and Gribble made several attempts to generate 1-phenylsulfonyl-2,3indolyne from 2-lithio-3-bromo-1-phenylsulfonylindole 25, but all attempts resulted
in failure and resulted in 26 (Scheme 9.7) [17]. For 2-lithio-3-bromobenzofuran, they
found from X-ray crystallography, this species exists as a distorted trans dimer and
thus it is not in a proper conformation for LiBr elimination. Garg’s computational
study also suggested that for the generation of 2,3-indolyne, very high energy is
required [18].
1. 2 equiv t-BuLi
2.
Br
Me
Br
N
SO2Ph
Br
Me
O –78 °C
D
N
SO2Ph
3. 25–55 °C
4. D2O
26
25
Scheme 9.7 Unsuccessful attempt to generate 2,3-indolyne. Source: Based on Conway and
Gribble [17].
9.4.3
2,3-Benzothiophyne Generation
In 1981, Reinecke et al. trapped the intermediate 10 in a cycloaddition reaction
with thiophene (Scheme 9.8). In a flash vacuum thermolysis (FVT) experiment
of thianaphthene-2,3-dicarboxylic acid anhydride 27 with thiophene produced
dibenzothiophene 28b in 35% yield via elimination of sulfur from 28a [21].
O
O
S
27
FVT
S
S
S
O
10
S
28a
S
28b
Scheme 9.8 2,3-Benzothiophyne trapping in a Diels–Alder adduct. Source: Based on
Reinecke et al. [21].
363
364
9 Hetarynes, Cycloalkynes, and Related Intermediates
9.4.4
3,4-Pyrrolyne Generation
In 1999, Wong and coworkers tried to trap 3,4-pyrrolyne 11 generated from the
pyrrole derivative 29 via cycloaddition reaction with furan (for the synthesis of 30)
and acrylonitrile (for the synthesis of 31) (Scheme 9.9) [19]. But the expected adduct
was formed only in <5% yield. Thus, it cannot be considered as an exclusive proof
for 3,4-pyrrolyne 11 generation.
TfO
Me3Si
I Ph
N
O
29
CH2Cl2, rt
Ot-Bu
KF, 18-crown-6
O
O
CN
N
N
O
Ot-Bu
N
Ot-Bu
O
11
O
30, 1.4% yield
Scheme 9.9
9.4.5
Ot-Bu
31, 1.4% yield
Attempt to trap 3,4-pyrrolyne. Source: Based on Liu et al. [19].
2,3-Thiophyne Generation
Reinecke et al. successfully trapped the 2,3-thiophyne 12 in the same way as
2,3-benzothiophyne 10. 2,3-Thiophyne 12 was generated from thiophene dicarboxylic acid anhydride 32 reaction, and the hetaryne reacted with thiophene to
form benzothiophene 33 in 59% yield (Scheme 9.10). Other dienes were also used
in the thiophyne-trapping experiment [21].
O
O
S
32
O
Scheme 9.10
et al. [21].
9.4.6
FVT
S
S
S
12
S
S
33
2,3-Thiophyne trapping with thiophene as diene. Source: Based on Reinecke
3,4-Thiophyne Generation
Wong group was successful in generating and trapping 3,4-thiophyne 13. Thiophyne was generated from the corresponding precursor 34 and this highly reactive
9.4 Methods of Preparation
intermediate was added to furan and benzene to give the cycloaddition products 35 and 36, respectively (Scheme 9.11). Other dienes such as anthracene,
2,3-dimethyl-1,3-butadiene, furan derivatives also gave cycloaddition products but
in low yield [20]. With butadiene, products 37a and 37b are formed. Although aryne
generation was difficult for five-membered heterocycles, longer C—S bonds in
these molecules help to release the strain and thus aryne generation was successful
for these molecules.
TfO
I Ph
TMS
S
34
CH2Cl2, rt
KF, 18-crown-6
S
O
O
S
S
35, 31% yield
36, 7% yield
13
+
S
37a
S
37b
Scheme 9.11 3,4-Thiophyne trapping in a Diels–Alder adduct. Source: Based on
Ye et al. [20].
9.4.7
2,3-Pyridyne Generation
Pyridine is an important heterocycle and various drug molecules contain pyridine
core. Moreover, in several natural products, pyridine moiety is present. To install
pyridine core onto those molecules, pyridyne generation will be one of the important
pathways. Thus, the advancement of pyridyne generation has changed with time.
Some of the methods are discussed in Sections 9.4.7.1–9.4.7.4.
9.4.7.1
2,3-Pyridyne from 3-Halopyridine
Since the addition of alkali metal amide to 3-halopyridine 38 generates 3,4-pyridynes
exclusively, the only way out to form 2,3-pyridynes 14 from 3-halopyridine is to block
365
366
9 Hetarynes, Cycloalkynes, and Related Intermediates
the 4-position of pyridine. Although the method was not very successful, only 5%
product formation was observed as a mixture of 3-amino pyridine (39a) 2-amino
pyridine (39b) (Scheme 9.12) [2, 35]. 2-Halopyridine cannot be used for this purpose
since it is difficult to understand whether the product is formed via SN Ar pathway
or aryne pathway.
CH3
CH3
Br
CH3
CH3
NH2
KNH2
N
N
38
14
N
N
39a
39b
NH2
Scheme 9.12 2,3-Pyridyne generation from metal halide. Source: Kauffmann [2]; Van Der
Plas et al. [35].
9.4.7.2
2,3-Pyridyne from Dihalide Precursor
Martens and Hertog demonstrated the use of dihalide pyridine precursor for
2,3-pyridyne 14 generation. Aryne was generated from 3-bromo-2-chloropyridine
40 in presence of lithium amalgam and trapped with furan, which would lead to
quinoline 41 as a sole product (Scheme 9.13) [38].
Br
N
Li (Hg)
O
O
N
Cl
40
N
N
14
41
Scheme 9.13 2,3-Pyridyne generation from 3-bromo-2-chloropyridine. Source: Based on
Martens and den Hertog [38].
9.4.7.3
From N-Aminotriazolo-Pyridine
The idea of generating 2,3-pyridyne 14 was also conceived by the Fleming group.
When pyridyne was generated via lead tetraacetate oxidation of N-aminotriazolopyridine 42, the expected adduct with tetraphenylcyclopentadienone was formed in
only 4% yield (Scheme 9.14) [39].
Ph
O
Ph
N
N
N
NH2
N
42
Ph
Pb(OAc)4
N
Ph
Ph
Ph
N
Ph
Ph
14
41a
Scheme 9.14 2,3-Pyridyne generation via oxidation of N-aminotriazolo-pyridine. Source:
Based on Fleet and Fleming [39].
9.4 Methods of Preparation
9.4.7.4 2,3-Pyridyne from 3-(Trimethylsilyl)pyridin-2-yl
Trifluoromethanesulfonate
Walters and Shay developed a facile method for the mild generation of 2,3-pyridyne
14. In presence of CsF, aryne was generated from 3-(trimethylsilyl)pyridin-2-yl trifluoromethanesulfonate 43 and trapped with furan derivative to give the cycloaddition
product. Later, the cycloaddition product was converted to quinoline derivative 41b
(Scheme 9.15) [41].
OCH3
TMS
N
CsF/ CH3CN
OTf
O
43
Scheme 9.15
Leroi [40].
9.4.8
CDCl3
O
4 day
N
OCH3
OCH3
N
OH
41b, 28% yield
Mild method for 2,3-pyridyne generation. Source: Based on Nam and
3,4-Pyridyne Generation
Several methods are available for 3,4-pyridyne 15 generation starting from thermolysis of diazonium carboxylate salt or proto-demetalation of aryl halide to mild aryne
generation via fluoride-induced elimination of trimethylsilyl aryl triflates. Although
some reactions may not proceed through the aryne mechanism, the isolation of
15 in nitrogen matrix and IR spectroscopy revealed that 15 is a valid and possible
intermediate [40]. Each method is discussed in this section.
9.4.8.1 3,4-Pyridyne from Thermolysis of Diazonium Carboxylates
In 1962, Kauffmann and Boettcher demonstrated the generation of 3,4-pyridyne
15 via thermolysis of diazonium carboxylates 43a. The in situ-generated 3,4pyridyne 15 undergoes Diels–Alder reaction with furan to produce 5,8-dihydro5,8-epoxyisoquinoline 44 (Scheme 9.16) [42].
O
O
N2
N
43a
O
–CO2
–N2
O
N
N
15
44
Scheme 9.16 Thermolysis of diazonium carboxylates for 3,4-pyridyne generation. Source:
Based on Kauffmann and Boettcher [42].
9.4.8.2 From 3-Halopyridine
Zoltewicz and Smith uncovered the generation of 3,4-pyridyne 15 from
3-halopyridine. Although both pyridynes could be generated, only 3,4-pyridyne 15
was observed under the reaction condition. The formation of 3,4-pyridyne 15 was
367
368
9 Hetarynes, Cycloalkynes, and Related Intermediates
understood from the partial dehydrohalogenation of 3-chloropyridine-2 or -4D in
presence of NaNH2 /NH3 . For 3-chloropyridine-2-D, deuterium content remains
same before and after the reaction, which indicated that the aryne was generated
from the 3,4-position of pyridine [43].
9.4.8.3 From Oxidation of N-Aminotriazolo-pyridine
Although Flaming and Fleet were not very successful with aryne generation at
2,3-position of pyridine, the same idea was helpful for 3,4-pyridyne generation.
When N-aminotriazolo-pyridine 45 was oxidized in the presence of lead tetraacetate
and trapped with diene, the expected isoquinoline derivative 46 was formed in 63%
yield (Scheme 9.17) [39].
Ph
NH2
N
Pb(OAc)4
N
N
N
O
Ph
Ph
N
Ph
Ph
Ph
N
Ph
Ph
45
15
46
Scheme 9.17 3,4-Pyridyne generation from N-aminotriazolo-pyridine. Source: Based on
Fleet and Fleming [39].
9.4.8.4 From 3-Bromo-4-(phenylsulfinyl)pyridine
In 1987, Furukawa et al. generated 3,4-pyridyne 15 from 3-bromo-4-(phenylsulfinyl)
pyridine 47 via phenyl magnesium bromide addition. The generated aryne was
trapped with furan to give the cycloaddition adduct 44 in 42% yield (Scheme 9.18)
[44].
O
S
Ph
Br
O
PhMgBr
THF, 60 °C
N
47
O
N
44
Scheme 9.18 3,4-Pyridyne generation from 3-bromo-4-(phenylsulfinyl)pyridine. Source:
Based on Furukawa et al. [44].
9.4.8.5 From ortho-Trialkylsilyl Pyridyl Triflates
Tsukazaki and Snieckus synthesized 4-trialkyl silyl-3-pyridyl triflate with the aid of
ortho metalation chemistry. This starting precursor helped to generate 3,4-pyridyne
in a very mild fashion. 4-Trialkylsilyl-3-pyridyl triflate 48 generated pyridyne
in presence of fluoride source and can undergo various cycloaddition reactions
(Scheme 9.19) [45]. This methodology can tolerate various functional groups and
thus is used worldwide for pyridyne generation.
9.4 Methods of Preparation
Ph
SiEt3
Ph
TBAF/THF
0 °C
OTf
N
Ph
Ph
Ph
Ph
N
48
Ph
Ph
46
O
Scheme 9.19 3,4-Pyridyne generation from ortho-trialkylsilyl pyridyl triflates. Source:
Based on Tsukazaki and Snieckus [45].
9.4.9
4,5-Indolyne Generation
9.4.9.1 From 5-Bromoindole
In 1967, Julia et al. developed the generation of 4,5-indolyne 16 from 5-bromoindole
49. In the presence of KNH2 , 4,5-indolyne 16 was generated to give 4- and
5-aminoindole (50a and 50b) products as a mixture of regioisomers (Scheme 9.20)
[46].
NH2
Br
H2N
KNH2, NH3
–33 °C
N
H
49
16
Scheme 9.20
N
K
N
H
50a
+
N
H
50b
4,5-Indolyne generation from 5-bromoindole. Source: Julia et al. [46].
9.4.9.2 From 4-Chloroindole Derivative
Iwao et al. used the indolyne formation pathway for the total synthesis of makaluvamines. During the synthesis of makaluvamines, the indole derivative 51 needed
to cyclize to generate six-membered heterocycle 52 (Scheme 9.21). This reaction
is envisioned to proceed via 4,5-indolyne intermediate 16 [47].
NH2
Cl
HN
LICA
MeO
51
N
Me
THF, 0 °C
N
Me
MeO
52
Scheme 9.21 4,5-Indolyne intermediate for the total synthesis of Makaluvamines. Source:
Based on Iwao et al. [47].
9.4.9.3 From Dibromoindole
In 2007, Buszek and coworkers successfully trapped 4,5-indolyne 16 intermediate
via cycloaddition with furan. The expected cycloadduct 54c was formed in excellent
369
370
9 Hetarynes, Cycloalkynes, and Related Intermediates
yield. Not only 4,5-indolyne 16 but all other triple bond–containing benzenoid rings
(produced from respective dibromo indole) were also trapped with furan in high
yields (Scheme 9.22) [48–51].
Br
Ph
Ph
Br
n
N
Me
53a 6,7-dibromo
53b 5,6-dibromo
53c 4,5-dibromo
Ph
BuLi (1.1 eq.)
Et2O, –78 °C to rt
O
O
N
Me
O
54a, 79% yield
O
54b, 86%
N
Me
Ph
N
Me
54c, 88%
Scheme 9.22 Successful trapping of all three indolyne with furan. Source: Buszek et al.
[48]; Brown et al. [49]; Buszek et al. [50].
9.4.9.4 From Silyltriflate Precursor
In 2007, Garg and coworkers demonstrated the 4,5-indolyne 16 generation
from 1-methyl-4-(trimethylsilyl)-1H-indol-5-yl trifluoromethanesulfonate 55
(Scheme 9.23). The precursor 55 was prepared from 5-(benzyloxy)-1H-indole.
The in situ–formed indolyne can undergo various reactions such as cycloaddition
reaction and nucleophilic addition reaction and can tolerate various functionalities.
The same methodology was extended for 5,6-indolyne 17 generations also. The
reactivity of these indolynes revealed that nucleophilic addition can happen at the
5-position for both indolynes selectively [52–54].
TMS
TfO
55
N
Me
TBAF, CH3CN
56
N
Me
N
Me
5,6-Indolyne was prepeared
using same methodology
Scheme 9.23 Indolyne generation from silyltriflate precursor. Source: Bronner et al. [52];
Cheong et al. [53]; Im et al. [54].
9.4.10 5,6-Indolyne Generation
As discussed, the expected 5,6-indolyne 17 can also be generated from dibromoindole precursor reported by the Buszek group [48]. Later, in 2007, Garg and coworkers
demonstrated the generation of 17, using the same synthetic manipulation used
for the generation of 16 (silyltriflate precursor). Moreover, in 2009, Buszek group
showed generation of all the precursors 16, 17, 18 from silyl triflate precursor having
a phenyl group present at the C3 position of indole [49].
9.4 Methods of Preparation
9.4.11 6,7-Indolyne Generation
9.4.11.1 From Dichloroindole Precursor
Buszek et al. uncovered the generation of 6,7-indolyne 18 from 6,7-dichloro-1methyl-3-phenyl-1H-indole 57 in reaction with tert-butyllithium. Intermediate 18
was trapped with furan and further functionalized to fully aromatic compound 58a
(Scheme 9.24) [48].
Ph
Ph
Ph
t-BuLi (4 equiv)
Cl
Cl
57
N
Me
Et2O, –78 °C to rt
N
Me
18
O
N
Me
O
58
Ph
N
Me
Me
Me Me
Scheme 9.24
et al. [48].
58a
6,7-Indolyne generation from dichloro precursor. Source: Based on Buszek
9.4.11.2 Through Proton–lithium Exchange
From the same group, a different methodology was developed to generate the same
intermediate 18. When they treated 5,6-difluoro-1-methyl-3-phenyl-1H-indole 59
with tert-butyllithium, 18 was generated through proton–lithium exchange. Again
the 6,7-indolyne was trapped with furan to give the cycloadduct 58b in 80% yield
(Scheme 9.25) [48]. It is noted that from the same group the silyl triflate precursor
was developed to generate substituted 18.
Ph
Ph
F
t-BuLi (4 equiv)
N
Me
F
59
F
Et2O, –78 °C to rt
O
Ph
F
N
Me
18
N
Me
O
58b
Scheme 9.25 6,7-Indolyne generation through proton–lithium exchange. Source: Based
on Buszek et al. [48].
9.4.11.3 From 7-Bromoindole Derivative
Mark Lautens et al. generated indolyne in the presence of LDA using 7-bromoindole
derivative 60 as a substrate. The in situ–generated indolyne underwent
371
372
9 Hetarynes, Cycloalkynes, and Related Intermediates
intramolecular ene reaction with a homoprenyl group attached with nitrogen
to afford tricyclic product 61 (Scheme 9.26) [55].
F
F
F
LDA (1.1 equiv)
N
N
THF, rt
N
Me
Br
Me
Me
Me
Me
60
61
Scheme 9.26 6,7-Indolyne generating and trapping with ene reaction. Source: Based on
Candito et al. [55].
9.4.12 Quinolynes Generation
9.4.12.1 3,4-Quinolyne from Halo Derivatives
When 3-Cl/3-Br/3-I quinoline derivatives 62 were reacted in the presence of lithium
piperidine/piperidine, almost 1 : 1 regioisomeric mixture of 3- or 4-(piperidin-1-yl)
quinoline 63 were produced. These reactions are supposed to proceed via the generation of 3,4-quinolyne 19 (Scheme 9.27) [3]. It is noted that silyltriflate precursor is
known for 2,3-quinolyne and it is used for various reactions [56].
X
N
Lithium piperidine
piperidine
N
N
N
19
62
62a, X = Cl
62b, X = Br
62c, X = I
Scheme 9.27
Reinecke [3].
N
+
63a
N
63b
For X = Cl, 63a : 63b = 48 : 52
For X = Br, 63a : 63b = 50 : 50
For X = I, 63a : 63b = 49 : 51
3,4-Quinolyne generation from halo derivative. Source: Based on
9.4.12.2 5,6- and 7,8-Quinolynes
Similarly, 5,6- and 7,8-dehydroquinolynes were generated from the corresponding
halo derivatives (Cl/Br) in the presence of lithium piperidine/piperidine in boiling
ether. In this case also, the products isomeric ratio was independent of the halogen
used [57].
9.4.12.3 7,8-Quinolyne from Quinoline 4-Methylbenzenesulfonate Derivatives
Collis and Burrell trapped the 7,8-quinolyne 65 via Diels–Alder reaction with
furan. 7,8-Quinolyne 65 was generated via organolithium-induced elimination
of 4-methylbenzenesulfonate (Scheme 9.28) [58]. The generated product 66 was
further converted to the fully aromatic molecules.
9.4 Methods of Preparation
O
RLi, THF
X
–78 °C to rt
N
N
OTs
Scheme 9.28
Burrell [58].
66
65
64a, X = H
64b, X = Br
N
O
7,8-Quinolyne generation and trapping. Source: Based on Collis and
9.4.12.4 3,4-Isoquinolyne Generation
3,4-Isoquinolyne was formed as an intermediate when 4-bromoisoquinoline 67 was
heated to 180 ∘ C in presence of anhydrous piperidine. 4-(Piperidin-1-yl)isoquinoline
68a was formed in major product (35% yield) with 3-(piperidin-1-yl)isoquinoline 68b
(4% yield) (Scheme 9.29). Although the formation of 4-(Piperidin-1-yl)isoquinoline
68a was major, the possibility of the AEn mechanism instead of EA cannot be ruled
out [3].
Br
N
N
N
H
N
67
Scheme 9.29
Reinecke [3].
N
+
68a, 35%
N
68b, 4%
Possible 3,4-isoquinolyne intermediate generation. Source: Based on
9.4.13 3,4-Dehydro-1,5-Naphthyridine
When bromo-1,5-naphthyridines (3- or 4-) 69 were treated with KNH2 in liquid
ammonia at −33 ∘ C, both regioisomers of amino-1,5-naphthyridines 70 were
obtained. Most likely, the hetaryne 20 was the common intermediate for the
generated products (Scheme 9.30). Depending upon the bromo derivatives used,
the product ratio is also changed for amino-1,5-naphthyridines [3, 59].
9.4.14 4,5-Pyrimidyne Generation
Although 4,5-pyrimidyne 21 generation is well known in the literature, the intermediate is not well explored and has only limited synthetic applications. Van der
Plas et al. showed the generation of 4-tert-butyl-5,6-pyrimidyne from its 2-/3-bromo
derivatives. Deuterium-labeling experiment was carried out to confirm that benzyne
mechanism was operating [60].
373
374
9 Hetarynes, Cycloalkynes, and Related Intermediates
N
Br
KNH
2, N
–33 H3
°C
N
NH2
N
69a
N
NH2
N
+
H3
,N
H 2 °C
N
K 33
–
Br
N
N
N
N
70b
70a
20
N
69b
Scheme 9.30
3,4-Dehydro-1,5-naphthyridine generation. Source: Based on Czuba [59].
In 1992, Promel and coworkers reported the occurrence of 2-tert-butyl-4,5didehydropyrimidine intermediate via oxidation of 5-(tert-butyl)-3H-[1–3]triazolo
[4,5-d]pyrimidin-3-amine 71. The generated pyrimidyne was trapped successfully
in various Diels–Alder reactions (Scheme 9.31) [61]. Later, in 2016, the Garg group
prepared 4-(triethylsilyl)pyrimidin-5-yl trifluoromethanesulfonate to generate
aryne via fluoride-induced elimination of silyltriflate, but the method was not
successful. Only thia-Fries rearrangement was observed in the presence of CsF [62].
N
N
N
N
NH2
N
71
Pb(OAc)4
O
Ph
O
N
O
N
72a
Scheme 9.31
N
Ph
N
21
Ph
Ph
Ph
Ph
N
Ph
N
Ph
72b
Cycloaddition of 4,5-pyrimidyne. Source: Based on Tielemans et al. [61].
9.4.15 Pyridyne-N-oxides Generation
Martenes and Hertog reported the generation of 2,3-pyridyne-N-oxide 22. When
2-chloropyridine-N-oxide was treated with KNH2 , 2-amino and 3-aminopyridine-N-oxide (74a, 74b) were formed (Scheme 9.32). However, from
3-chloropyridine-N-oxide, only 3-aminopyridine-N-oxide was formed, which
could not confirm that the reaction is proceeding via 22 [37, 63].
Kauffmann identified 3,4-pyridyne as an intermediate when 3-chloropyridineN-oxide was reacted at 100 ∘ C with lithium piperidine to produce 3-piperidino
and 4-piperidino compounds [2, 64]. This reaction was envisaged to proceed via
3,4-pyridyne-N-oxide intermediate.
9.5 Reactions of Hetarynes
NH2
KNH2, NH3
N
O
Cl
N
O
N
O
–33 °C
73
22
74a
NH2
+
N
O
74b
Scheme 9.32 Pyridyne-N-oxides generation. Source: Martens and den Hertog [37];
Martens and den Hertog [37, 63].
9.4.16 Indolinyne Generation
Hoye and coworkers established an elegant method for the generation of indolinyne
76 via hexadehydro Diels–Alder reaction (HDDA). In this strategy, the substrate
containing three alkynes groups reacts to generate the reactive intermediate 76,
which furnishes the indoline molecule (Scheme 9.33) [65–69]. Using this strategy,
one can prepare indoline molecule with multiple substitutions on the benzene ring.
It may be noted that Lee group also reported an almost similar aryne generation
strategy and explored various reactions of this intermediate [70, 71].
CO2Et
EtO2C
NTs
CO2Et
PhMe
120 °C
OTBS
N
Ts
OTBS
75
76
N
TBS Ts
76a
Scheme 9.33 Indolinyne generation via HDDA. Source: Hoye et al. [65]; Niu et al. [66]; Niu
and Hoye [67]; Chenet al. [68]; Hoye et al. [69].
9.5 Reactions of Hetarynes
Hetarynes can undergo various types of reactions. Cycloaddition reaction is very
popular in hetaryne field. As discussed, cycloaddition product formation is an indirect method to confirm whether aryne is formed or not. Thus, for majority of cases,
aryne generation–trapping agents (furan, etc.) were used. So those reactions are not
discussed again here. Cycloaddition, where selectivity is controlled, will be discussed
because those reactions are synthetically useful. Other than cycloaddition, hetarynes
can undergo nucleophilic addition reaction and insertion reaction. When piperidine
was used for hetaryne generation, nucleophilic addition of piperidine to hetaryne
was observed. Several other nucleophilic addition reactions were known in the literature. Insertion reaction is very well explored in aryne chemistry but not well
explored in hetaryne field.
9.5.1
Cycloaddition Reactions
Selectivity is one of the issues for hetaryne cycloaddition reaction. The substitution of different groups has some effect on selectivity. Guitián revealed that halide
375
376
9 Hetarynes, Cycloalkynes, and Related Intermediates
substitution on the C-2 position of pyridine 77 influences the selectivity of cycloaddition products 78a and 78b. Chloro substitution increased the selectivity up to 2.4 : 1,
although bromo or fluoro showed no selectivity during cycloaddition (Scheme 9.34)
[72, 73].
PhO2S
TMS
O
CsF, MeCN
77
O
77a, X = Br
77b, X = Cl
77c, X = F
+
Me
SO2Ph
N
Me
X
Me
X
N
N SO Ph
2
Me
O
OTf
N
N
Me
X
N
78a
78b
For 77a, 78a : 78b = 1 : 1
For 77b, 78a : 78b = 2.4 : 1
For 77c, 78a : 78b = 1.1 : 1
Me
Scheme 9.34 Substitution effect on the selectivity of cycloaddition. Source: Díaz et al.
[72]; Díaz et al. [73].
Garg and Goetz showed that selectivity can be fully controlled by the substitution.
[3+2] Cycloaddition of 3,4-pyridyne with nitrone has an immense substitution
effect. Up to 10.7 : 1 selectivity was observed (81a : 81b) in presence of sulfamoyl
group at C-2 position, whereas without any substitution effect selectivity was 1.9 : 1
(81a : 81b). Again, placing bromo group at C-4 position of pyridine reverses the
selectivity (81a : 81b = 1 : 3.3). This substrate selective cycloaddition reaction could
be useful for various applications (Scheme 9.35) [74]. Iwayama and Sato developed
the nickel-catalyzed [2+2+2] cycloaddition with 3,4-pyridyne for synthesis of
isoquinoline derivatives [75]
t
OTf
t
+
N
Bu
X
79
80
79a, X = H, Y = H
79b, X = OSO2NMe2, Y = H
79c, X = H, Y = Br
Scheme 9.35
Garg [74].
N
O
Ph
CsF
Y
Ph
N
X
81a
t
Bu
N
O
Ph
O N
TMS
Y
Bu
Y
+
N
X
81b
For 79a, 81a : 81b = 1.9 : 1
For 79b, 81a : 81b = 10.7 : 1
For 79c, 81a : 81b = 1 : 3.3
Selectivity control in cycloaddition reaction. Source: Based on Goetz and
In the case of indole system, 4,5-indolyne showed 2.4 : 1 regioselectivity during
cycloaddition with benzyl azide. For 5,6-indolyne selectivity was 1.6 : 1. But in
the case of 6,7-indolyne, single regioisomer was obtained (Scheme 9.36) [53]. The
expected regioselectivity can be explained by aryne distortion model.
9.5 Reactions of Hetarynes
TMS
TfO
BnN3
55
N
Me
F– source
82a
TfO
BnN3
TMS
83
N
Me
–
F source
N N
N
N N
Bn N
Bn
N
N
N
Bn
N
Me
N
Me
82b
82a : 82b = 2.4 : 1
N
N
84a
N
Me
N
Bn
84b
N
Me
84a : 84b = 1.6 : 1
BnN3
TfO
N
TMS Me
F– source
Bn N
N N
N
Me
86
85
Scheme 9.36 Selectivity of Indolyne for cycloaddition with benzyl azide. Source: Based on
Cheong et al. [53].
9.5.2
Nucleophilic Addition Reaction
Various nucleophilic addition reactions are well known for pyridynes and indolynes.
Nucleophilic addition reaction on 2,3-pyridyne is selective and nucleophile can
add at C-2 position of pyridine exclusively. As Larock and Fang demonstrated,
2,3-pyridyne generated from silyltriflate precursor can undergo nucleophilic
addition with N-methyl aniline to produce N-methyl-N-phenylpyridin-2-amine 87
in 65% yield (Scheme 9.37) [56].
TMS
+
N
HN
Me
CsF
MeCN
N
N
Me
Slow addition
OTf
43
Scheme 9.37
Larock [56].
87
Selective nucleophilic addition on 2,3-pyridyne. Source: Based on Fang and
However, compared to 2,3-pyridine, the addition of 3,4-pyridyne was not selective.
Side product formation was the main limitation of previously used aryne generation methodologies. Thus, often strong nucleophile was employed to minimize the
side product. As an example, Nisi and Zoltewicz reported the generation of an equal
amount of 3- and 4-(methylthio)pyridine 89 using methylmercaptide as nucleophile,
where the hetaryne was generated from 88 (Scheme 9.38) [76].
377
378
9 Hetarynes, Cycloalkynes, and Related Intermediates
SMe
Br
NaNH2, NH3
–33 °C
SMe
+
NaSCH3
N
88
N
N
89a
89b
89a : 89b = 1 : 1
Scheme 9.38 Regioselectivity issue in nucleophilic addition reaction for 3,4-pyridyne.
Source: Based on Zoltewicz and Nisi [76].
Leake and Levine showed that 3-bromopyridine 88 in presence of acetophenone
and NaNH2 produced 4-aminopyridine 90 and 1-phenyl-2-(pyridin-4-yl)ethan-1-one
91. The product 91 was formed via nucleophilic addition of acetophenone enolate to
in situ–generated pyridyne 15. Although this reaction was free from the regioselectivity issues, both nucleophiles added to highly reactive pyridyne to produce mixture
of products (Scheme 9.39) [77]. This was the first report for 3,4-pyridyne 15 generation using 3-bromopyridine 83.
O
NH2
NaNH2, NH3
Br
–33 °C
+
O
N
Ph
88
Ph
N
Me
90
N
91
Scheme 9.39 Selectivity in presence of different nucleophiles. Source: Based on Levine
and Leake [77].
Silyltriflate precursor of 3,4-pyridyne is also free from side reaction, but selectivity is still not very good. For example, N-methylaniline gave only 1.9 : 1 ratio of 3and 4-regioisomer (92a and 92b). But Garg’s methodology was helpful to achieve
good selectivity [74]. It showed that sulfamoyl group at the C-2 position forced the
upcoming nucleophile to add from C-4 position. However, C-5 bromo substitution
restricted the nucleophilic addition at C-4 and 92b was formed as a major product,
where nucleophilic addition happens from C-3 (Scheme 9.40).
Me
TMS
Y
OTf
N
X
CsF
Ph
H
N
79
79a, X = H, Y = H
79b, X = OSO2NMe2, Y = H
79c, X = H, Y = Br
N
Ph
Me
Ph
N
Me
Y
Y
+
N
X
92a
N
X
92b
For 79a, 92a : 92b = 1.9 : 1
For 79b, 92a : 92b > 15 : 1
For 79c, 92a : 92b = 1 : 5.8
Scheme 9.40 Selective nucleophilic addition using substitution effect. Source: Based on
Goetz and Garg [74].
9.5 Reactions of Hetarynes
The nucleophilic addition reaction in indolyne is mostly regioselective. For 4,5and 5,6-indolyne, nucleophile adds at C-5 position selectively but for 6,7-indolyne,
nucleophile adds selectively at C-6 position. The same trend was observed for
cycloaddition to indolyne also. Regioselectivity varies depending upon the nucleophile used. Aniline addition to 4,5-indolyne gave 12.5 : 1 regioselectivity, but for
4-methylbenzenethiol addition, selectivity dropped to 2 : 1 [54] For 4,5-indolyne,
nucleophilic addition at C-4 is possible if C-6 position is occupied by bromo
substitution as demonstrated by Garg and coworkers [22].
9.5.3
Insertion Reaction
The insertion reaction is very much familiar in aryne chemistry. But it is not explored
deeply in hetaryne field. Sato et al. developed the insertion of cyclic urea to hetarynes. This methodology is applicable for 2,3-pyridyne, 3,4-pyridyne, as well as
2,3-quinolyne also. For 3,4-pyridyne, regioisomers (93a and 93b) were observed, but
for others, exclusively single regioisomer 94 and 96 (for hetaryne generated from 95)
was obtained (Scheme 9.41) [78].
N
TES
CsF (2.2 equiv)
rt, 3 h
OTf
O
Me N
48
O
Me
N
+
N
N
N
Me
O
93a
N Me
Me
N
N
Me
93b
86% 93a : 93b = 65 : 35
O
TMS
N
CsF (2.2 equiv)
rt, 1 h
O
OTf
Me N
43
N
N Me
Me
N
N
Me
94, 53%
O
TMS
N
95
Scheme 9.41
CsF (2.2 equiv)
rt, 1 h
O
OTf
Me N
N
N Me
Me
N
N
Me
96, 29%
Urea insertion onto hetarynes. Source: Based on Saito et al. [78].
In 2015, Oestreich and coworkers developed the insertion of bis(pinacolato)diboron
onto indolynes. The reaction is applicable for all three indolynes (for example generated from 97) and the insertion product 98 was further functionalized selectively
(C-7 substituted) via Suzuki–Miyaura cross-coupling to afford 99. The remaining
379
380
9 Hetarynes, Cycloalkynes, and Related Intermediates
boron functionality was also functionalized to produce diaryl indole derivative 100
(Scheme 9.42) [79].
TfO
N
TMS Me
KF (2.0 equiv)
18-crown-6 (2.0 equiv)
Pt(dba)2 (5.0–7.5 mol%)
t-BuNC (25–30 mol%)
(pinB)2 (1.5 equiv)
DME, 85 °C
Bpin
Bpin
97
N
Me
98
(dppf)PdCl2 (10 mol%)
Ar1-I (1.0 equiv)
KOH (1.7 equiv)
Bpin
N
Bpin Me
98
Bpin
Ar1
99
Scheme 9.42
et al. [79].
N
Me
DME/ H2O 30 : 1
45 °C
(Short reaction time)
(dppf)PdCl2 (10 mol %)
Ar2-I (1.0 equiv)
KOH (1.7 equiv)
DME/ H2O 23 : 1
90 °C
(Long reaction time)
Bpin
1
Ar
N
Me
99
Ar2
Ar1
N
Me
100
Bis(pinacolato)diboron insertion to indolynes. Source: Based on Pareek
As discussed for 3,4-pyridynes, the regioselectivity was one major issue in
insertion reactions. But placing substitution at different positions can improve the
selectivity and after the reaction, substitution can also be removed. For insertion
to 3,4-pyridyne, Garg’s substitution effect was excellent to improve the selectivity.
For C-4 substitution, only C-3 addition product (101) was observed and for C-2
exclusively C-4 addition product (101) was formed. But without any substitution,
the products were obtained with 2.1 : 1 regioisomeric ratio (Scheme 9.43) [74].
9.6 Applications in Synthesis
Although earlier methods of hetaryne generation have some limitations, now
with the advancement of hetaryne generation methodologies, the hetarynes are
widely used for complex synthetic targets (specially pyridyne and indolyne). Using
pyridyne as an intermediate ellipticine, macrostomine, eupolauramine, perlolidine
can be accessed [24, 25, 72, 73, 80–85]. Indolynes can be used for the synthesis
of different makaluvamines, lysergic acid, members of the welwitindolinone,
9.6 Applications in Synthesis
Me N
Y
TMS
Y
CsF
OTf
O
O
N
X
79
Me N
N
N Me
+
Y
X
N
N
101a
Me
X
101b
For 79a, 101a : 101b = 2.1: 1
For 79b, 101a only
For 79c, 101b only
79a, X = H, Y = H
79b, X = OSO2NMe2, Y = H
79c, X = H, Y = Br
Scheme 9.43
Garg [74].
O
N Me
Me
N
Regioselectivity for 3,4-pyridyne insertion. Source: Based on Goetz and
indolactam alkaloid families, and indole diterpenoid tubingensin A, tubingensin B
[22, 23, 47, 86–90].
9.6.1
Application of Pyridyne
Since a long time, pyridyne had been used for total synthesis. In 1976, Singh and
coworkers synthesized perlolidine 105 using pyridyne as an intermediate. Starting
from readily available 2-amino pyridine 102, after five steps, the derivative 103
was synthesized. Then, treatment of 103 with KNH2 generated the pyridyne and
produced 104. After successive steps, perlolidine 105 was synthesized from 104
(Scheme 9.44) [84, 85].
HN
Me
N
Br
H2N
N
–33 °C
BnO
102
HN
BnO
KNH2, NH3
N
103
BnO
N
N
N
104
O
N
H Perlolidine
105
Scheme 9.44 Perlolidine synthesis by Singh and coworkers. Source: Kessar et al. [84];
Kessar and Singh [85].
Moody and May synthesized ellipticine 110 in three steps starting from indole.
At the last step, pyridyne was generated from 109 by heating, and the generated
381
382
9 Hetarynes, Cycloalkynes, and Related Intermediates
pyridyne underwent Diels–Alder reaction with 108 (Scheme 9.45). At the last
step, ellipticine 110 and iso ellipticine were formed and were separated via
column chromatography [80, 81]. Gribble and Sha also synthesized ellipticine
via Diels–Alder reaction with pyridyne [82, 83]. As discussed in Section 9.5.1.
(Scheme 9.33), Guitián and coworkers investigated the substitution effect on
3,4-pyridyne with various dienes. This indicated that the chloro substitution can
give good selectivity and Guitián also showed that Diels–Alder product 78a could
be elaborated to ellipticine [72, 73].
Me
CO2H
Lactic acid, KOH
Heat
N
H
O
O
N
H
108
N
H
107
+
Me
N
N
Me
N
HO2C
Me
109
O
O
BF3-Et2O
N
H
106
Me
Me
Ac2O
Me
108
Me
N
N
MeCN
Heat
N
H
Ellipticine
Me
110
Scheme 9.45 Ellipticine synthesis by Moody and coworkers. Source: May and Moody [80];
May and Moody [81].
Eupolauramine was synthesized by Couture and coworkers using pyridyne as
a reactive intermediate. In the early steps of synthesis, pyridyne was generated
from 2-chloronicotinic acid derivative 112 formed from 111, and the intramolecular cyclization afforded the desired products 113a and 113b, which underwent
sequence of reactions to furnish eupolauramine (Scheme 9.46) [25].
(S)-Macrostomine 117 was synthesized from (S)-Nicotine by Comins and coworkers. In the intermediate steps of (S)-Macrostomine 117 syntheses, pyridyne was generated from 115, and trapped with 3,4-dimethoxyfuran to afford the cycloadduct 116.
After the cycloaddition, two more steps were performed to achieve the synthesis of
117 (Scheme 9.47) [24].
9.6.2
Application of Indolyne
Like pyridynes, indolynes were also known for total synthesis for a long time. For
example, Julia and coworkers reported the synthesis of lysergic acid using indolyne
as an intermediate. In their synthesis, indolyne was generated from 5-bromoindoline
118 using NaNH2 . NaNH2 also abstracted a proton from 118, which resulted in an
intramolecular cyclization to deliver the tetracycle 120. The regiochemistry of 120
was controlled by geometric constraints. The cyclized product could be elaborated
to lysergic acid 121 (Scheme 9.48) [23].
9.6 Applications in Synthesis
1. KHMDS (2 equiv)
2. –78 °C to rt
3. H3O+
H
CO2H
N
Cl
N
Me
O
P
Ph
Ph
O
Ph P O
Ph
113a
O
N
DCC, DMAP, CH2Cl2
N
Cl
111
112
N Me
N
Me
O
P
Ph
Ph
1. KHMDS (2 equiv)
2. –78 °C to rt
3. OH–/H2O
O
N Me
N
O
113b
N Me
N
OMe
Eupolauramine 114
Scheme 9.46 Hetaryne-mediated eupolauramine synthesis by Couture. Source: Based on
Hoarau et al. [25].
Cl
Cl
OMe
1. 1.1 n-BuLi
THF, –78 °C,
1h
N
Me
N
115
Scheme 9.47
et al. [24].
MeO
O
O
2.
Cl
MeO
OMe
MeO
OMe
N
N
Me
O
O
116
MeO2C
MeO2C
N Me
H
H
N Me
H
NaNH2, NH3
N Me
H
H
–33 °C
N
Ac
118
N
117 (S)-Macrostomine
(S)-Macrostomine synthesis by Comins. Source: Based on Enamorado
MeO2C
Br
N
Me
H
N
Ac
N
Ac
119
120
HO2C
N Me
H
lysergic acid
N
H
Scheme 9.48
121
Lysergic acid synthesis by Julia and coworkers. Source: Julia et al. [23].
383
384
9 Hetarynes, Cycloalkynes, and Related Intermediates
(±)-Cis-trikentrin A 124 and (±)-herbindole A 127 were synthesized by Buszek
and coworkers via an intermolecular Diels–Alder reaction using indolyne (generated from 122 and 125) and cyclopentadiene leading to the formation of 123 and
126 as the key steps. This approach integrated Bartoli indole synthesis for efficient
synthesis of the trikentrins and herbindoles (Scheme 9.49) [50, 91].
n-BuLi, PhMe
–78 °C to rt
N
TBS
N
TBS
Br
Br
122
n-BuLi, PhMe
–78 °C to rt
Me
Br
Br
125
(±)-Cis-trikentrin A Me
124
123
Me
N
H
Me
Me
Me
Me
Me
N
TBS
N
TBS
N
H
Me
Me
126
(±)-Herbindole A 127
Scheme 9.49 Trikentrin and herbindole synthesis by Buszek group. Source: Buszek et al.
[91]; Brown et al. [91].
As discussed, Iwao and coworkers synthesized makaluvamines using 4,5-indolyne
formation as a key step (Scheme 9.21) [47]. Members of the welwitindolinone families ((−)-N-methylwelwitindolinone C isothiocyanate, oxidized welwitindolinones,
(−)-N-methylwelwitindolinone C isonitrile, and N-methylwelwitindolinone D
isonitrile) were synthesized by Garg and coworkers using 4,5-indolyne as an
effective intermediate and details of this methodology are discussed in Chapter 11
[86–88].
Garg and coworkers also applied indolyne methodology toward the total synthesis of indolactam alkaloids. The synthesis of the four indolactam alkaloids
was performed from one common intermediate. This intermediate was obtained
through intermolecular nucleophilic addition at C-4 position of 4,5-indolyne.
This method is also discussed in Chapter 11 [22]. Furthermore, the synthesis
of tubingensin A and tubingensin B was reported by Garg and coworkers using
carbazolyne intermediate and the details are also presented in detail in Chapter 11
[90, 92].
9.7 Introduction to Cycloalkynes
Cyclohexyne or more generally strained cycloalkynes are the aliphatic variants of
benzyne intermediate having a strained C—C triple bond in the cyclic aliphatic
system. The reactivity and isolability of cycloalkynes depend on the ring size.
9.8 History of Cycloalkynes
Smaller the ring size, higher the reactivity. The smallest possible cycloalkyne,
i.e. cyclopropyne, is not even generated or detected spectroscopically due to the
enormous angle deformation. Similarly, there is no report on the generation or
trapping of cyclobutyne other than the isolation of an osmium complex with
cyclobutyne ligand [93]. The five-, six-, and seven-membered cycloalkynes are also
very reactive, and these can only be synthesized in situ in presence of a suitable
trapping agent. Compared to these three cycloalkyne intermediates, medium-ring
cycloalkynes are quite stable and cyclooctyne is the smallest isolable cycloalkyne.
These medium-ring cycloalkynes are used extensively in the click chemistry. In
the context of this part of the chapter, a brief discussion on the history, methods of preparation, reaction, and application of five-, six-, and seven-membered
cycloalkynes and their heteroatom-embedded analogs are presented here. A closely
related intermediate strained cyclic allenes also will be discussed in this chapter.
9.8 History of Cycloalkynes
The history of strained cyclic alkynes is closely related to that of aryne intermediate.
After the initial assumption for the existence of aryne intermediate by Stoermer
and Kahlert in 1902 [1], Favorskii and Boshowskii in 1912 suggested a cyclohexyne intermediate for the formation of dodecahydrotriphenylene 129 from
1,2-dibromocyclohexene 128 (Scheme 9.50) [94]. Similarly, in 1936, a cyclopentyne trimer was prepared by the reaction of 1,2-dibromocyclopentene with
sodium [95].
Na
Br
Br
128
via
129
Scheme 9.50 Dodecahydrotriphenylene from 1,2-dibromocyclohexene. Source: Favorskii
and Boshowskii [94].
Later in 1944, Wittig and Harboth reported a low-yield method for the synthesis of 1-phenylcyclohexene 131 from the coupling of phenyl lithium with
1-chlorocyclohexene 130 in ether at 100 ∘ C (Scheme 9.51) [96]. The formation of
1-phenylcyclohexene was explained via a direct nucleophilic substitution, and
ignored the possibility of cyclohexyne formation as this intermediate was thought
to be structurally impossible.
To explore the possibility the formation of 1-phenylcyclohexene 131 from
1-chlorocyclohexene 130 and phenyl lithium via a cyclohexyne intermediate, Scardiglia and Roberts in 1957 devised the reaction with a 14 C-labeled
385
386
9 Hetarynes, Cycloalkynes, and Related Intermediates
Cl
PhLi
ether
Ph
130
131
Scheme 9.51 Coupling of phenyllithium with l-chlorocyclohexene. Source: Based on
Wittig and Harborth [96].
1-chlorocyclohexene 132 (Scheme 9.52) [97]. When the equimolecular ratio of
14 C-labeled 1-chlorocyclohexene 134 and 135 (prepared from 133) was heated with
phenyl lithium at 150 ∘ C, almost 28% of the 1-phenylcyclohexene was formed, which
upon oxidation with sodium permanganate, benzoic acid with 23% 14 C-labeling
was observed. Thus, 23% of the 1-phenylcyclohexene 141 labeled at 1-position was
formed. This is comparable with the theoretical 25% of 141. This small difference
between the theoretical and experimental values can be ignored owing to some
nonrearranging reaction. Thus, the coupling reaction of 1-chlorocyclohexene and
phenyl lithium was taking place via cyclohexyne intermediate and not via a direct
nucleophilic substitution as in the case of direct nucleophilic substitution no
1-phenylcyclohexene 141 labeled at 1-position would have formed.
Cl Cl
O
Cl
Cl
PCl5
PhLi
+
132
133
+
150 °C
–HCl
134
1:1
135
136
137
1. PhLi
2. H+, H2O
Ph
Ph
Ph
Ph
+
138
+
139
+
140
141
Scheme 9.52 14 C-Labelled l-chlorocyclohexene with phenyllithium. Source: Based on
Scardiglia and Roberts [97].
1-phenylcyclohexene 131 might have also formed via an allenic intermediate
1,2-cyclohexadiene 142 (Scheme 9.53). But this possibility was eliminated as in this
case no 1-phenylcyclohexene 141 labeled at 1-position would have formed. Here,
it should be noted that in 1966 Wittig trapped allenic intermediate via a [4+2]
cycloaddition reaction.
Finally, in 1960, Wittig successfully trapped cyclopentyne, cyclohexyne, and
cycloheptyne intermediate via a [4+2] cycloaddition with 1,3-diphenyl isobenzofuran starting from the dibromide 145 to afford finally the naphthalene derivative 147
via the initially formed cycloadduct 146 (Scheme 9.54) [98].
9.10 Methods of Cycloalkyne Generation
Cl
Cl
PhLi
+
–HCl
134
135
1:1
142
1. PhLi
2. H+, H2O
Ph
Ph
Ph
+
+
139
140
Scheme 9.53
Roberts [97].
Ph
+
143
144
Probability of allenic intermediate. Source: Based on Scardiglia and
Ph
O
n
Br
Mg
Br
THF
n = 1,2,3
145
Scheme 9.54
Ph
Ph
n
Ph
O
n
n
Ph
146
Ph
147
Trapping of cycloalkynes. Source: Based on Wittig et al. [98].
9.9 Different Types of Cycloalkynes
Depending upon the ring size, strained cycloalkynes can be divided broadly
into three categories (five-, six-, and seven-membered cycloalkynes), namely
cyclopentyne 148, cyclohexyne 149, and cycloheptyne 150. Cycloalkynes, having
a heteroatom in the ring, are generally termed as hetero cycloalkynes. If the
skeletal ring contains a sulfur atom, it is called thiacycloalkyne, e.g. tetramethylthia
cyclopentyne 151, and if the ring has an oxygen atom, it termed as oxa-cyclohexyne.
3,4-Oxa-cyclohexyne 152 is an example of oxa-cyclohexyne. In the case of nitrogen,
the terminology is aza-cyclohexyne, 2,3-piperidyne 153, and 3,4-piperidyne 154 fall
under this category. Similarly, 155 is a cyclohexenynone, a keto group containing
cyclohexyne and 156 is norbornyne, a bicyclic cycloalkyne (Scheme 9.55).
9.10 Methods of Cycloalkyne Generation
Strained cycloalkynes are very reactive, so they cannot be isolated and must be generated in situ in the reaction medium. There are various methods available for the
387
388
9 Hetarynes, Cycloalkynes, and Related Intermediates
Cyclopentyne
148
S
Cyclohexyne
149
Cycloheptyne
150
O
N
R
Thiacyclopentyne 3,4-Oxacyclohexyne 2,3-Piperidyne
151
152
RO
153
O
RN
3,4-Piperidyne
154
Scheme 9.55
Cyclohexenynone
Norbornyne
155
156
Different types of cycloalkynes.
generation of cycloalkynes, some methods are in principle similar to the generation
of aryne intermediates. Selected methods are discussed in Sections 9.10.1–9.10.2.
9.10.1 Traditional Methods of Cycloalkyne Generation
9.10.1.1 Base-Induced 1,2-Elimination
Cycloalkynes can be generated from 1-halocycloalkenes by deprotonation of β-vinyl
hydrogen by a strong base. In 1944, Wittig used L-chlorocyclohexene 130 and
phenyl lithium for the generation of cyclohexyne 149, but the yield was only 5%
(Scheme 9.56) [96]. The main problem with the base-induced elimination is the
competitive generation of 1,2-cycloalkadienes [99].
Cl
130
PhLi
ether
Ph
149
131
Scheme 9.56 Generation of cyclohexyne from 1-chlorocyclohexene. Source: Based on
Wittig and Harborth [96].
Futija and coworkers used iodonium salt 157 for the mild generation of substituted
cyclohexyne 158 (Scheme 9.57) [100].
In 2017, Okano and coworkers generated cyclohexynes and cycloheptynes
from corresponding enol triflates 159 with a mild bulky base, magnesium
bis(2,2,6,6-tetramethylpiperidide) by controlling the reactivity of intermediate
anionic species 160 (Scheme 9.58) [101].
9.10 Methods of Cycloalkyne Generation
–
BF4
+
IPh
AcONBu4
CHCl3
R
R = Me, t-Bu, Ph
R
157
158
Scheme 9.57
[100].
Generation of cyclohexyne from iodonium salt. Source: Based on Fujita et al.
Mg(TMP)2·2LiCl
31
Mg(TMP)
THF, rt
OTf
OTf
159
160
Scheme 9.58
[101].
149
Generation of cycloalkyne from enol triflates. Source: Based on Hioki et al.
9.10.1.2 Metal–Halogen Exchange/Elimination
Another approach involves the metal–halogen exchange/elimination of 1,2dihalocycloalkenes 145 mediated by metals (Mg or Na) [98]. But one has to use
stoichiometric amount of metals for the generation of cycloalkynes. Using this
approach, cyclopentyne 148, cyclohexyne 149, and cycloheptyne 150 could be
generated (Scheme 9.59).
Br
n Br
n = 1,2,3
145
MgBr
Mg
THF
n
Br
n
161
Scheme 9.59 Generation of cycloalkynes from 1,2-dihalocycloalkenes. Source: Based on
Wittig et al. [98].
9.10.1.3 Fragmentation of Aminotriazoles
1-Tosylamino-1,2,3-triazole anions 162 upon photolytic or thermal fragmentation
produce cycloalkynes with the evolution of nitrogen gas (Scheme 9.60) [102].
N
N
N
NLiTs
162
Scheme 9.60
Willey [102].
hv or heat
–N2
149
Generation of cycloalkyne from aminotriazole anion. Source: Based on
389
390
9 Hetarynes, Cycloalkynes, and Related Intermediates
9.10.1.4 Fragmentation of Diazirine
Thermal or photolytic degradation of isolable bis-diazirine derivatives evolves nitrogen gas and produces cycloalkyne intermediates. This procedure is applicable for
the generation of cyclohexyne 149 and cycloheptyne 150 in good yields. Interestingly,
norbornyne 156 could be generated by thermolysis of the norbornyl bisdiazirine
derivative 163 (Scheme 9.61) [103].
N
N
N
N
40–60 °C
–N2
163
156
Scheme 9.61
Generation of norbornyne. Source: Based on Al-Omari et al. [103].
9.10.1.5 Oxidation of 1,2-Bis-hydrazones
The Curtius method of alkyne synthesis has been successfully applied for the generation of strained cycloalkynes. Oxidation of 1,2-bis-hydrazonocycloalkanes 164 with
strong oxidant (HgO) generates cycloalkynes with the evolution of nitrogen from
the initially formed diazo compound 165. Although the yields are low, this procedure can be used for generation of cyclopentyne 148, cyclohexyne 149, cycloheptyne
150, and tetramethylthiacyclopentyne 151 (Scheme 9.62) [104, 105]. Due to the use
of strong oxidant, this method has less functional group tolerance and hence not
widely used.
N NH2
n N NH2
n = 1,2,3
164
N NH
HgO
n
N N
–2N2
n
165
Scheme 9.62 Generation of cycloalkyne from 1,2-bis-hydrazones. Source: Wittig and Krebs
[104]; Bolster and Kellogg [105].
9.10.1.6 Rearrangement of Vinylidenecarbenes
When bromomethylene cycloalkanes are heated with a strong base, it generates
vinylidene carbene intermediate, which immediately rearranges to cycloalkyne
intermediate. For instance, cyclohexyne 149 can be generated by heating bromomethylene cyclopentane 166 with potassium tert-butoxide via the rearrangement
of the corresponding vinylidene carbene 167. Similarly, cyclopentyne can be
produced from bromomethylene cyclobutane (Scheme 9.63) [106].
9.10.2 Fluoride-Induced Cycloalkyne Generation
In 1983, Kobayashi and coworkers discovered the fluoride-induced 1,2-elimination
of 2-(trimethylsilyl)aryl triflates to generate aryne in solution. Following the success
9.10 Methods of Cycloalkyne Generation
KOtBu
n
n = 1,2
166
Br
200–240 °C
n
n
149
167
Scheme 9.63 Generation of cycloalkyne from vinylidene carbene. Source: Based on
Erickson and Wolinsky [106].
of this mild and base-free method, in 1998 Guitián and coworkers developed the
aliphatic variant of Kobayashi’s aryne precursor, 2-(trimethylsilyl)cyclohexenyl
triflate 169. This precursor was synthesized from 168 in two steps with 78% yield
(Scheme 9.64) [107]. Similarly, 2-(trimethylsilyl)cyclopentenyl triflate was prepared
by Guitián and coworkers in 2002 for the mild generation of cyclopentyne [108].
Recently, Garg and coworkers prepared silyl tosylate precursor for milder and
controlled generation of cyclohexyne via the fluoride-induced cyclohexyne generation [109]. This fluoride-induced cyclohexyne generation is highly preferred by
synthetic chemists over traditional methods as it is a mild, base-free condition, and
compatible with various functional groups. Various other silyltriflate precursors to
the strained cycloalkynes and heterocycloalkynes have been prepared over the last
few years for mild generation of the cycloalkynes.
TMS
TMS
1. L-selectride
2. PhNTf2
O
168
F-Source
rt
OTf
169
Scheme 9.64
et al. [107].
149
Fluoride-induced cyclohexyne generation. Source: Based on Atanes
9.10.2.1 Generation of 3,4-Oxacyclohexyne
Garg and coworkers reported the generation 3,4-oxacyclohexyne 152 via the
fluoride-induced β-elimination of silyl triflate precursor 171. The precursor was
synthesized in four steps starting with commercially available 4-oxotetrahydropyran
170 (Scheme 9.65) [110].
1. LDA, THF, –78 °C
then, TMSCI
2. NBS, THF, 0 °C
O 3. DABCO, TESCl
DMF, 23 °C
O
170
4. n-BuLi, THF, –78 °C
then, Tf2O
Scheme 9.65
et al. [110].
OTf
O
SiEt3
171
F-source
rt
O
152
Fluoride-induced generation of 3,4-oxacyclohexyne. Source: Based on Shah
391
392
9 Hetarynes, Cycloalkynes, and Related Intermediates
9.10.2.2 Generation of 2,3-Piperidyne
In 1988, Wentrup and coworkers detected the 2,3-piperidyne 153a at low temperature. This was generated from the pyrolysis of isoxazolone 172 via the rearrangement
of the intermediate carbene 173 (Scheme 9.66) [111].
N
H
172
N
O
O
FVP
680–780 °C
N
H
N
H
173
Scheme 9.66
153a
Pyrolysis of isoxazolone. Source: Based on Wentrup et al. [111].
The silyl triflate precursor 175 of the 2,3-piperidyne 153b was synthesized by
Danheiser and coworkers from readily available lactam 174 in a three-step process
(Scheme 9.67) [112].
1. KHMDS, toluene-THF, –78 °C
then, Br2
2. n-BuLi,TMSCl, THF, –78 °C,
N
Ts
174
O 3. KHMDS, toluene–Et O–THF
2
–78 °C, then, Tf2O
TMS
N
Ts
F-source
rt
OTf
175
N
Ts
153b
Scheme 9.67 Fluoride-induced generation of 2,3-piperidyne. Source: Based on Tlais and
Danheiser [112].
9.10.2.3 Generation of 3,4-Piperidyne
Generation of the 3,4-piperidyne 154a was described by Garg and coworkers
via the fluoride-induced 1,2-elimination of silyl triflate from the corresponding
aza-cycloalkyne precursor 177. It was prepared from the commercially available
4-methoxypyridine 176 by the following synthetic route (Scheme 9.68) [113].
OMe
N
176
Scheme 9.68
et al. [113].
1. LDA, THF, –15 °C then, TMSCl
2. NaBH4, MeOH, –78 °C
3. CbzCl, Et2O, –78 °C then, H2O
4. L-selectride, THF, –78 °C,
then, Tf2O
OTf
CbzN
TMS
177
F-source
rt
CbzN
154a
Fluoride-induced generation of 3,4-piperidyne. Source: Based on McMahon
9.10.2.4 Generation of Cyclohexenynone
Recently, Li and coworkers reported the generation of cyclohexenynone 155a
and 182 from the corresponding silyl triflate precursor 179 and 181. The cyclohexenynone was synthesized from 178 and 180 by oxidative dearomatization
(Scheme 9.69) [114].
9.11 Reactions of Cycloalkynes
OH
Me
TMS
OTf
PhI(TFA)2
MeO
Me
TMS
MeOH, rt
OTf
F-source
O
OH
Me
TMS
PhI(TFA)2
Me
OMe
MeOH, rt
TMS
O
MeO
Me
rt
155a
179
178
O
F-source
Me
OMe
rt
OTf
OTf
180
Scheme 9.69
et al. [114].
O
181
182
Fluoride-induced generation of cyclohexenynone. Source: Based on Qiu
9.11 Reactions of Cycloalkynes
Strained cycloalkynes and heterocyclohexynes are very reactive, so they can
participate in various types of reactions. Cycloalkynes are very good dienophile
and it can be trapped by various dienes like furans, 1,3-diphenylisobenzofuran
and tetraphenylcyclopentadienone. Cycloalkynes can also participate in arylation reactions and insertion reactions. Multicomponent reactions and molecular
rearrangements are still not well explored for cycloalkynes.
9.11.1 Cycloaddition Reactions
Cycloaddition reactions are the most common reaction of cycloalkynes as the
generation of cycloalkynes is confirmed via isolation of different cycloadducts.
Some of the representative examples with cycloalkynes are presented in Sections
9.11.1.1–9.11.1.3.
9.11.1.1 Diels–Alder Reaction
Cycloalkynes are excellent dienophiles in [4+2] cycloaddition reactions. In 1998,
Guitián and coworkers successfully generated cyclohexyne from the silyltriflate precursor, and then trapped the cyclohexyne with pyrones 183a–d for the synthesis of
tetrahydro naphthalenes 184a–d (Scheme 9.70) [107].
In 2019, Garg and coworkers reported the synthetic route for the generation
of heteroatom containing polycyclic aromatic hydrocarbon (PAH) 186 via two
successive cycloadditions and elimination of nitrogen and carbon dioxide from 185
(Scheme 9.71) [115].
9.11.1.2 [2+2] Cycloaddition
[2+2] Cycloaddition is not very common in cycloalkynes chemistry. The [2+2]
cycloaddition of cyclohexenynone 182 generated from 181 with 1,1-dimethoxyethene
generates the cycloadduct 183 in 62% yield (Scheme 9.72) [114].
393
394
9 Hetarynes, Cycloalkynes, and Related Intermediates
R1
TMS
R1
O
OTf
O
N
169
CsF, dioxane
100 °C, 20 h
R2
O
N
184
R2
O
a, R1 = CO2Et, R2 = Me, 86%
183
b, R1 = CO2Me, R2 = Bn, 81%
c, R1 = CO2Et, R2 = Bn, 82%
d, R1 = OMe, R2 = Bn, 86%
Scheme 9.70 Generation of tetrahydro naphthalenes via Diels–Alder reaction. Source:
Based on Atanes et al. [107].
TMS
Ph
OTf
+
CbzN
N
N
TMS
Ph
O
O CsF, CH CN
3
23 °C,
CbzN
–N2
Ph
154a
O TfO
O
Ph
169
CbzN
CsF, CH3CN
23 °C,
–CO2
Ph
185
Ph
186 71%
Scheme 9.71 Generation of PAH via Diels–Alder reaction with cyclohexyne. Source: Based
on Darzi et al. [115].
O
OMe
Me
OMe CsF, CH CN
3
O
Me
OMe
O
OMe
Me
OMe
rt
TMS
OMe
OTf
181
62% yield
183
182
Scheme 9.72
OMe
[2+2] Cycloaddition. Source: Based on Qiu et al. [114].
9.11.1.3 1,3-Dipolar Cycloaddition
Cycloalkynes are excellent dipolarophiles, and hence they can add to various
1,3-dipoles such as nitrones, nitrile oxides, nitrile imines, azomethine imines,
azides and diazo compounds (Scheme 9.73).
a
+
b+
–
c
149
Dipolar
a
Cycloaddition
c
b
1,3-Dipole
Scheme 9.73
1,3-Dipolar cycloaddition.
For example, Garg and coworkers reported the 1,3-dipolar cycloaddition of
cyclohexyne generated from the precursor 169 with benzyl azide 184 leading to the
9.11 Reactions of Cycloalkynes
synthesis of tetrahydro benzotriazole 185 (Scheme 9.74) [116]. The use of CsF in
THF was best for this transformation.
N
+
N
N
TMS
+
OTf
60 °C
Bn
184
169
N
CsF, THF
185
N
N
Bn
94% yield
Scheme 9.74 1,3-Dipolar cycloaddition of benzyl azide and cyclohexyne. Source: Based on
Medina et al. [116].
9.11.2 Alkenylation Reactions
Similar to arynes, charged or uncharged nucleophiles add to strained cycloalkynes
or heterocycloalkynes and upon protonation produce the formal alkenylated
product. When 2,3-piperidyne 153b is generated in presence of thiophenol, it adds
to the 2,3-piperidyne 153b regioselectively at the C-3 position and the generated
anion, which was subsequently protonated to furnish a thioalkenylated product 186
(Scheme 9.75) [112].
TMS
N
Ts
CH3CN, rt
OTf
N
Ts
175
SPh
PhSH
KF/18-crown-6
87% Yield
186
153b
Scheme 9.75
N
Ts
Alkenylation using thiophenols. Source: Based on Tlais and Danheiser [112].
9.11.3 Insertion Reactions
Insertion reactions are very common in aryne chemistry, but it is not well explored
in the strained cycloalkyne field. In 2009, Stoltz and coworkers demonstrated that
cyclohexyne can insert into β-keto ester 187 for the formation of C—C σ-bond
inserted product 188. This insertion product was in situ treated with aqueous
ammonium hydroxide for the synthesis of tetrahydroisoquinoline derivative 189 in
a one-pot procedure (Scheme 9.76) [117].
O
TMS
O
O
+
169
Scheme 9.76
[117].
CsF, CH3CN
187
OH
aq. NH4OH
OMe 80 °C, 1 h
OTf
OMe
O
188
N
60 °C
54% yield
189
Cyclohexyne insertion into β-keto ester. Source: Modified from Allan et al.
395
396
9 Hetarynes, Cycloalkynes, and Related Intermediates
Later, in 2010, Carreira and coworkers successfully inserted cyclohexyne generated from 157 into a variety of cyclic ketones 190 for the generation of medium-sized
fused rings 191 (Scheme 9.77) [118].
–
BF4
+
O
O
IPh
KOEt3, THF
+
–78 °C to rt
157
Scheme 9.77
et al. [118].
190
191
Cyclohexyne insertion into cyclic ketones. Source: Modified from Gampe
9.12 Application in Synthesis
Arynes and heteroarynes are widely used in the natural product synthesis (discussed
in detail in Chapter 11), but there are only a few reports where cycloalkynes were
used for the synthesis of complex natural products. For example, in 2011, Carreira
and coworkers reported the total synthesis of guanacastepenes O and N 197 and
198 via a formal insertion of cyclohexyne 149 into pentalenone 193 as a key step.
Treatment of Fujita’s cyclohexyne precursor 157 with pentalenone 193 and KOCEt3
furnished cyclobutanol 195, which under iron-promoted ring opening generated the
enone 196. Finally, this enone 196 was elaborated to guanacastepenes O 197 and
guanacastepenes N 198 (Scheme 9.78) [119].
9.13 Strained Cyclic Allenes
Strained cyclic allenes such as 1,2-cycloalkadienes and their hetero analogs
are a class of highly strained intermediates related to cyclohexynes. It was
reported by Wittig in 1966 [120]. Since then, it was largely ignored by the synthetic chemists, and thus remained relatively underdeveloped than other related
intermediates like arynes and cyclohexynes. Depending on the ring size, the
strained 1,2-cycloalkadiene can be divided into five-, six-, and seven-membered
1,2-cycloalkadiene. Among them, 1,2-cyclohexadiene 200 is the most studied intermediate. So, in this section, mainly the preparation and reactions of
1,2-cyclohexadiene and their hetero analogues will be discussed along with the
1,2-cyclopentadiene 201 and 1,2-cycloheptadiene 202 (Scheme 9.79).
9.13.1 Generation of 1,2-Cycloalkadienes
Owing to the relatively high angle strain, five-, six-, and seven-membered
1,2-cycloalkadienes are very reactive and thus cannot be isolated and must be
generated in situ. 1,2-Cycloalkadienes can be generated by different methods.
Selected methods are discussed in this section.
9.13 Strained Cyclic Allenes
O
Me
5 steps
36 %
Me
O
Me
Me
192
157
O
O
O
KOCEt3, THF
OK
149
–78 °C to rt
Me
Me
O
Me
Me
Me
193
194
[2+2]
Cycloaddition
O
O
O
90 °C then, DBU
51%
Me
Me
Me
196
O
O
AcO
Me
Me
Me
Me
O
OH
H
Me
Me
Me
195
O
OH
O
O
O
[Fe2(CO)9], PhH
and
AcO
Me
Guanacastepene O 197
OH
O
Me
Me
Me
Guanacastepene N 198
Scheme 9.78 Synthesis of guanacastepenes O and N. Source: Based on Gampe and
Carreira [119].
200
Scheme 9.79
201
202
1,2-Cycloalkadienes.
9.13.1.1 Base-Induced 1,6-Elimination
In 1966, Wittig generated 1,2-cyclohexadiene 200 from 1-bromocyclohexene 199 and
KOt-Bu in DMSO by the 1,6-elimination of HCl. But the competitive 1,2-elimination
for the generation of cyclohexyne is the main drawback of this type of base-induced
process (Scheme 9.80) [120]. The generated 1,2-cyclohexadiene 200 could undergo
a cycloaddition to afford the [4+2] adduct 203.
397
398
9 Hetarynes, Cycloalkynes, and Related Intermediates
Ph
O
KOt-Bu
DMSO
Br
199
Ph
Ph
O
203 Ph
200
Scheme 9.80 Generation of 1,2-cyclohexadiene from 1-bromocyclohexene. Source: Based
on Wittig and Fritze [120].
9.13.1.2 Rearrangement of Cyclopropylidenes
This approach involves the rearrangement of the generated cyclopropylidenes to
the cyclic allene. When 6,6-dibromo bicyclo[3.1.0]hexane 204 was treated with
methyl lithium at low temperature, the 1,2-cyclohexadiene 200 was generated by
the rearrangement of the initially formed cyclopropylidene 205 (Scheme 9.81) [121].
Similarly, 1,2-cyclopentadiene 201 [122] and 1,2-cycloheptadiene 202 [123] were
also generated using analogous procedure.
Br
MeLi in ether
Br
–15 °C
204
200
205
Scheme 9.81 Generation of 1,2-cyclohexadiene via rearrangement of cyclopropylidene.
Source: Based on Moore and Moser [121].
This cyclopropylidene 205 can also be generated from bicyclo[3.1.0]hexanecarbonyl chloride 206 by vacuum pyrolysis at 800 ∘ C. The carbonyl chloride 206
was first converted to the ketene 207, which loses a molecule of CO to generate the
carbene 205, which, in turn, rearranges to the 1,2-cyclohexadiene 200 (Scheme 9.82)
[124].
COCl
206
FVP
O
800 °C
207
–CO
205
200
Scheme 9.82 Generation of 1,2-cyclohexadiene via pyrolysis of ketene. Source: Modified
from Wentrup et al. [124].
9.13.1.3 Fluoride-Induced Elimination
In 1990, Shakespeare and Johnson reported the fluoride-induced generation of
1,2-cyclohexadiene 200 by the 1,6-elimination of silyl bromide precursor 208
(Scheme 9.83) [125]. Similarly, 1,2-cycloheptadiene 202 can also be prepared by this
method [126].
Later in 2009 Guitián and coworkers prepared the silyl triflate precursor 210
for the mild generation of 1,2-cyclohexadiene 200. The precursor 210 can be
9.13 Strained Cyclic Allenes
Br
208
TMS
CsF
DMSO
200
Scheme 9.83 Fluoride-induced generation of 1,2-cyclohexadiene. Source: Based on
Shakespeare and Johnson [125].
prepared easily from 209 in a two-step procedure (Scheme 9.84) [127]. Recently,
Garg and coworkers reported the silyl tosylate precursor for milder generation of
1,2-cyclohexadiene 200 and 1,2-cycloheptadiene 202 [109].
O
1. L-selectride
then aq. NH4Cl
OTf
TMS
2. LDA
then PhNTf2
TMS
209
F – source
rt
210
200
Scheme 9.84 Preparation of the silyl triflate precursor of 1,2-cyclohexadiene. Source:
Based on Quintana et al. [127].
The fluoride-induced method for 1,2-cycloalkadienes is mild and base-free, and
thus compatible with various functional groups. A variety of strained cyclic allene
and heterocyclic allenes are prepared by this procedure; some examples are given
below.
9.13.1.3.1 Generation of Azacyclic Allene
In 2018, Garg and coworkers demonstrated the fluoride-induced generation of
azacyclic allene 214 from the silyl triflate precursor 213. The precursor 213 was
synthesized from commercially available 4-methoxy pyridine 211, which was
elaborated to silyl derivative 212 in few steps, followed by a 1,4-reduction and
triflation (Scheme 9.85) [128].
H
OMe
N
211
Scheme 9.85
[128].
CbzN
O
1. L-selectride
then H+ or MeI
SiEt3
2. LDA or KHMDS,
Comins' reagent
212
OTf
CbzN
R
SiEt3
R = H or Me
213
F– source
rt
CbzN
R
R = H or Me
214
Preparation of azacyclic allene precursor. Source: Modified from Barber et al.
9.13.1.3.2 Generation of Oxacyclic Allene
The silyl triflate precursor 216 to the oxacyclic allene 217 was prepared by Garg and
coworkers in 2019. It was prepared from the easily available bromo-ketone 215 in
good yields by a four-step synthetic strategy outlined in Scheme 9.86 [129].
399
400
9 Hetarynes, Cycloalkynes, and Related Intermediates
O
O
Br
215
Scheme 9.86
et al. [129].
1.DABCO,Et3SiCl
2. nBuLi, THF, –78 °C
3. LDA , THF, –78 °C
4. Comins' reagent,
THF, –78 °C to 23 °C
OTf
O
SiEt3
F– source
O
rt
216
217
Preparation of oxacyclic allene precursor. Source: Modified from Yamano
9.13.1.3.3 Generation of Cycloalkatriene
In 1990, Shakespeare and Johnson generated the 1,2,3-cyclohexatriene intermediate 219 via the fluoride-induced degradation of the cyclohexadiene precursor 218
and successfully trapped the intermediate 219 with 1,3-diphenylisobenzofuran as a
Diels–Alder cycloadduct 220 (Scheme 9.87) [126].
Ph
O
TMS
CsF
DMSO
Ph
Ph
O
OTf
218
Scheme 9.87
219
Ph
220
Generation of 1,2,3-cyclohexatriene. Source: Based on Almehmadi [126].
9.13.2 Reaction of 1,2-Cycloalkadienes
Reactions of 1,2-cycloalkadienes are not well explored as in cyclohexyne or aryne
field. These strained cyclic allenes are very good dienophiles; thus, they can be
trapped by various dienes via Diels–Alder [4+2] cycloaddition reaction. [2+2]
and [3+2] cycloadditions are also common in 1,2-cycloalkadienes. But still, this
strained intermediate has not been utilized for other types of reactions common for
similar strained intermediates like insertion reaction, multicomponent coupling,
and molecular rearrangements.
9.13.2.1 Diels–Alder Addition
The Diels–Alder reaction of 1,2-cycloalkadienes began in 1966 with the successful
trapping of the 1,2-cyclohexadiene intermediate 200 with 1,3-diphenylisobenzofuran
via a [4+2] cycloaddition reaction. Since then, a variety of dienes like furan and
cyclopentadiene have been used to trap the cyclic allenes (Scheme 9.88) [120].
In 2019, Garg and coworkers demonstrated the Diels–Alder reaction of enantioenriched cyclic allene intermediate 222 generated from the corresponding cyclic
allene precursor 221 with 2,5-dimethylfuran without any loss of enantiopurity in
the Diels–Alder cycloadduct 223 (Scheme 9.89) [126]. Here, the point chirality of
9.13 Strained Cyclic Allenes
Ph
O
Ph
Ph
O
Ph
203
200
Scheme 9.88
Fritze [120].
Diels–Alder reaction of 1,2-cycloalkadiene. Source: Based on Wittig and
the cyclic allene precursor 221 was transferred to the intermediate 222 as axial
chirality, which further relayed to the cycloadduct as point chirality.
OTf
TMS
O
O
H
O
CsF, CH3CN
rt
Me
Me
H
Me
Me
O
O
Ph
Ph
Ph
222
221
81% ee
223
81% ee
Scheme 9.89 Diels–Alder reaction of enantioenriched cyclic allene. Source: Based on
Almehmadi and West [126].
9.13.2.2 [2+2] Cycloaddition
In the absence of any trapping agents, cyclic allenes 200 dimerize via [2+2] cycloaddition reaction. Additionally, in 1970, Moore and Moser successfully trapped
1,2-cyclohexadiene with styrene in a [2+2] annulation to form the cyclobutane
derivative 224 (Scheme 9.90) [121].
Br
Br
204
Scheme 9.90
Moser [121].
MeLi in ether
–15 °C
205
200
Ph
H
224
Ph
[2+2] cycloaddition with styrene. Source: Modified from Moore and
9.13.2.3 1,3-Dipolar Cycloaddition
Until recently, cycloaddition reactions of cyclic allenes were restricted to [4+2] and
[2+2] cycloaddition only. In 2016, Garg and coworkers reported the first 1,3-dipolar
cycloaddition of 1,2-cyclohexadiene 200 with nitrones 105 leading to the synthesis of adduct 226 (Scheme 9.91) [130]. West and coworkers in 2020 demonstrated
the 1,3-dipolar cycloaddition of 1,2-cycloheptadiene with different nitrones, nitrile
oxides, and azomethine imines [126].
401
402
9 Hetarynes, Cycloalkynes, and Related Intermediates
Ph
OTf
O
CsF, CH3CN
SiEt3
200
Scheme 9.91
West [126].
N
Ph
t-Bu
N t-Bu
105
80 °C
225
H
H
226
(8.9 : 1 dr)
1,3-Dipolar cycloaddition with nitrones. Source: Based on Almehmadi and
9.14 Conclusions
With the advent of new strategies for the mild generation of hetarynes and
cycloalkynes, these intermediates are now much more accessible. Although
cycloaddition and nucleophilic addition reactions are well known in these fields,
multicomponent reactions are underdeveloped with hetarynes or cycloalkynes,
unlike aryne chemistry. Many natural products were synthesized using these in
situ–generated intermediates and more total syntheses are expected in the future
employing the hetaryne generation. It is reasonable to believe that easy generation,
compatible reaction conditions, and broad applications of these intermediate will
inspire organic chemists to find more possibilities and stimulating applications in
this field.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Stoermer, R. and Kahlert, B. (1902). Ber. Dtsch. Chem. Ges. 35: 1633–1640.
Kauffmann, T. (1965). Angew. Chem. Int. Ed. 4: 543–557.
Reinecke, M.G. (1982). Tetrahedron 38: 427–498.
Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). Synlett: 2599–2604.
Goetz, A.E. and Garg, N.K. (2014). J. Org. Chem. 79: 846–851.
Goetz, A.E., Shah, T.K., and Garg, N.K. (2015). Chem. Commun. 51: 34–45.
Roberts, J.D., Simmons, H.E., Carlsmith, L.A., and Vaughan, C.W. (1953).
J. Am. Chem. Soc. 75: 3290–3591.
Wittig, G. and Pohmer, L. (1956). Chem. Ber. 89: 1334–1351.
Huisgen, R. and Rist, H. (1954). Naturwiss. 41: 358–359.
Berry, R.S., Spokes, G.N., and Stiles, M. (1962). J. Am. Chem. Soc. 84:
3570–3577.
Chapman, O.L., Mattes, K., McIntosh, C.L. et al. (1973). J. Am. Chem. Soc. 95:
6134–6135.
Sauer, J. and Huisgen, R. (1960). Angew. Chem. Int. Ed. 72: 294–315.
Huisgen, R. and Sauer, J. (1960). Angew. Chem. Int. Ed. 72: 91–108.
Kauffmann, T., Risberg, A., Schulz, U.J., and Weber, R. (1964). Tetrahedron
Lett.: 3563.
References
15 Bordwell, F.G., Lampert, B.B., and McKellin, W.H. (1949). J. Am. Chem. Soc. 71:
1702–1705.
16 Reinecke, M.G. (1982). Five-membered hetarynes. In: Reactive Intermediates,
vol. 2 (ed. R.A. Abramovitch), 367–510. New York, Chapter 5: Plenum.
17 Conway, S.C. and Gribble, G.W. (1992). Heterocycl. 34: 2095–2108.
18 Goetz, A.E., Bronner, S.M., Cisneros, J.D. et al. (2012). Angew. Chem. Int. Ed.
124: 2812–2816.
19 Liu, J.-H., Chan, H.-W., Xue, F. et al. (1999). J. Org. Chem. 64: 1630–1634.
20 Ye, X.-S., Li, W.-K., and Wong, H.N.C. (1996). J. Am. Chem. Soc. 118:
2511–2512.
21 Reinecke, M.G., Newsom, J.G., and Chen, L.-J. (1981). J. Am. Chem. Soc. 103:
2760–2769.
22 Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). J. Am. Chem. Soc. 133:
3832–3835.
23 Julia, M., Le Goffic, F., Igolen, J., and Baillarge, M. (1969). Tetrahedron Lett. 10:
1569–1572.
24 Enamorado, M.F., Ondachi, P.W., and Comins, D.L. (2010). Org. Lett. 12:
4513–4515.
25 Hoarau, C., Couture, A., Cornet, H. et al. (2001). J. Org. Chem. 66: 8064–8069.
26 SánchezSanz, G., Alkorta, I., Trujillo, C., and Elguero, J. (2012). Tetrahedron 68:
6548–6556.
27 Nam, H.H., Leroi, G.E., and Harrison, J.F. (1991). J. Phys. Chem. 95: 6514–6519.
28 Rau, N.J. and Wenthold, P.G. (2011). J. Phys. Chem. A 115: 10353–10362.
29 Debbert, S.L. and Cramer, C.J. (2000). Int. J. Mass spectrom. 201: 1–15.
30 Bunnett, J.F. and Singh, P. (1981). J. Org. Chem. 46: 4567–4569.
31 Sparrapan, R., Mendes, M.A., Carvalho, M., and Eberlin, M.N. (2000). Chem.
Eur. J. 6: 321–326.
32 Gozzo, F.C. and Eberlin, M.N. (1999). J. Org. Chem. 64: 2188–2193.
33 Kauffmann, T., Boettcher, F., and Hansen, J. (1961). Angew. Chem. Int. Ed.
73: 341.
34 Kauffmann, T. (1962). Ann. Chem. 659: 102.
35 Van Der Plas, H.C., Woźniak, M., and Van Den Haak, H.J.W. (1983). Reactivity
of naphthyridines toward nitrogen nucleophiles. In: Advances in Heterocyclic
Chemistry, vol. 33 (ed. A.R. Katritzky), 95–146. Elsevier.
36 Kauffmann, T., Hansen, J., Udluft, K., and Wirthwein, R. (1964). Angew. Chem.
Int. Ed. 76: 590.
37 Martens, R.J. and den Hertog, H.J. (1964). Recl. Trav. Chim. Pays-Bas 83:
621–630.
38 Martens, R.J. and den Hertog, H.J. (1962). Tetrahedron Lett. 3: 643–645.
39 Fleet, G.W.J. and Fleming, I. (1969). J. Chem. Soc. C: 1758–1763.
40 Nam, H.-H. and Leroi, G.E. (1988). J. Am. Chem. Soc. 110: 4096–4097.
41 Walters, M.A. and Shay, J.J. (1997). Synth. Commun. 27: 3573–3579.
42 Kauffmann, T. and Boettcher, F.-P. (1962). Chem. Ber. 95: 949–955.
43 Zoltewicz, J.A. and Smith, C.L. (1969). Tetrahedron 25: 4331–4337.
403
404
9 Hetarynes, Cycloalkynes, and Related Intermediates
44 Furukawa, N., Shibutani, T., and Fujihara, H. (1987). Tetrahedron Lett. 28:
2727–2730.
45 Tsukazaki, M. and Snieckus, V. (1992). Heterocycl. 33: 533–536.
46 Julia, M., Huang, Y., and Igolen, J. (1967). C.R. Acad. Sci., Ser. C 265: 110–112.
47 Iwao, M., Motoi, O., Fukuda, T., and Ishibashi, F. (1998). Tetrahedron 54:
8999–9010.
48 Buszek, K.R., Luo, D., Kondrashov, M. et al. (2007). Org. Lett. 9: 4135–4137.
49 Brown, N., Luo, D., VanderVelde, D. et al. (2009). Tetrahedron Lett. 50: 63–65.
50 Buszek, K.R., Brown, N., and Luo, D. (2009). Org. Lett. 11: 201–204.
51 Garr, A.N., Luo, D., Brown, N. et al. (2010). Org. Lett. 12: 96–99.
52 Bronner, S.M., Bahnck, K.B., and Garg, N.K. (2009). Org. Lett. 11: 1007–1010.
53 Cheong, P.H.-Y., Paton, R.S., Bronner, S.M. et al. (2010). J. Am. Chem. Soc. 132:
1267–1269.
54 Im, G.-Y.J., Bronner, S.M., Goetz, A.E. et al. (2010). J. Am. Chem. Soc. 132:
17933–17944.
55 Candito, D.A., Dobrovolsky, D., and Lautens, M. (2012). J. Am. Chem. Soc. 134:
15572–15580.
56 Fang, Y. and Larock, R.C. (2012). Tetrahedron 68: 2819–2826.
57 Kauffmann, T., Boettcher, F.-P., and Hansen, J. (1962). Liebigs Ann. Chem. 659:
102–109.
58 Collis, G.E. and Burrell, A.K. (2005). Tetrahedron Lett. 46: 3653–3656.
59 Czuba, W. (1963). Recl. Trav. Chim. Pays-Bas 82: 997.
60 Van der Plas, H.C., Smit, P., and Koudijs, A. (1968). Tetrahedron Lett. 9: 9–13.
61 Tielemans, M., Areschka, V., Colomer, J., and Promel, R. (1992). Tetrahedron
48: 10575–10586.
62 Medina, J.M., Jackl, M.K., Susick, R.B., and Garg, N.K. (2016). Tetrahedron 72:
3629–3634.
63 Martens, R.J. and den Hertog, H.J. (1967). Recl. Trav. Chim. Pays-Bas 86:
655–669.
64 Kato, T. and Niitsuma, T. (1973). Heterocycl. 1: 233–236.
65 Hoye, T.R., Baire, B., Niu, D. et al. (2012). Nature 490: 208–212.
66 Niu, D., Willoughby, P.H., Woods, B.P. et al. (201). Nature 501: 531–534.
67 Niu, D. and Hoye, T.R. (2014). Nat. Chem. 6: 34–40.
68 Chen, J., Baire, B., and Hoye, T.R. (2014). Heterocycl. 88: 1191–1200.
69 Hoye, T.R., Baire, B., and Wang, T. (2014). Chem. Sci. 5: 545–550.
70 Yun, S.Y., Wang, K.-P., Lee, N.-K. et al. (2013). J. Am. Chem. Soc. 135:
4668–4671.
71 Wang, K.-P., Yun, S.Y., Mamidipalli, P., and Lee, D. (2013). Chem. Sci. 4:
3205–3211.
72 D𝚤az, M.T., Cobas, A., Guitián, E., and Castedo, L. (1998). Synlett: 157–158.
73 D𝚤az, M.T., Cobas, A., Guitián, E., and Castedo, L. (2001). Eur. J. Org. Chem.:
4543–4549.
74 Goetz, A.E. and Garg, N.K. (2013). Nat. Chem. 5: 54–60.
75 Iwayama, T. and Sato, Y. (2009). Chem. Commun.: 5245–5247.
76 Zoltewicz, J.A. and Nisi, C. (1969). J. Org. Chem. 34: 765–766.
References
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
Levine, R. and Leake, W.W. (1955). Science 121: 780.
Saito, N., Nakamura, K., Shibano, S. et al. (2013). Org. Lett. 15: 386–389.
Pareek, M., Fallon, T., and Oestreich, M. (2015). Org. Lett. 17: 2082–2085.
May, C. and Moody, C.J. (1984). J. Chem. Soc., Chem. Commun.: 926–927.
May, C. and Moody, C.J. (1988). J. Chem. Soc., Perkin Trans. 1: 247–250.
Gribble, G.W., Saulnier, M.G., Sibi, M.P., and Obaza-Nutaitis, J.A. (1984). J. Org.
Chem. 49: 4518–4523.
Sha, C.-K. and Yang, J.-F. (1992). Tetrahedron 48: 10645–10654.
Kessar, S.V., Gupta, Y.P., Pahwa, P.S., and Singh, P. (1976). Tetrahedron Lett. 17:
3207–3208.
Kessar, S.V. and Singh, P. (2001). Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 40: 1129–1131.
Huters, A.D., Quasdorf, K.W., Styduhar, E.D., and Garg, N.K. (2011). J. Am.
Chem. Soc. 133: 15797–15799.
Quasdorf, K.W., Huters, A.D., Lodewyk, M.W. et al. (2012). J. Am. Chem. Soc.
134: 1396–1399.
Styduhar, E.D., Huters, A.D., Weires, N.A., and Garg, N.K. (2013). Angew.
Chem. Int. Ed. 52: 12422–12425.
Fine Nathel, N.F., Shah, T.K., Bronner, S.M., and Garg, N.K. (2014). Chem. Sci.
5: 2184–2190.
Goetz, A.E., Silberstein, A.L., Corsello, M.A., and Garg, N.K. (2014). J. Am.
Chem. Soc. 136: 3036–3039.
Brown, N., Luo, D., Decapo, J.A., and Buszek, K.R. (2009). Tetrahedron Lett. 50:
7113–7115.
Corsello, M.A., Kim, J., and Garg, N.K. (2017). Nat. Chem. 9: 944–949.
Adams, R.D., Chen, G., Qu, X. et al. (1992). J. Am. Chem. Soc. 114:
10977–10978.
Favorskii, A.E. and Boshowskii, V. (1912). Ann. 390: 122.
Favorskii, A.E. (1936). J. Gen. Chem. USSR 6: 720.
Wittig, G. and Harborth, G. (1944). Ber. 77: 306.
Scardiglia, F. and Roberts, J.D. (1957). Tetrahedron 1: 343–344.
Wittig, G., Krebs, A., and Pohlke, R. (1960). Angew. Chem. Int. Ed. 73: 324.
Bottini, A.T., Corson, F.P., Fitzgerald, R., and Frost, K.A. II, (1972). Tetrahedron
28: 4883–4904.
Fujita, M., Kim, W.H., Sakanishi, Y. et al. (2004). J. Am. Chem. Soc. 126:
7548–7558.
Hioki, Y., Okano, K., and Mori, A. (2017). Chem. Commun. 53: 2614–2617.
Willey, F. G. (1964). Angew. Chem. Int. Ed. 3: 138.
Al-Omari, M., Banert, K., and Hagedorn, M. (2006). Angew. Chem. Int. Ed. 45:
309–311.
Wittig, G. and Krebs, A. (1961). Chem. Ber. 94: 3260–3275.
Bolster, J.M. and Kellogg, R.M. (1981). J. Am. Chem. Soc. 103: 2868–2869.
Erickson, K.L. and Wolinsky, J. (1965). J. Am. Chem. Soc. 87: 1142–1143.
Atanes, N., Escudero, S., Perez, D. et al. (1998). Tetrahedron Lett. 39: 3039–3040.
Iglesias, B., Peña, D., Perez, D. et al. (2002). Synlett: 486–488.
405
406
9 Hetarynes, Cycloalkynes, and Related Intermediates
109 McVeigh, M.S., Kelleghan, A.V., Yamano, M.M. et al. (2020). Org. Lett. 22:
4500–4505.
110 Shah, T.K., Medina, J.M., and Garg, N.K. (2016). J. Am. Chem. Soc. 138:
4948–4954.
111 Wentrup, C., Blanch, R., Briehl, H., and Gross, G. (1988). J. Am. Chem. Soc.
110: 1874–1880.
112 Tlais, S.F. and Danheiser, R.L. (2014). J. Am. Chem. Soc. 136: 15489–15492.
113 McMahon, T.C., Medina, J.M., Yang, Y.-F. et al. (2015). J. Am. Chem. Soc. 137:
4082–4085.
114 Qiu, D., Shi, J., Guo, Q. et al. (2018). J. Am. Chem. Soc. 140: 13214–13218.
115 Darzi, E.R., Barber, J.S., and Garg, N.K. (2019). Angew. Chem. Int. Ed. 58:
9419–9424.
116 Medina, J.M., McMahon, T.C., Jimenez-Ose’s, G. et al. (2014). J. Am. Chem. Soc.
136: 14706–14709.
117 Allan, K.M., Hong, B.D., and Stoltz, B.M. (2009). Org. Biomol. Chem. 7:
4960–4964.
118 Gampe, C.M., Boulos, S., and Carreira, E.M. (2010). Angew. Chem. Int. Ed. 49:
4092–4095.
119 Gampe, C.M. and Carreira, E.M. (2011). Angew. Chem. Int. Ed. 50: 2962–2965.
120 Wittig, G. and Fritze, P. (1966). Angew. Chem. Int. Ed. 5: 846.
121 Moore, W.R. and Moser, W.R. (1970). J. Org. Chem. 35: 908–912.
122 Algi, F., Özen, R., and Balci, M. (2002). Tetrahedron 43: 3129–3131.
123 Taylor, K.G., Hobbs, W.E., Clark, M.S., and Chancy, J. (1972). J. Org. Chem. 37:
2436–2443.
124 Wentrup, C., Gross, G., Maquestiau, A., and Flammang, R. (1983). Angew.
Chem. Int. Ed. 22: 542–543.
125 Shakespeare, W.C. and Johnson, R.P. (1990). J. Am. Chem. Soc. 112: 8578–8579.
126 Almehmadi, Y.A. and West, F.G. (2020). Org. Lett. 22: 6091–6095.
127 Quintana, I., Peña, D., Pérez, D., and Guitián, E. (2009). Eur. J. Org. Chem.:
5519–5524.
128 Barber, J.S., Yamano, M.M., Ramirez, M. et al. (2018). Nat. Chem. 10: 953–960.
129 Yamano, M.M., Knapp, R.R., Ngamnithiporn, A. et al. (2019). Angew. Chem. Int.
Ed. 58: 5653–5657.
130 Barber, J.S., Styduhar, E.D., Pham, H.V. et al. (2016). J. Am. Chem. Soc. 138:
2512–2515.
407
10
Hexadehydro Diels–Alder (HDDA) Route to Arynes and
Related Chemistry
Rachel N. Voss and Thomas R. Hoye
University of Minnesota, Department of Chemistry, 207 Pleasant St SE, Minneapolis, MN 55455, USA
10.1 Introduction
The hexadehydro Diels–Alder (HDDA) reaction involves the thermal generation of
benzynes by cycloisomerization of precursors having, minimally, a 1,3-diyne tethered to an additional alkyne, the latter the diynophile. In situ trapping agents then
capture the reactive benzyne. Since 2012, there has been an explosion of reports that,
collectively, demonstrate considerable generality of this process. This chapter represents an effort to highlight some of the key features of these developments. It is
not intended to be all encompassing in its scope, a task beyond the purview of this
Handbook, nor are the examples presented in chronological order. However, one of
the authors here (TRH) has recently coauthored a comprehensive review where citations to (and examples from) all reports of experimental results of HDDA reactions
(through mid-2020) are included [1]. That document is organized quite differently
from this chapter; there, reactions are categorized according to the types of new
bonds that are formed during each known mode of trapping process. Interested readers are directed to that resource for details beyond those captured here. Finally, the
topics presented in this chapter are somewhat randomly organized, so readers might
want to scan the headers and/or figure graphics to identify those items of greatest
interest.
10.2 History
10.2.1 Overview of the Family of Dehydro-Diels–Alder Reactions
The Diels–Alder (DA) reaction is one of the most venerable of all chemical transformations. The DA transformation is ubiquitous, being the subject of myriad
synthetic and mechanistic studies since being first reported [2]; for example,
SciFinder® records over 16 600 publications having “Diels” + “Alder” in their titles.
In the example introduced in most textbooks of elementary organic chemistry, the
conjugated diene 1,3-butadiene engages the dienophile ethylene to produce the
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
408
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
[4+2]
H
H
H
H
(a)
H H
H H
H
[4+2]
H
H
[4+2]
C6H8
(b)
H
H
H
[1,5]
H
H
H
H
H
H
•
•
H
H
C6 H6
H
H
H
H
H
C6H6
(c)
(d)
H
H H
H H
•
•
H
H H
C6H10
[4+2]
H
H
•
•
H
H
H
H
•
•
Trap
H
C6H4
Figure 10.1 Diels–Alder reactions of progressively less saturated pairs of 4π- and
2π-components. (a) Diels–Alder, (b) didehydro-Diels–Alder, (c) tetradehydro-Diels–Alder,
and (d) hexadehydro-Diels–Alder.
cyclic six-membered hydrocarbon cyclohexene (Figure 10.1a). Pairwise removal
of dihydrogen (i.e., formal oxidation) from these prototypical reactants leads to
cyclic products having progressively higher oxidation states (i.e., higher degrees of
unsaturation). Collectively, these are recognized as dehydro-Diels–Alder reactions
[3]. The most highly oxidized variant (Figure 10.1d) corresponds to the reaction
between 1,3-butadiyne and, as a diynophile, ethyne. But this transformation is
unique compared with the others of intermediate levels of oxidation, because it
would produce the hydrocarbon o-benzyne (C6 H4 ), a well-known (and highly
versatile) reactive intermediate that can only be observed under conditions where it
does not encounter other reaction partners (e.g., in the gas-phase [4], in inert frozen
matrices [5], or inside a protective cavitand [6]).
10.2.2 First Example of a Tetradehydro-Diels–Alder (TDDA) Reaction
The first example of what today can be recognized as a dehydro-Diels–Alder
reaction was reported in 1898 (Figure 10.2) [2a]. Phenylpropiolic acid (1), when
refluxed in acetic anhydride, gave the naphthalene derivative 3, as recognized today
10.2 History
H
1
Ac2O
Δ
1
COOH
COOH
O
O
H
O
O
2
O
H 3
O
Figure 10.2 First example, from 1898 [2a], of what today can be termed a
tetradehydro-Diels–Alder (TDDA) reaction. Source: Michael et al. [2a].
by way of the intermediate strained allene 2. Interestingly, this work predates the
initial report of Diels and Alder of reactions between dienes and dienophiles by
three decades! [2b] Many dehydro-Diels–Alder reactions have been described in
the intervening century, and this body of work is captured in the comprehensive
review by Müller in 2008 [3].
10.2.3 Earliest Triyne to Benzyne Cycloisomerization (i.e., HDDA)
Reactions
The earliest experimental evidence that clearly established the viability of the
transformation of a conjugated diyne with a third alkyne [7] to produce a benzyne
intermediate was reported more or less simultaneously in 1997 in two independent
studies carried out in the laboratories of Johnson at New Hampshire and Ueda
at Osaka [8]. These are summarized in Figures 10.3a,b, respectively. Johnson and
coworkers carried out the flash vacuum pyrolysis of 1,3,8-nonatriyne (4) [8a], the
prototypical substrate for an intramolecular cyclization of the type introduced in
Figure 10.1d. This resulted in a highly efficient transformation to indene (6), indane
(7), and “some soot.” Indene is at the same oxidation state as the triyne substrate
4 and indane is reduced by one unsaturation unit. On the basis of both computations of the parent butadiyne plus ethyne reaction and a deuterium-labeling
study, the researchers demonstrated that this transformation in all likelihood
proceeded through the indanyne 5. In the initial Ueda report, the tetrayne 8
gave rise, at room temperature, to the pair of anthracene-trapped products 11
and 12, which were proposed to arise by capture of the “1,2-didehydrobenzene
diradicals” 9 and 10, respectively [8b]. The Ueda team proceeded to investigate
a number of related systems over the next decade, nearly always with an eye
toward studying the DNA-cleaving potential of these reactive intermediates as
analogs of the Bergman 1,4-diradical species (and the enediyne family of natural
products) [9].
Subsequently, the Sterenberg group at Regina in 2004 reported the interesting,
unusual transformation of the dinuclear, mixed metal complex 13 (Figure 10.3c)
[10]. At ambient temperature in a solution of tetrahydrofuran (THF), this gave rise
to the bridged benzene derivative 15. THF was identified as the source of the hydrogen atoms delivered to the intermediate 14 by using THF-d8 .
409
Δ
580 ºC
6
5
4
7
(a)
Ph
TMS
TMS
Ph
TMS
HO
HO
Ph
TMS
TMS
Ph
HO
PhH
HO
rt
•
•
HO
9
8
•
10
•
11
:
12
(72%) : (8%)
(b)
Ph2P
PPh2
PtCl2
(OC)5W
Ph2P
(c)
PPh2
13
THF
rt
Ph2P
Ph2
P PtCl
(OC)5W
PPh2
Ph2P
14
Ph2P
2
Ph2
P PtCl
(OC)5W
2
PPh2
Ph2P
15
Figure 10.3 Earliest examples of triyne cycloisomerizations to benzynes. (a) Johnson flash vacuum prolysis of 1,3,8-nonatriyne, (b) Ueda trapping of
"1,2-didehydrobenzene diradical" with anthracene, and (c) Sterenberg metal-templated [4+2] cycloaddition.
10.2 History
10.2.4 First Minnesota Examples (and the Naming) of the “HDDA”
Reaction
Our initial foray at Minnesota into this class of reaction arose unintentionally [11].
In 2011, a researcher here attempted to prepare the enynone 17 (by oxidation of
the alcohol precursor 16) but observed that the unexpected, isomeric tricyclic compound 19 had formed instead. We surmised that this ambient-temperature cycloisomerization reaction, occurring in the setting of the fortuitous presence of a silyl ether
substituent, had proceeded by way of the benzyne 18, an isomer of 17. This transformation initiated a focused effort to explore additional aspects of this reaction. Our
first designed substrate, the enone 20, smoothly and spontaneously converted into
the isomeric indenone derivative 22 (via 21) as the only observed product. This reaction was measured to have a half-life of c. seven hours at ambient temperature. Even
in this first example, a new type of aryne-trapping reaction, captured by a nucleophilic silyl ether [12], had been revealed. This was the first of many previously
unknown types of reaction whose discovery has been enabled by the reagent-free,
thermal reaction conditions used for generation of HDDA-benzynes.
This cycloisomerization was quickly established to have considerable generality [13]. In the initial 2012 report [11], the nomenclature of the broader
“dehydro-Diels–Alder” terminology was parsed into subcategories that reflect the
specific degree of oxidation of the alkenes/alkynes participating in the net [4+2]
cycloaddition leading to six-membered carbocycles. Thus, didehydro-Diels–Alder,
tetradehydro-Diels–Alder (TDDA), and HDDA reactions, all variants on the classic textbook Diels–Alder (hereafter, DA) cycloaddition, reflect the progressively
increased degrees of unsaturation of the reactants and products (cf. Figure 10.1).
Various examples of our first HDDA reactions (Figure 10.5) demonstrated that
the 1,3-diyne and diynophile partners needed to be tethered, nearly always, by a
R1
R2
CH2OTBS
OTBS
OTBS
O
O
OTBS
16 R1 = H, R2 = OH
17 R1,R2 = = O
MnO2
rt
O
OTBS
19 (53%)
18
rt
TBS
(a)
O
TMS
rt
t1/2 = 7 h
O
O
TMS
OTBS
(b)
20
TBSO
21
TMS
O
TBS
22 (94%)
Figure 10.4 (a) The unanticipated transformation leading to the recognition that the
HDDA reaction was general and (b) the first (at Minnesota) designed substrate launching
that eventuality.
411
412
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
A
B
R
diyne
(TsN)O
23a
23
23b
23c
23d
O
R
(b)
O
AcO
MeO2C
MeO2C
(PhN)O
TsN
C
(a)
O
O
Diynophile
23e
O
23f
O
O
O
R
R = SiR′3 or H
H
H
H
Benzene
Norbornene
PhNHAc
H
OAc
(c)
AcOH
H
H
Phenol
H
N
Ph
Ac
HO
Figure 10.5 (a) Examples of three-atom tethers (ABC) that enable the HDDA
cycloisomerization; (b) examples of intramolecular trapping reactions; (c) examples of
intermolecular trapping reactions. Source: Hoye et al. [11a]; Baire et al. [11b].
three-atom linker (cf., ABC in 23, Figure 10.5a; one substrate had a five-atom linker).
Benzyne formation is always the rate-limiting event. The subsequent trapping of
the reactive benzyne intermediate, whether intramolecular (Figure 10.5b) or intermolecular (Figure 10.5c) in nature, is always a fast, subsequent step. Substrates 23
vary in the ease with which they isomerize to the initial benzyne intermediate. Reactions were typically performed between 85 and 120 ∘ C for one to two days to reach
>95% consumption of the triyne, although it should be noted that the rate of the
HDDA reaction is also dependent on the nature of the substituent R on the terminus of the diynophile. Most dramatic in that regard, when R is an alkynyl group in
tetrayne substrates with the linkers shown in 23a, the cyclization temperature was
reduced from 110 to 65 ∘ C to achieve a comparable rate of conversion [14].
10.3 Early Demonstration of New Modes of
Aryne-Trapping Reactivity: Ag- and B-Promoted Carbene
Chemistry
In another early study in this emerging field, researchers in the laboratory of
Daesung Lee at Illinois, Chicago, demonstrated novel carbene-like reactivity in
HDDA benzynes [15]. For example, when the symmetrical tetrayne 24 was heated in
the presence of various silver(I) salts, the cyclopentanoisoindoline derivative 26 was
efficiently generated. This outcome was rationalized by invoking an intramolecular
10.4 De novo Construction of Arenes
n
n
n
Bu
Bu
Bu
n
Bu
AgOTf
TsN
n
Bu
toluene
90 ºC
TsN
TsN
TsN
H
Et
Ag
24
Et
H
26 (96%)
Ag
25
Et
(a)
O
TBS
O
toluene
120 ºC
(b)
27
TBS
O
TBS
O
BF3•OEt2
TBS
H
BF3
BF3
28
H
29 (82%)
Figure 10.6 (a) Ag(I) promotion of carbene reactivity (C–H insertion) within an
HDDA-benzyne. (b) The first instance of boron activation of a vicinal dicarbene.
CH-insertion within the silver carbenoid 25. In a related overall transformation,
Shen et al. recently showed that the triyne 27 produced the tetracyclic product 29,
but this process was effected by the action of boron trifluoride etherate [16]. Lewis
acidic boron reagents were not previously known to induce carbene-like behavior;
thus, this represents another example in which benzynes produced thermally
by the HDDA reaction have allowed the discovery of new modes of reactivity.
Computational support for boron-benzyne adducts like 28 was also provided
(Figure 10.6).
10.4 De novo Construction of Arenes: A New Paradigm
for Synthesis of Highly Substituted Benzenoid Natural
Products
The de novo nature of arene construction via HDDA reactions provides a strategically unique approach for the chemical synthesis of certain benzenoid natural products. This new paradigm is exemplified by the key event used to construct the arene
in the target structures in Figure 10.7. In the first, herbindole B (35, Figure 10.7a), the
HDDA reaction of 30 gives the net HBr addition product 31 with methylene bromide
serving as the source of those atoms. Notable about the synthesis is the manner in
which the various sites on this initial HDDA product are manipulated to reveal (i) the
ethyl and methyl groups (31 to 32), the atoms required for the cyclopentannulation reaction (32 to 34 via 33), and the ultimate oxidation of indoline to indole in
herbindole B (35) [17].
The fluorene core of selaginpulvin C (39) [18] was efficiently created by the facile
cyclization of the tetrayne 37, prepared in situ by the MnO2 oxidation of alcohol 36
(Figure 10.7b). The fluorenone 38 was readily elaborated to the quaternized fluorene
in 39.
413
414
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
OH
OH
TMS
Grubbs II
CH2Br2
TMS
80 °C
N
Ts
NTs
Steps
N
Ts
(iii) TBAF
(iv) Sonogashira
Sonogashira
31
30
(a)
Br
(i) NaOH
(ii) H2, PtO2
NH
R
32 R = Br
[O]
33 R =
CH(Me)OAc
34 (indoline)
35 (indole)
Herbindole B
OMe
OH
OH
R1
R2
OMe
HO
O
MeO
TMS
MnO2, rt
36 R1 = H; R2 = OH
37 R1,R2 = =O
(b)
Me
TMS
rt
H
MeO
HO
H
38 (59%)
Cyclooctane
Selaginpulvilin C, 39
TMS
O
H
TMS
TsN
(c)
Me
40
41
DCE, 100 °C
R = prenyl
R2
Me
R
N
Ts
Me
4π-opening
N
O
6π-closure
42
R
TBAF, THF
80 °C (91%)
O
R1
43 R1 = Ts; R2 = TMS (89%)
mahanimbine, 44 R1 = R2 = H
Figure 10.7 Strategic advantage of de novo arene ring construction demonstrated in
syntheses of (a) herbindole B, (b) selaginpulvin C, and (c) mahanimbine.
A third example is seen in the synthesis of the carbazole-containing alkaloid
mahanimbine (44) [19]. The diynamide 40, when heated in the presence of citral
(41), gave rise to a carbazolyne that was trapped in a net [2+2] reaction with the
carbonyl group to produce the benzoxetene intermediate 42. Under the reaction
conditions, this proceeded through consecutive electrocyclic ring-opening (4π) and
-closing (6π) events [20] to produce the pyranocarbazole 43 in a notably efficient
fashion (89%).
10.5 Diradical Mechanism of the HDDA
Cycloisomerization of Triyne to Benzyne
The mechanism of the HDDA cycloisomerization of three alkynes to a benzyne
has been studied computationally as well as experimentally. Both concerted and
stepwise pathways, the latter by way of a (delocalized) diradical intermediate, are
worthy for consideration. In fact, computations suggest that, depending on the
exact pair of reacting species, these can have quite similar energies of activation
[8a, 21]. The computed activation barriers typically range from c. 30–40 kcal mol−1 .
10.5 Diradical Mechanism of the HDDA Cycloisomerization of Triyne to Benzyne
R
R
Toluene-d8
N
Ts
TBSO
110 °C
HDDA
R
N
Ts
•
TBS
45a-g
O
R′
O
46a-g
R
CF3
H
CONEt2
CO2Me
COEt
~krel
0.67
1
4.7
43
80
490
CHO
–CMe 1,500
C–
–
Slow
Fast
R
[4π + 2π]
classical DA
RSE
R
+1.9
0
–4.9
–4.9
–6.7
–7.7
–12.1
–CMe
C–
–
H
CONEt2
CO2Me
COEt
CF3
CHO
COR′
R′ = n-heptyl
~krel
0.1
Slow
1
5
84
210
1,680
4,700 Fast
σp
0.03
0
0.26
0.34
0.34
0.54
0.42
Figure 10.8 Impact of substituents on rates of HDDA reactions (of 45) vs. classical DA
reactions (of 46) of alkynyl diynophiles and dienophiles, respectively. (RSE = radical
stabilizing energy). Source: Modified from Wang et al. [22].
Whether the diradical or concerted mechanism is energetically favored depends
on the nature of the linker group, ABC. To the extent it has been explored, the
exact computational method used appears to have a relatively minor effect on that
conclusion. Importantly, and somewhat surprisingly at first glance, the overall free
energy change that accompanies the conversion of triyne to benzyne is downhill
c. 40–50 kcal mol−1 – that is, the HDDA cyclization is a rare example of a highly
exergonic transformation that gives rise to a highly reactive intermediate! The
nature of the substituent at the terminus of the diynophile also significantly impacts
the ease of the reaction. A bystander alkyne, the presence of which is, perforce, the
case for tetraynyl HDDA substrates (tethered bis-1,3-diynes), is computed to be a
particularly effective activator [21f, j].
To distinguish between a diradical vs. a concerted cycloisomerization pathway
experimentally, Wang et al. designed a study in which the impact of various substituents at the terminus of the diynophile was examined (Figure 10.8) [22]. The
relative rates of reaction for these triynes (45a–g) were found to correlate with resonance stabilization energies (RSE) significantly better than for the Hammett σp
values (i.e., cation stabilization) for each substituent. Conversely, the rates of classical [4+2] Diels–Alder cycloaddition reactions of 46a–g, in which the dienophile was
substituted with the same set of substituents as in the triyne substrates 45, showed
an expected response to the electron-withdrawing strength of the substituents. In
the two most extreme examples, the CF3 and 1-propynyl groups showed a dramatic
rate-enhancing and -diminishing effect, respectively, on the HDDA reactions of 45,
just the opposite of their impact on the DA reactions of 46. This is strong evidence
in support of a stepwise cycloisomerization pathway in which radical stabilization
is much more important than simple electronic perturbation and highest-occupied
molecular orbital (HOMO)/lowest-unoccupied molecular orbital (LUMO) interaction, as is true of concerted DA reactions.
415
416
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
10.6 Additional Contributions from the Lee Group
(University of Illinois, Chicago (UIC))
Researchers at UIC have made many additional (cf. Figures 10.6a and 10.7a,b, above)
important contributions to the body of HDDA chemistries. Some of the most prominent are summarized in Figure 10.9. In each instance, a key feature of the trapping
event is indicated in brackets. They demonstrated in 2013 that not only would Ag(I)
promote C–H insertion reactions with appropriately tethered alkanes (Figure 10.6a),
but that alkenes would efficiently participate in Alder-ene processes (e.g., 47 to 48,
Figure 10.9a) [23a–c] and that fluorination (and trifluoromethylation) of the benzyne could also be achieved (e.g., 49 to 50, Figure 10.9b) [23d]. They established
that various nucleophiles (e.g., amines [49 to 51] in Figure 10.9c) will trap the thermally generated benzynes [23e, f]. They also showed that acetonitrile would engage
the electrophilic benzyne in Ritter-type reactions, leading to benzamide derivatives
(e.g., 49 to 52, Figure 10.9d) [23g]. In another recent advance, they reported a remarkable dearomatization reaction that used the high potential energy of the aryne to fuel
the otherwise energetically unlikely transformation shown by the example of 53 to
54 in Figure 10.9e [23h]. Most recent of all, isocyanides, in the presence of various
weak acids, were shown to trap the benzynes derived from a variety of tetraynes
related to 49 (cf. 49′ ) to give 55 [23h].
10.7 Additional Notable Modes of Aryne Reactivity
10.7.1 HDDA Benzynes as Dienophiles in Diels–Alder [4𝛑+2𝛑]
Cycloaddition Reactions with Aromatic Dienes
Ever since the pioneering studies of Wittig (trapping of o-benzyne by furan) [24],
arynes have long been recognized for their effectiveness in engaging a wide variety of
dienes; especially notable are those cases where the thermodynamics of the cycloaddition might otherwise be unfavorable, as is often the case with DA cycloadditions
of furan or simple benzene derivatives. HDDA reactions culminating with such
reactions are known. In addition to Ueda and coworkers trapping with anthracene
(11 and 12, Figure 10.3b [in benzene solution, incidentally]), they demonstrated
that benzene itself, in the absence of another sufficiently reactive trapping agent,
would engage the benzyne 57 (56 to 58, Figure 10.10a) [25]. Bimolecular reactions
with substituted furans (59 to 60, Figure 10.10b) [26] as well as intramolecular
trapping of arenes, including naphthalenes (61 to 62, Figure 10.10c) [27], are also
possible. N-Methyimidazole gives rise to [4+2] adducts such as 63 that undergo
further fragmentation and oxidation to benzomaleimides (64, Figure 10.10d) [28].
10.7.2
Trapping of Natural Products: Phenolics
Some remarkable levels of selectivity were revealed by a study in which HDDAbenzynes were generated in the presence of multifunctional natural products
10.7 Additional Notable Modes of Aryne Reactivity
n
nBu
Bu
n
Bu
10 mol %
Ag(OTf)2
TsN
NTs
NTs
NTs
Toluene
90 ºC
N
Ts
N
Ts
H
48 (93%)
47
(a)
TMS
TMS
150 mol%
AgBF4
TMS
TsN
TMS
49
Toluene
90 °C
TMS
TMS
TsN
TsN
F
BF4–
Ag
(b)
50 (85%)
TMS
NEt3
TMS
TsN
TMS
49
Toluene
90 °C
TMS
TMS
TMS
TsN
TsN
H
H
NEt2
Et2N
51 (80%)
(c)
TMS
TMS
TMS
TsN
TMS
49
10 mol%
AgSbF6
H2O
TMS
MeCN
10 equiv H2O
90 °C
TMS
TsN
TsN
NH
N
Ag
Me
O
52 (78%)
(d)
n
n
Bu
10 mol%
AgOTf
N
O2S
OAc
Br
CF3
53
n
Bu
Toluene
90 °C
Bu
OAc
N
O2S
Br
H
OAc
N
O2S
H
CF3
Me
H
H
Br
CF3
54 (76%)
(e)
Figure 10.9 Highlights of contributions from the Lee group (University of Illinois,
Chicago). (a) Alder-ene. Source: Karmakar et al. [23a]; Gupta et al. [23b]; Gupta et al. [23c],
(b) silver-mediated fluorination. Source: Modified from Wang et al. [23d], (c) amine
(nucleophile) trapping, (d) Ritter-type transformations. Source: Modified from Ghorai and
Lee [23g], (e) arene dearomatization by HDDA benzynes. Source: Modified from Karmakar
et al. [23h], and (f) isonitrile trapping gives products complementary to those of the
Ritter-type (d, above).
417
418
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
R1
R1
C
R1
N
R1
R2
H–Nu
R1
Toluene
150 °C
X
R1
X
X
N
NR2
R2
H
49′
Nu
55
(f)
Figure 10.9
(Continued)
TMS
TMS
O
TMS
S
S
RT
(a)
S
S
56
57
O
H
EtO2C
O
CO2Et
OAc
O
O
CO2Et
CO2Et
CO2Et
59
EtO2C
O
TMS
O
60 (61%)
O
TMS
O
TMS
O
CDCl3
(c)
OAc
O
O
1,2-DCB
140 ºC
OAc
58 (90%)
O
O
O
(b)
S
O
S
O
O
85 ºC
62 (89%)
61
Ph
Me
Ph
N
i
PrO2C
iPrO
(d)
2C
Ph
Ph
Toluene
O2
100 ºC
Ph
i
N
i
Ph
PrO2C
2C
Me
iPrO
PrO2C
i
PrO2C
N
63
N
64 (87%)
O
O
N
Me
Figure 10.10 Examples of Diels–Alder trapping of often inert, aromatic “dienes” by HDDA
benzynes. (a) Benzene DA reaction, a rare event. Source: Modified from Kawano et al. [25],
(b) substituted furan trapping. Source: Based on Chen et al. [26], (c) intramolecular capture
by a naphthalene. Source: Modified from Pogula et al. [27], and (d) imidazole capture,
fragmentation, and oxidation. Source: Based on Hu et al. [28].
10.7 Additional Notable Modes of Aryne Reactivity
TMS
O
TMS
O
O
TMS
PhH
85 ºC
H
65
66
TMS
O
Me
Me
H
Me
Me Phenol
H
O
O
67 (79%)
HO
(a)
Me
Me
Me
Me
Me
O
HO
Me
Me
85 ºC
Vitamin E
Me
N
Ms
R
PhH
Me
N
Ms
R=
68
H
O
69a (47%) Me
N
N
DABCO
vit.
E
R
Me
Me
Me
O
Me
N
Ms
Me
O
R
O
R
H
O
69b (35%) Me
Me
O
Me
PhH
85 ºC
N
Ms
Me
N
N
Ms
Me
H
N
70
(b)
Me
Me
O
N
Me
H
N
71 (79%)
R
Me
O
Me
D
N
C
MeO
68 +
MeO
H
H
H
Me
NMs
O
N
O
brucine
Me OH
C
85 °C
H
HO
(c)
Ar
estradiol
N D
O
ArOH
Me
N D
ArO
N
H
H
Me
H
Me
PhH
NMs
N
O
H
MeO
OMe
72
O
O
MeO
OMe
73 (52%)
Figure 10.11 Examples of (notably chemoselective) reactions of HDDA benzynes with
multifunctional, phenolic natural products. (a) Phenol-ene-like reaction. Source: Modified
from Zhang et al. [30], (b) Vitamin E, and (c) three-component reaction with brucine and
estradiol
possessing numerous potential sites for reaction [29]. Phenol itself has been
shown to react with HDDA benzynes by way of an ene-type process portrayed in 66
(65 to 67, Figure 10.11a) [30]. Even the fully substituted phenolic ring in vitamin E is
efficiently captured by the benzyne to provide the dearomatized cyclohexadienones
69 from 68 in excellent combined yield (Figure 10.11b). However, if a trapping agent
more reactive than phenol, 1,4-diazabicyclo[2.2.2]octane (DABCO) in the case of
formation of 71, is also present, then a staged three-component reaction intervenes.
That is, the role of the phenol in vitamin E is completely diverted to produce the
dabconium phenoxide ion pair 70, which then proceeds to 71. In a reaction of yet
419
420
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
greater complexity, the two natural products brucine and estradiol were trapped, in
sequence, via the 1,3-zwitterion 72 from capture of the benzyne by the alkaloid’s
aliphatic nitrogen atom, only then to abstract the more acidic phenolic proton in
estradiol en route to the product 73 (Figure 10.11c).
10.7.3
Trapping of Natural Products: Colchicine and Quinine
Colchicine traps the benzyne from 68 in an unprecedented fashion, engaging the
carbonyl oxygen in a net (3+2) cyclization to the tropylium ion-like zwitterion
74 that proceeds to product 75 (Figure 10.12a). In perhaps the most dramatic
example of a selective cyclization, quinine, in which 11 different potential sites of
reactivity can be envisioned, proceeds by largely one pathway to 77, presumably
via the zwitterion 76 (Figure 10.12b). Collectively, these results underscore an
often-overlooked important adage – namely that highly reactive is not a synonym for unselective [31]. Thus, even though the cycloisomerization of triyne to
benzyne is the rate-limiting step in HDDA reactions, there still is considerable
selectivity expressed in the product-determining manifold of potential competing
pathways.
Me
Me
O
OMe
68
+
OMe
Me
Me
AcHN
PhH
85 °C
N
Ms
AcHN
O
OMe
Close and
N
Ms
AcHN
O
OMe
1,5-H shift
OMe
MeO
OMe
OMe
Colchicine
74
(a)
OMe
75 (58%)
MeO
OMe
MeO
Me
Me
N
68 +
MsN
N
N
Me
N
MeO
N
OMe
Quinine
Me
85 °C
OH
(b)
MsN
PhH
O
76
OMe
O
77 (49%)
Figure 10.12 Additional examples of (notably chemoselective) reactions of HDDA
benzynes with multifunctional natural products. (a) Reactions of HDDA benzynes with
colchicine and (b) reactions of HDDA benzynes with quinine.
N
10.8 New Reaction Modes and New Mechanistic Understanding
10.8 New Reaction Modes and New Mechanistic
Understanding
10.8.1 Three-Component Reactions
Trapping of arynes with a pair of complementary and suitably coordinated reactants,
processes amounting to three-component reactions, is well established [32]. Not
surprisingly, similar reactions can be identified for the thermally produced HDDA
benzynes, although the types of compatible coreactants that can be orchestrated
to perform can often be different from, and complementary to, those that succeed
with classically produced benzynes. Cyclic aliphatic amines generate zwitterionic
species upon their initial addition to the benzyne (cf. the DABCO in Figure 10.11b).
In the presence of protic acids, these can be protonated and ring-opened (e.g., 78
to 80 via 79, Figure 10.13a) [33]. By a similar process, heteroaromatic amines of
the pyridine family generate pyridinium-like zwitterions (cf. 82) that can then be
Bn
N
Me
Ph
Me 1.5 equiv
MsN
Me
78 (69%)
Me
Bn
MsN
PhH
85 °C
PhO–
Me
N
Me
MsN
O
Ph
79 (69%)
OPh
N
Bn Ph
80 (70%; : = 3:1)
(a)
TMS
O
MeO
Me
TMS
O
TMS
O
Me
Me
PhH
81
85 °C
+
OMe Quinoline
+
PhNCO
MeO
MeO
O
MeO
C
82
O
MeO
N
Ph
C
N
H
83 (91%)
(b)
NO2
S
O
TMS
2.5 equiv
HN
Me
PhH
90 °C
Me
84
O
NO2
TMS
O
HN
CN
S
Me Me
4.4 equiv
HN
Me Me
85
TMS
S
3
CN
86 (69%)
(c)
Figure 10.13 Examples of three-component reactions of HDDA benzynes. (a) Aliphatic
cyclic amines (here, aziridine) and protic nucleophiles (here, phenol). Source: Modifiied
from Ross and Hoye [33], (b) pyridinyl aromatics (here, quionline) and electrophiles (here,
phenylisocynate). Source: Modified from Arora et al. [34], and (c) sulfide (here,
tetrahydothiophene) and carbon nucleophile (here, p-nitrophenylacetonitrile). Source:
Modified from Chen et al. [35].
421
422
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
captured by various electrophiles, including ketones and aldehydes, electron-poor
alknyes and alkenes, and isocyanates (e.g., 81 to 83 via 82, Figure 10.13b) [34]. In
a third example, cyclic sulfides generate zwitterions that undergo intramolecular
proton transfer to produce transient sulfonium ylides, which then can engage,
for example, suitable acidic carbon-based protic acids (e.g., 84 to 86 via 85,
Figure 10.13c) [35].
10.8.2 Dihydrogen Transfer Reactions
HDDA-benzynes allowed the discovery of an unprecedented, concerted removal of
two hydrogen atoms from vicinal H–CX–H arrays (X = C or O). Thus, dihydrogen
transfer to benzynes 87, 90, or 93 was seen when each was generated in the
presence of cyclic hydrocarbons (e.g., 65 to 88, Figure 10.14a) [36], cyclic ethers
(cf. Figure 10.3b [10] and, e.g., 89 to 91, Figure 10.14b [36]), or primary or secondary
alcohols (e.g., 92 to 94, Figure 10.14c) [37]. Both experimental and computational
studies indicate that these redox processes proceed through previously unrecognized, concerted transition-state structures. For example, when 89 was heated in
a solution of equimolar amounts of THF-h8 and THF-d8 , only nondeuterated and
O
TMS
TMS
Me
TMS
O
Me
O
Me
H
90 ºC
H
H
65
H
88 (97%)
+ cyclooctene
87
(a)
H/D
H/D
O
O
TMS
89
O
R
H/D
TMS
O
H/D
90 °C
50:50
THF-h8
THF-d8
AcO
TMS
O
90
H/D OAc
H/D
91 (75%; h2:d2 = 6:1; no hd)
(b)
OH
H
O
TMS
O
nPr
(c)
TMS
δ+
TMS
92
O
nPr
0.013 M
CDCl3
85 °C
δ–
(H or)D
O
93
H(or D)
n
Pr
H(or D)
(H or)D
94 (60%)
+ cyclohexanone
Figure 10.14 Various dihydrogen-transfer reagents reduce the benzyne by concerted
processes. (a) H2 transfer from hydrocarbons. Source: Modified from Niu et al. [36], (b) H2
transfer from THF. Source: Modified from Niu et al. [36], and (c) H2 transfer from alcohols.
Source: Modified from Willoughby et al. [37].
10.8 New Reaction Modes and New Mechanistic Understanding
O
O
TMS
TMS
O
CHCl3
TMS
O
O
85 °C
O
95
H
H
96
97 (88%)
(a)
OTES
Et3SiO
OTES
CDCl3
TsN
65 ºC
98
TsN
TsN
O
SiEt3
Et3SiO
O
SiEt3
100 (91%)
99
(b)
TMS
O
Me
F3C
MeO
OMe
cycloadd
then
S
loss of MeO
H2C=CH2
MeO
Et2N
MeO
81
CF3
101
O
Me
NEt2
C6H6
90 °C
MeO
TMS
O
S
TMS
Me
S
EtN
CF3
102 (68%) H
(c)
Ph
TMS
O
Me
Me
81
TMS
O
TMS
Me
Me
Me
C6 H 6
90 °C
MeO
O
HN N
MeO
MeO
H
103
N
N
Ph
Me
Me
MeO
MeO
H
N
N
104 (99%)
Ph
Me
Me
OMe
(d)
Figure 10.15 Additional examples of new classes of aryne-trapping reactions. (a) The
aromatic ene reaction. Source: Modified from Niu and Hoye [39], (b) trapping by silyl ethers,
(c) atypical [3+2]-cycloaddition, (d) diaziridine trap. Source: Modified from Arora et al. [41].
dideuterated forms of 91 were observed, consistent with the simultaneous transfer
shown in 90 rather than a stepwise net H2 -transfer that would be involved if hydrogen atom abstraction were the first step. The alcohol-mediated redox reactions are
effective at low concentrations of the alcohol; at higher concentrations, addition of
the RO–H to produce ArOR ethers occurs via a purported concerted addition of an
alcohol dimer to the benzyne [37]. As depicted in 93, the monomeric alcohol reacts
in a regioselective manner, as established by complementary deuterium-labeling
studies; the C–H can be viewed to add in hydride-like fashion to the more electrophilic benzyne carbon [38] and the O–H as a lagging proton-like donation to the
more electron-rich carbon [37].
10.8.3 Aromatic ene, Silyl Ether, Thioamide, and Diaziridine Reactions
Other examples of new types of reaction or of new mechanistic insights are shown
in Figure 10.15. First, a properly poised benzylic hydrogen atom, as in the triyne
423
424
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
substrate 95, is able to be transferred in a rare type of dearomatizing ene reaction.
The TS 96 capitalizes on that arrangement to produce, following rearomatization,
the pentacyclic 97 (Figure 10.15a) [39]. The initial ene product, an intermediate
isotoluene, is sufficiently long lived that it can also be captured if Alder enophiles
are present in the reaction medium (not shown). The length of the tether connecting
the pendant arene to diyne is critical, as demonstrated by those having less ideally
situated arenes, which undergo competitive [4+2] cycloadditions with the pendant
arene itself (cf. Figure 10.10b). Second, in the serendipitous observation of HDDA
cycloisomerization of 17, a silyl ether was fortuitously poised to intercept the benzyne, producing an aryl silane. This formal O—Si bond insertion reaction (cf. 18
to 19 and 21 to 22, Figure 10.4) was previously unknown for arynes. Density functional theory (DFT) analysis suggests that the energetics for a stepwise process via
a zwitterion such as 99 (Figure 10.15b, in the conversion of 98 to 100) vs. a concerted, single-step insertion of the benzyne directly into the silyl ether proceed with
comparable activation energies [12]. Third, an unprecedented, pseudo-1,3-dipolar
cycloaddition process (cf. 101) was discovered when the benzyne was generated in
the presence of thioamides (e.g., 81 to 102, Figure 10.15c). Fourth, diaziridines, long
known to react with simple electron-deficient alkynes [40], captured an HDDA benzyne to produce ring-cleaved hydrazones in a mechanistically similar fashion (e.g.,
81 to 104, Figure 10.15d) [41]. Interestingly, the more substituted nitrogen atom of
the diaziridine selectively engages the electrophilic benzyne sp-carbon (cf. 103). One
can think of the large potential energy of the strained formal triple bond in the aryne
as the thermodynamic fuel that drives these atypical types of reaction.
10.9 New Routes to Polycylic, Highly Fused Aromatic
Products
10.9.1 Naphthynes via Double-HDDA, Intramolecular-HDDA, and
Highly Functionalized Naphthalenes
The HDDA reaction can serve as a powerful platform for accessing structurally complex polycyclic aromatic frameworks, often with high efficiency and, sometimes,
through novel transformations. This was first demonstrated in early examples from
the Ueda group, in which a sequential cycloisomerization provided a naphthyne
intermediate (e.g., 105 to 106), revealed by the formation of trapped products such as
107 (Figure 10.16a) [42]. In a rare example of an intramolecular HDDA reaction (cf.
Figure 10.3c), the cyclic triyne 108 was cyclized to the furan-trapped adduct 110 (via
109, Figure 10.16b) [43]. Symmetrical tetraynes having the general structure of 111
have been efficiently trapped by furan derivatives (as well as pyrroles, thiophenes,
and cyclopentadienes) to produce adducts 112 [44], which can, in principle [45], be
deoxygenated to reveal an additional arene (cf. 113, Figure 10.16c). Tetraynes like 111
have also been cyclized and trapped by tetraphenylcyclopentadienone (TPCPD) to
produce adducts such as 114. These were demonstrated to be efficient blue emitters
in prototypical OLED devices [46].
HO
HO
HO
25 °C
PhH
Ph
107 (60%)
106
105
(a)
Ph
Ph
O
70 ºC
108
(b)
O
O
109
110 (54%)
Ar
Ph
Ph
Ph
O
Ph
X
X
(c)
111
Ph
R
2 equiv
toluene
70 °C
Ph
Ph
X
O
112
(73-93%)
deoxygenation
O
R
Ph
reductive
X
Ar
MeO2C
MeO2C
Ph
Ph
113
114
Ph
Ph
Figure 10.16 Examples of readily accessed, fused-ring, polycyclic aromatic motifs by HDDA reaction strategies. (a) Naphthyne generation via double
HDDA. Source: Based on Miyawaki et al. [42], (b) a rare intramolecular HDDA. Source: Based on Nobusue et al. [43], and (c) furan and TPCPD trapping en
route to new arenes.
426
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
10.9.2 Trapping with Perylene, Domino HDDA, and Tandem
HDDA/TDDA
The polycyclic aromatic agent perylene can be used to capture an HDDA benzyne in
its bay region (cf. 116) to give, following spontaneous ejection of dihydrogen, adducts
such as 117 in a single step (e.g., 115 to 117, Figure 10.17a) [47]. In a domino-HDDA
process, the polyyne 118 proceeded, consecutively, via naphthyne and anthracyne
intermediates to the tetracyne 119, which could be trapped by the cyclopentadienone
fused-ring derivative 120 en route to the hexacene derivative 121 (Figure 10.17b)
[48]. Very recently, an interesting sequential HDDA-then-TDDA double cyclization
of the symmetrical tetrayne 122 was reported (Figure 10.17c) [49]. It gave rise to,
initially, 123 in which the benzyne became the enynophile in a TDDA reaction en
route to 124. This result is more intriguing in light of the fact that the corresponding disulfide (i.e., where the Me2Si moiety is replaced by a sulfur atom) substrate
does, instead, a double-TDDA cyclization, highlighting a redirecting effect of the
silicon atom.
Ph
Ph
Ph
Ph
Ph
MeO2C
MeO2C
CHCl3
80 °C
–H2
Ph
MeO2C
MeO2C
MeO2C CO2Me
115
(a)
116
Ph
O
O
O
Ph
117 (56%)
TMS
O
H
TMS
5 equiv
1. MsOH
o-DCB
130 °C
119
Ph
2. Δ
(–CO)
Me2
Si
Me2
Si
(i) TDDA
(ii) tautomerize
HDDA
MeO
OMe
122
Me2
Si
OMe
OMe
EtCN
150 °C
Si
Me2
Ph
121
(44%, three steps)
120
118
(b)
Ph
Cl
Ph
Cl
(c)
O
MeO
Si
Me2
123
MeO
Si
Me2
124 (81%)
Figure 10.17 More examples of readily accessed fused-ring, polycyclic aromatic motifs by
HDDA reaction. (a) Perylene trap. Source: Modified from Xu et al. [47], (b) domino HDDA via
a tetracyne. Source: Modified from Xiao and Hoye [48], and (c) domino HDDA via a
naphthacyne. Source: Mitake et al. [49].
10.10 One-Offs
10.10 One-Offs
10.10.1 Enal, Formamide, Diselenide, and (N-heterocyclic carbene)
NHC-Borane Trapping
A group of otherwise unrelated but interesting examples of transformations is
gathered in Figure 10.18. As with conventional benzynes [50], engagement with
conjugated enals leads to benzopyrans via oxetanes (cf. Figure 10.7d) and
o-quinonemethides such as 126 (e.g., 125 to 127, Figure 10.18a) [51]. In a similar
fashion, when 128 is heated in 1:1 DMF:H2 O, the carbonyl group of the amide
Ph
MeO2C
MeO2C
125
O
Ar
toluene
Ar
100 ºC
[2+2] and
4π -ring
opening
Ar =
Cl
Ar
MeO2C
MeO2C
O
126
Ar
128
Ar = Cl
O
Me
127 (88%)
Ar
O
iPrO2C
iPrO2C
Cl
H2 O
115 °C
Ar
MeO2C
MeO2C
H
O N CH3
H3C
129
MeO2C
MeO2C
Ph
H
Ph (SePh)2
131
toluene
90 °C
Se
Ph
OH O
Ph
132
Ph
Se
Ph
H 133
134 (78%)
nPr
nPr
TsN
nPr
135
N iPr
H
iPr
N
H2B
137
nPr
TsN
BH3
iPr N
136
(d)
nPr
THF
80 °C
TsN
Ph
EtO2C
EtO2C
Se
PhSe Se
(c)
nPr
H
130 (72%)
Ph
Ph
Me
Ph
Ar
Me2N
(b)
EtO2C
EtO2C
Ar
MeO2C
MeO2C
Ph
(a)
Ar
Ar
Ar
Me
Ar
iPr
N
iPr
N
H2B
138 (72%)
= 60:40
iPr
N
Figure 10.18 Miscellaneous examples, demonstrating novel modes of trapping. (a) Enal
trapping. Source: Meng et al. [51a]; Wang et al. [51b], (b) formamide trapping. Source: Based
on Hu et al. [52], (c) diselenide trapping. Source: Based on Hu et al. [53], and (d) net
hydroboration. Source: Modified from Watanabe et al. [54].
427
428
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
engages the benzyne to produce the oxetane derivative 129, which undergoes
electrocyclic ringopening and hydrolysis to generate the salicylaldehyde derivative
130 (Figure 10.18b) [52]. Diphenyldiselenide traps the HDDA benzyne from 131 in
an unexpected fashion, providing the selenophene 134, we might suggest via species
such as 132 and 133 (Figure 10.18c) [53]. In another unusual transformation, when
used to capture the benzyne from 135, the borane⋅NHC complex 136 gives rise to
the net hydroboration product 138, likely by way of the transient zwitterion 137
(Figure 10.18d) [54].
10.10.2 Cu(I)-Catalyzed Hydroalkynylation, Ether vs. Alcohol
Competition, Photo-HDDA, and a Kobayashi Benzyne as an HDDA
Diynophile
Cu(I)-Catalyzed hydro- and halocupration of HDDA benzynes is feasible [55].
The chemoselectivity observed for the reactions of but-3-yn-1-ol is instructive
(Figure 10.19a). In the absence of Cu, simple alcohol addition to the benzyne from
139 ensues (to give the aryl ether 140), but the chemoselectivity of reaction is
entirely reversed when substoichiometric CuCl is present, leading to the arylalkyne
142, likely via a 1,2-alkynylaryl copper species such as 141. Reactions of glycidol
derivatives (and other hydroxyalkyl-substituted cyclic ethers) show a different
mode of reaction with HDDA benzynes than they do in the reactions with benzynes
made using conventional fluoride ion generation. The latter predominantly gives,
at low temperature, simple O–H addition products (e.g., 143, Figure 10.19b) [56]. In
contrast, the HDDA benzyne from 144 gives products resulting from attack, instead,
by the epoxide oxygen to give, e.g., 145, which then undergoes rearrangement and
ring fragmentation en route to the ketone 146 [57]. A photochemical variant of
the HDDA (the hv-HDDA) reaction is possible, at least for substrates containing
a bisaryl-substituted tetrayne such as that present in 147 (Figure 10.19c). This
proceeds, even at subambient temperature, through an intermediate benzyne that
shows all the hallmarks (e.g., it gives the same distribution of minor byproducts)
of the same reactive species that is generated by heating 147 (t1/2 = 12 hours at
75 ∘ C). Capture by the internal methoxy group produces 148 and demethylation (by
traces of water, Cl3 C− , or Cl− ) results in the formation of the dibenzofuran 149 [58].
The multiaryne cascade (benzyne-to-benzyne-to-naphthyne) reaction between the
diynyl triflamide 150 and the 1,2-bisbenzyne precursor 151 [59] integrates a key
HDDA reaction as one component (153 to 154, Figure 10.19d). In this example, the
naphthyne is trapped by a tethered silyl ether, leading to 155. This demonstrates
how new strategic developments incorporating an HDDA event can be conceived
and reduced to practice [60].
10.11 Outgrowths from HDDA Chemistry
10.11.1 Processes that Outcompete Aryne Formation in Potential
HDDA Substrates
A final pair of topics (Figure 10.20) demonstrates how the HDDA platform can
be expanded in atypical fashion, again in each of these instances in unanticipated
10.11 Outgrowths from HDDA Chemistry
5 mol %
CuCl
0.5 equiv
NaAsc
Me
Me
CH3CN
TsN
Me
139
Me
80 °C
N
Ts
O
H
CH3CN
80 °C
OH
H
Me
Me
Me
Me
N
Ts
140 (77%)
N
Ts
[Cu]
HO
141
H
142 (80%)
HO
(a)
O
OTf
Me
TMS
TMS
TMS
HO
KF, 18-c-6
THF, –20 °C
O
O
H
143
(44%)
O
MeO
144
OMe
Me
O
Me
Me
HO
ClCH2CH2Cl
85 °C
O
TMS
O
Me
O
O
MeO
Me
MeO
Me
Me
Me
145
O
146 (51%)
(b)
MeO
MeO2C
MeO2C
147
300 nm
rt or
–70 °C
pyrex
CDCl3
MeO2C
MeO2C
MeO
O
Me
(c)
OTs
K2CO3
OTs 18-c-6
+
(d)
MeO2C
MeO2C
OTf
151
TMS PhCl
130 °C
TfN
O
149 (90%)
148
OTBS
TfHN
150
OMe
OMe
OTBS
D
O
TBSO
TBS
TfN
152
154
TfN
155 (76%)
TBSO
TfN
153
Figure 10.19 Miscellaneous examples, demonstrating novel modes of trapping.
(a) Cu(I)-catalyzed hydroalkynylation, (b) ether > hydroxyl competition. Source: Based on
Thangaraj et al. [56], (c) the photochemical HDDA reaction, and (d) benzyne to benzyne to
naphthyne.
ways. These outgrowths also result from the thermodynamic potential that the
multialkynes endow into the substrates. When treated with a weak base, the cycloisomerization of the diyne nitrile 156 takes a different course resulting in formation
of 159 (Figure 10.20a). This new process was named a “pentadehydro”-Diels–Alder
reaction, not because of any mechanistic relationship to DA or HDDA reactions,
but because the intermediate allene 157 has five sp-hybridized atoms (not six,
as with HDDA cycloisomerizations) that become incorporated in the strained,
α,3-dehydroazatoluene intermediate 158 [61]. This is then trapped by piperidine to
429
430
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
N
H
N
TsN
Me
RT
Me net
[4 + 2]
N
TsN
H
156
N
H
158 (an aza-α,3dehydrotoluene
(a)
159 (70%)
R
•
+
Ph E
E
161
E = CO2Me
E
E
•
160
R
E
160 °C
Ph
Ph
Ph
Ph
o-DCB
(0.05 M)
H
N
H
H
Me
TsN
TsN
C
157
N
Me
E
Ph
162
Ph
163 and 164
(1.4:1, 59%)
(b)
Figure 10.20 Intervention of other, faster processes starting from potential HDDA
substrates. (a) The pentadehydro Diels–Alder reaction and (b) Tether length matters:
cyclobutadienes instead of benzynes.
give the pyridine derivative 159. This transformation was also significant because
it represented the first time that a nitrile, the aza-surrogate of an alkyne, had
participated in a cycloisomerization of a substrate with six degrees of unsaturation
(cf. Figure 10.21). In a second unexpected outcome, the tetrayne 160, in which the
tether comprises four (sp3 -C) atoms rather than the three-atom linkage essentially
required for HDDA cyclizations (cf. Figure 10.5a), produced the four-membered
cyclobutadiene 162 (red arrow) rather than the six-membered (blue arrow) benzyne. This presumably reflects a kinetic preference for the cyclization of the
diradical 161; the ring fused to the cyclobutadiene is now six-membered, and the
bicyclic[4.2.0]substructure is less strained than in the cases where the fused ring is
five-membered [62]. The intermediacy of 162 was only recognized once the reaction
was performed in the presence of various electron-deficient traps, here dimethyl
acetylenedicarboxylate to give 163 and 164 (Figure 10.20b), because no tractable
adducts were formed when typical, electron-rich aryne capture reagents were used.
Clearly, subtle ring-strain effects arising from the size of the eventual fused ring
have a strong influence on how the diradical cyclizes.
10.11.2 Aza-HDDA Reaction
Replacement of a terminal carbon atom in a HDDA triyne substrate with a nitrogen
atom presents the opportunity to effect a cycloisomerization to form a pyridyne
rather than benzyne intermediate. This would constitute an aza-HDDA reaction
(Figure 10.21) [63]. Based on the location of the nitrogen atom, either a 3,4-pyridyne
such as 166 (Figure 10.21a) or a 2,3-pyridyne (Figure 10.21b) could be formed. DFT
studies suggest that these have considerably different levels of geometric distortion
[38], which is consistent with the differences in selectivity upon reaction with
nucleophilic trapping agents. For example, the nitrile–diyne substrate 165 gives
10.12 Guidelines and Practical Issues: Strategic Considerations
N
N
H
O
N
O
o-DCB
175 °C
165
167
166
(59%; 2.1:1)
(a)
N
TBS
N
O
TBS
O
N
N
O
169
o-DCB
H
N
168
N
MeO
MeO
MeO
OMe
TBS
H
O
120 °C
170
O
171 (68%)
(b)
Figure 10.21 The aza-HDDA reaction gives 3,4-pyridynes (cf. 166) or 2,3-pyridynes
(precursor to 170). (a) Aza-HDDA reactions involving nitriles as diynophiles and
(b) aza-HDDA reactions involving yne-nitriles as 1-aza-1,3-diynes. Source: Modified from
Thompson and Hoye [63].
the dienone 167 as a mixture of substantial amounts of the regioisomers arising
from each of the pyridyne carbons in 166 by 2,4,6-trimethylphenol. In contrast, the
aza-diyne-containing substrate 168 reacts with, for example, tropinone (169) to give
the amine-trapped product 171, via zwitterion 170, as the sole regioisomer.
The aza-HDDA variant has several limitations. The reaction is slower; some substrates require reaction temperature greater than 200 ∘ C. This greater activation barrier stems from the fact that a C—N triple bond is considerably stronger than a C—C
triple bond. Product yields for many of the reported aza-HDDA reactions are below
50%, and the synthesis of substrates is not as easy as for analogous HDDA triynes.
Even with this more limited scope, the aza-HDDA reaction still represents a useful
process for accessing certain highly substituted pyridine derivatives.
10.12 Guidelines and Practical Issues: Strategic
Considerations
10.12.1 Complementarity of Classical vs. HDDA Benzyne Chemistries
From a strategic perspective, the HDDA reaction is quite complementary to classical
methods for aryne generation and utilization. The latter constitutes a net substitution reaction of a precursor arene (Figure 10.22a). That is, a benzenoid aromatic
substrate 172 is activated by a reagent(s) to produce a benzyne 173, which is then
trapped to produce a product 174 that contains the same six-membered ring that
was present in the starting substrate. By contrast, HDDA reactions (Figure 10.22b)
create new benzenoid rings in de novo fashion (cf. 23 to 176 via 175). Because of the
431
432
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
R
A
B
172
Reagents
to induce
removal
of A—B
Byproducts
from the
removal of A—B
R
Trap by R
T1—T2
T1
2
T
174
173
(a)
R1
R1
A
R1
Δ
R2
A
B
B
R2
C
23
Trap by
T1—T2
C
175
A
R2
C
T1
B
2
176 T
(b)
Figure 10.22 Strategic difference between (a) classical aryne net substitution chemistry
and (b) de novo construction of the benzyne and its trapped products.
requirement for the triyne to be tethered in the precursor to render the cycloisomerization intramolecular, HDDA benzynes (and the derived final trapped products)
are of greater structural complexity compared to those involved in the majority of
classical benzyne reactions. For these primary reasons, the HDDA reaction should
be viewed as orthogonally complementary to classical approaches to making and
using arynes. Neither strategy is superior in all settings – far from it.
10.12.2 Regioselectivity Issues and the Nature of the Nucleophilic
Trapping Agent
Because HDDA benzynes are, of necessity, unsymmetrically substituted (cf. 175,
Figure 10.22b), even when the precursor is a symmetrical tetrayne, regiochemical
issues are a consideration when the trapping reagent is also not symmetrical.
The great majority of benzyne-trapping reactions can and should be viewed as
an in-plane attack on the electrophilic benzyne π-bond by a nucleophile. The
distortion analysis [38] mentioned earlier in the context of the aza-HDDA reaction
(cf. Figure 10.21) is also quite effective at rationalizing/predicting the preferred site
of nucleophilic addition. More specifically, the benzyne carbon atom computed
to have the larger internal bond angle is more electrophilic because of the greater
p-character imparted to its in-plane component of the strained benzyne π-bond [38].
For symmetrical trapping agents regioselectivity is often not an issue, as seen from
many examples above, include furan, H2 -transfer agents, benzene, dihalogenation
(e.g., with CuCl2 ) [64], and bis-sulfide formation (via disulfide [disulfane] trapping)
[65]. Because of the electrophilic nature of the benzyne, when two traps of the same
class of nucleophile simultaneously present in a reaction mixture, the one with
greater electron density typically will react faster. For example, anisole, present in
<1 vol% in a reaction solvent of benzene will far outcompete the trapping of the
benzyne by the benzene in a [4+2] cycloaddition process. The exceptionally high
degree of polarizability of the aryne π-bond is responsible for the polar nature of
its reactions and to its remarkable versatility. “Said differently, an aryne represents
10.12 Guidelines and Practical Issues: Strategic Considerations
one of the softest and most malleable of all carbon-based electrophiles.” [37] Consequently, soft, polarizable nucleophiles can be expected to add in preference to harder
nucleophiles of higher electron density. For example, small amounts of sulfides
effectively trap even in alcohol or aqueous solutions. As a corollary to the reality of
this property of polar reactivity, radical additions to the strained π-bond are rare.
10.12.3 Limitations Imposed by Trapping Agents
In planning a potential HDDA reaction strategy, it is worth keeping two limiting
conditions in mind. If the trapping reagent reacts too quickly with the polyyne substrate (i.e., the benzyne precursor), it will prematurely intervene prior to the requisite
cycloisomerization event. Examples of this incompatibility include the reaction of
primary or secondary amines with ynone or ynoate substrates and the excessive
reactivity of typical hydroboration reagents and dihalogens. If, on the other extreme,
the trapping event is too slow, the benzyne will often turn back and cannibalize
more of its polyyne precursor, often in myriad manners leading to intractable, highly
conjugated, brown–black material. Fortunately, the “window of opportunity” for
successful HDDA reactions defined by those limiting extremes is quite large, as the
myriad examples described in this chapter attest. Rare instances of selective reactions between an HDDA benzyne and its precursor triyne are shown in Figure 10.23
(e.g., 177 to 178 and 179 to 180), rationalized by the intermediates in brackets [62].
All of the successful substrates 177 shared the property of having R1 and R2 be either
a bulky substituent (quaternized alkyl or trialkylsilyl) or a hydrogen atom.
10.12.4 Formal Equivalent of the Elusive Bimolecular HDDA Reaction
The need for the HDDA substrates to include a three-atom tether between the
1,3-diyne and the diynophile has been evident throughout the examples described in
this chapter. The temperature requirements to achieve convenient reaction times
O
O
R1
2 O
O
O
177
tBu
Dimerization
O
R2
Δ
tBu
179
O
O
R1
180 (45%)
t1/2 ~ 3 h
@ 130 °C
R2
O
R2
O
tBu
O
Ring
opening
tBu
O
O
R1
178
15 examples
(31–83%)
Figure 10.23
tBu
O
Net
[2 + 2]
Net
[4 + 2]
Selective self-dimerization reactions of a class of triyne substrates 177.
433
434
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
S
S
R1
R2
S
Δ
•
S
S
S
•
R1
trap
Ra–Ni
•
R1
trap
R2
181
H
trap
182
H
•
R1
R2
R2
183
184
Figure 10.24 Traceless tethers, demonstrated here by reductive cleavage of a dithia-acetal
linker, establish, in effect, an intermolecular HDDA reaction.
vary widely, depending largely upon the exact nature of the tether structure. However, in one study, it was shown that the tether can be deleted after having played its
role of bringing the reactive diyne/diynophile pair into proximity. This is achieved by
the use of sulfur-containing substrates such as 181 (Figure 10.24). The benzyne 182
was efficiently trapped to provide 183. Removal of the tether by, in this case, Raney
nickel reduction provided 184 [66]. This tactic establishes the formal equivalent of
an inter- or bi-molecular HDDA reaction, a process otherwise yet to be realized.
10.12.5 Aspects of Substrate Design
The energy of activation of the initial, rate-limiting cycloisomerization events varies
widely, largely dictated by two factors. First, the exact nature of the three-atom linker
plays a significant role. Second- vs. third-row atoms impact the intervening bond
lengths. The presence of an embedded ring or Z-alkene reduces the degrees of freedom in the linker, thereby increasing the fraction of polyynes in a reactive conformation or geometry at any instant in time. More sp2 -hydridized atoms tend to increase
rates by shortening the distance between the proximal carbon atoms of the diyne and
diynophile; partial bond formation between those two atoms is a component of the
transition structure of the rate-determining step regardless of whether the mechanism is stepwise-diradical (cf. Figure 10.8) or concerted in nature. Second, the nature
of the substituents on the terminus of the diyne and, especially, the diynophile
impacts the ease of cyclization considerably [21g]. These substituent effects do
not follow the classical Diels–Alder dienophile activation paradigm in which
frontier molecular orbital mixing energies dictate reactivity (for example and most
typically, lowering of the dienophile LUMO by the incorporation of more strongly
electron-withdrawing substituents). Instead and to the extent it has been systematically studied, the trend is that substituents more capable of stabilizing the radical
character of the putative diradical intermediate (i.e., having greater radical stabilizing energies [RSEs]) formed as the first elementary step in the rate-determining
cycloisomerization enhance the rate of reaction (cf. Figure 10.8) [22].
10.12.6 Limitations Imposed by Substituents on the Diynophile
Finally, it should be noted that triyne substrates in which the terminal substituent
on a mono-alkynyl diynophile (i.e., R1 in substrates such as 23 [Figure 10.22b], 177
[Figure 10.23], or 181 [Figure 10.24]) is an arene, alkene, or alkyl group bearing a
10.13 Guidelines and Practical Issues: Experimental Considerations
propargylic C—H bond are generally not suitable benzyne precursors. Arene and
alkene groups often enter into TDDA reactions faster than HDDA and alkyl groups
are susceptible to faster or at least competitive propargylic ene reactions.
10.13 Guidelines and Practical Issues: Experimental
Considerations
10.13.1 Pristine Reaction Conditions (and Solvent Choices)
As pointed out earlier, the thermal-only nature of the HDDA cycloisomerization
stands in sharp contrast, and is quite complementary, to the classical methods
that are used to generate arynes [67]. Those nearly always employ reagents such
as strong bases, nucleophiles, oxidants, or reducing agents to activate the benzyne
precursor, and they produce byproducts that accompany benzyne generation.
As also mentioned earlier, because of this pristine reaction-free environment,
previously unobserved or incompatible types of benzyne-trapping reaction and/or
new fundamental aspects of the mechanisms of many trapping reactions are able to
be observed or learned from these “heat-only” reactions.
Solvent compatibility with the HDDA-benzyne is an issue for consideration. Some
solvents are quite reactive and will interfere with an intended trapping reaction. For
example, THF, cyclopentane, and cyclooctane are known to donate two hydrogen
atoms to the benzyne (cf. Figure 10.14); cyclohexane, decalins [66], and acyclic
hydrocarbons also do so, but at a slower rate. Some solvents are only marginally
reactive – benzene, toluene, chlorobenzene, and 1,2-dichlorobenzene are examples.
These will eventually trap many benzynes in a [4+2] DA reaction, but in many
instances trapping reactions with other added trapping agents are faster. Acetonitrile, ethyl acetate, and chloroform are often good choices, although for certain
trapping processes, carbanionic character can emerge on the benzyne carbon adjacent to the site of nucleophilic attack and protonation by these weak Brønsted acids
is observed, sometimes with productive outcomes. 1,2-Dichloroethane is a particularly inert candidate, rendering it often a good choice as a reaction medium. Because
they react readily as nucleophiles, dimethyl sulfoxide (DMSO), dimethyl formamide
(DMF), amines, and alcohol solvents are not good choices for HDDA reactions. In
this vein, it should be remembered that reagent bottles of chloroform quite often
contain substantial amounts of ethanol (0.75% is typical) as an inhibitor (of autoxidation and subsequent phosgene and HCl formation), which can interfere with other
desired trapping processes. Finally, because the deuterated variants of several of the
solvents just mentioned are conveniently available (i.e., CDCl3 , C6 D6 , and CD3 CN),
they are well suited for use in direct nuclear magnetic resonance (NMR) monitoring
of initial scouting reactions or for monitoring reaction rate, progress, selectivity, and
overall reaction cleanliness by direct inspection (e.g., [27]) of the reaction mixture.
10.13.2 Reaction Conditions: Tolerance for Water and Oxygen
Two features of HDDA reactions lend favorably to the relative ease and convenience
of performing these transformations. First, the rate of reaction of HDDA-generated
435
436
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
benzynes with water, a relatively hard nucleophile, is slow. That means that experiments can be carried out in normal laboratory solvents without the need to predry
them exceptionally carefully. As mentioned above, the high degree of polarizable
character of bent, strained aryne π-bonds are a major contributor to their preference for reaction with soft (i.e., polarizable) nucleophilic trapping reagents. Second, because it is rare that any (long-lived) radical intermediates are present on the
potential energy surface of the overall reaction, the HDDA cycloisomerization and
subsequent trapping events are not affected in any appreciable way by the presence
of oxygen. Hence, careful deoxygenation of the reaction environment prior to heating the polyyne to promote reaction is not crucial and components of trapping agents
that might otherwise be susceptible to radical polymerization are tolerated. In other
words, because of the tolerance of water and oxygen, special care of the reaction
conditions is typically not needed.
10.13.3 Reaction Conditions: Temperature, Pressure, and Alkyne
Stability
The temperature of the reaction medium required to achieve a convenient rate of
reaction is another consideration that factors into the choice of solvent. Because
reaction temperatures required to achieve a convenient rate of reaction are often
higher than those of the atmospheric boiling points of solvents that are otherwise
convenient choices for the reaction medium, it is often advantageous to perform the
reaction in a sealed vessel at elevated pressure. The Antoine equation, an empirical
correlation between a solvent’s vapor pressure and its temperature, is a very
useful tool for judging the internal pressure that will be reached. We use an Excel
spreadsheet to inform many of our experiments [68]. As one example, we often
use chloroform at temperatures above its ambient pressure boiling point (61.75 ∘ C
at 760 mm Hg−1 ). The Antoine equation shows the following P/T relationships:
30 psi@85 ∘ C, 60 psi@112 ∘ C, and 90 psi@130 ∘ C. Incidentally, the vapor pressure of
decalin at 300 ∘ C is estimated to be 115 psi. Pyrex glass pressure ratings are dependent on the diameter and wall thickness of the object [69]. As an added precaution,
we prefer to use threaded culture tubes with rounded bottoms, likely stronger
than the squared-off, flat bottoms of glass vials. Use of screw-caps with an internal
Teflon lining, backed by a soft rubberized layer, creates an excellent and inert seal
to the lip of the threaded culture tube. Solvent loss is typically unobservable. We
once held a capped culture tube, c. 1 cm in diameter and containing c. 2 mL of
dichloromethane, at 200 ∘ C (!) for 24 hours. There was no loss of solvent or failure
of the glass culture tube; the Antoine equation suggests that the internal pressure
was c. 550 psi. Of course, this experiment was performed in a hood and behind
a safety blast shield, and we recommend that every experiment done in a sealed
vessel, where >1 atm of pressure is anticipated, be done behind a safety shield.
While on the topic of safety, it is appropriate to comment on the thermodynamic
stability of alkynes themselves. Because of the inherently low bond dissociation
energy of a carbon–carbon triple bond, alkynes carry an inherently high degree of
potential energy. This is the very source of the energy that fuels triyne conversion
10.13 Guidelines and Practical Issues: Experimental Considerations
to the highly reactive intermediate benzyne (computed exergonicities of, typically,
ΔG∘ = –40 to –50 kcal mol−1 (!)) [21]. Unsubstituted alkynes are kinetically prone
to rapid decomposition – for example, ethyne (acetylene) detonates under pressure
and 1,3-butadiyne [70] and 1,3,5-hexatriyne (a natural product! [71]) decompose
violently as condensed materials. When handling low-molecular-weight, terminal
alkynes with additional weak bonds (e.g., 1-bromopropyne), it is advisable to
prepare, analyze, and then react them in solution rather than to purify them as neat
substances. Finally, differential scanning calorimetry (DSC) analysis of multiyne
HDDA substrates of relative low molecular weight, especially if one or both termini
are unsubstituted, is recommended for initial assessment of inherent stability
properties [72, 73].
10.13.4 Reaction Conditions: Substrate Concentration
Another point to be considered is the substrate concentration of the reaction
solution. Because of the ability of the HDDA-benzynes to react further in, necessarily, bimolecular events with functionality in the substrate polyyne (or in some
instances the trapped products) the initial substrate concentration can be an issue.
In cases where the trapping reaction is quite fast, this is rarely a concern, but
some otherwise-desired trapping agents have an inherently slow rate constant for
capturing the reactive benzyne. This can sometimes be countered by use of a larger
excess of that coreactant, but if the steady-state concentration of the benzyne rises
too high because of its slow consumption by the external agent, then undesired
reactions can intervene. These are instances where performing the experiment at
higher dilution (i.e., lower [polyyne]t=0 ) can improve the selectivity for the desired
trapping pathway. At the other extreme, one study using the highest possible concentration of substrate (i.e., neat) and trapping agent (i.e., intramolecular) showed
that the reaction could be performed in the absence of solvent and still provide
remarkably efficient conversion to monomeric, trapped product [72]. Additionally,
it was observed that the onset temperatures of the exothermic events measured by
DSC of the neat samples, correlated, at least qualitatively, with the rates of their
HDDA cyclization in solution.
10.13.5 The Value of Half-Life Measurements
Finally, there have been several reports of HDDA reactions being catalyzed by
various transition metal complexes [74]. In such studies, it is incumbent to clearly
demonstrate that the presence of the metal is actually enhancing the rate of the
rate-determining cycloisomerization reaction. We suggest that this be done by measuring the approximate half-life for the uncatalyzed, thermal conversion rather than
drawing inferences from, e.g., isolated yields of products at time points corresponding to many t1/2 s. One convenient protocol we have used for measuring the half-life
of the rate-determining, unimolecular, HDDA cycloisomerization involved heating
a substrate in the high-boiling (and nearly inert) solvent 1,2-dichlorobenzene,
removing an aliquot of the reaction solution at various time points (including t0 ),
437
438
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
diluting directly into CDCl3 , and integrating the diminution over time of substrate
resonances vs. the 13 C-coupled satellite resonances of the aromatic protons in
the solvent (see Supporting Information of Ref. [14]). Regardless of the analytical
method used, it is always helpful to establish the approximate half-life of the
HDDA cyclization for any new substrate that is examined. This information adds
to the fundamental body of knowledge and understanding associated with the
ever-growing compendium [1] of HDDA chemistry.
References
1 Fluegel, L.L. and Hoye, T.R. The hexadehydro-Diels–Alder reaction: Benzyne generation via cycloisomerization of tethered triynes. Chem. Rev. 121:
2413–2444.
2 (a) Michael, A. and Bucher, J.E. (1898). Über die Einwirkung von Eissigsäureanhydrid auf Phenylpropiolsäure. Chem. Zentrblt.: 731–733. (b) Diels, O. and
Alder, K. (1928). Syntheses in the hydroaromatic series. Justus Liebigs Ann.
Chem. 460: 98–122.
3 Wessig, P. and Müller, G. (2008). The dehydro-Diels–Alder reaction. Chem. Rev.
108: 2051–2063.
4 Diau, E.W.-G., Casanova, J., Roberts, J.D., and Zewail, A.H. (2000). Femtosecond
observation of benzyne intermediates in a molecular beam: Bergman rearrangement in the isolated molecule. Proc. Natl. Acad. Sci. U.S.A. 97: 1376–1379.
5 (a) Chapman, O.L., Mattes, K., McIntosh, C.L. et al. (1973). Photochemical transformations. LII. Benzyne. J. Am. Chem. Soc. 95: 6134–6135. (b) Münzel, N.
and Schweig, A. (1988). UV/VIS absorption spectrum, geometry and electronic
structure of transient o-benzyne. Chem. Phys. Lett. 147: 192–194.
6 Warmuth, R. (1997). o-Benzyne: strained alkyne or cumulene?—NMR characterization in a molecular container. Angew. Chem. Int. Ed. 36: 1347–1350.
7 Fields, E.K. and Meyerson, S. (1966). Arynes by pyrolysis of acid anhydrides.
J. Org. Chem. 31: 3307–3309.
8 (a) Bradley, A.Z. and Johnson, R.P. (1997). Thermolysis of 1,3,8-nonatriyne: evidence for intramolecular [2+4] cycloaromatization to a benzyne intermediate.
J. Am. Chem. Soc. 119: 9917–9918. (b) Miyawaki, K., Suzuki, R., Kawano, T.,
and Ueda, I. (1997). Cycloaromatization of a non-conjugated polyenyne system:
synthesis of 5H-benzo[d]fluoreno[3,2-b]pyrans via diradicals generated from
1-(2-(4-(2-alkoxyethylphenyl)butan-1,3-diynyl))phenylpetan-2,4-diyn-1-ols and
trapping evidence for the 1,2-didehydrobenzene diradical. Tetrahedron Lett. 38:
3943–3946.
9 (a) Ueda, I., Sakurai, Y., Kawano, T. et al. (1999). An unprecedented arylcarbene formation in thermal reaction of non-conjugated aromatic enetetraynes
and DNA strand cleavage. Tetrahedron Lett. 40: 319–322. (b) Torikai, K.,
Otsuka, Y., Nishimura, M. et al. (2008). Synthesis and DNA cleavage activity of water-soluble non-conjugated thienyl tetraynes. Bioorg. Med. Chem. 16:
References
10
11
12
13
14
15
16
17
18
19
20
21
5441–5451. (c) Bergman, R.G. (1973). Reactive 1,4-dehydroaromatics. Acc. Chem.
Res. 6: 25–31.
Tsui, J.A. and Sterenberg, B.T. (2009). A metal-templated 4+2 cycloaddition
reaction of an alkyne and a diyne to form a 1,2-aryne. Organometallics 28:
4906–4908.
(a) Hoye, T.R., Baire, B., Niu, D. et al. (2012). The hexadehydro-Diels–Alder reaction. Nature 490: 208–212. (b) Baire, B., Niu, D., Willoughby, P.H. et al. (2013).
Synthesis of complex benzenoids via the intermediate generation of o-benzynes
through the hexadehydro-Diels–Alder reaction. Nat. Protoc. 8: 501–508.
Hoye, T.R., Baire, B., and Wang, T. (2014). Tactics for probing aryne reactivity: mechanistic studies of silicon–oxygen bond cleavage during the trapping of
(HDDA-generated) benzynes by silyl ethers. Chem. Sci. 5: 545–550.
(a) Diamond, O.J. and Marder, T.B. (2017). Methodology and applications of
the hexadehydro-Diels–Alder (HDDA) reaction. Org. Chem. Front. 4: 891–910.
(b) Holden, C. and Greaney, M.F. (2014). The hexadehydro-Diels–Alder reaction:
a new chapter in aryne chemistry. Angew. Chem. Int. Ed. 53: 5746–5749.
Woods, B.P., Baire, B., and Hoye, T.R. (2014). Rates of hexadehydro-Diels–Alder
(HDDA) cyclizations: impact of the linker structure. Org. Lett. 16: 4578–4581.
Yun, S.Y., Wang, K., Lee, N. et al. (2013). Alkane C−H insertion by aryne intermediates with a silver catalyst. J. Am. Chem. Soc. 135: 4668–4671.
Shen, H., Xiao, X., Haj, M. et al. (2018). BF3 -promoted, carbene-like, C–H insertion reactions of benzynes. J. Am. Chem. Soc. 140: 15616–15620.
Karmakar, R., Wang, K.-P., Yun, S.Y. et al. (2016). Hydrohalogenative aromatization of multiynes promoted by ruthenium alkylidene complexes. Org. Biomol.
Chem. 14: 4782–4788.
Karmakar, R. and Lee, D. (2016). Total synthesis of selaginpulvilin C and D
relying on in situ formation of arynes and their hydrogenation. Org. Lett. 18:
6105–6107.
Wang, T. and Hoye, T.R. (2016). Hexadehydro-Diels−Alder (HDDA)-enabled
carbazolyne chemistry: single step, de novo construction of the pyranocarbazole
core of alkaloids of the Murraya koenigii (curry tree) family. J. Am. Chem. Soc.
138: 13870–13873.
(a) Heaney, H. and Jablonski, J.M. (1968). Reactions of arynes in the synthesis
of 2H-chromens. Chem. Commun. 1139–1139. (b) Wang, T., Oswood, C.J., and
Hoye, T.R. (2017). Trapping of hexadehydro-Diels–Alder benzynes with exocyclic,
conjugated enals as a route to fused spirocyclic benzopyran motifs. Synlett 28:
2933–2935.
For reports that include computational studies of both the forward (i.e., triynes
to benzyne) and back (i.e., benzyne pyrolysis back to triynes) HDDA reactions,
see: (a) Deng, W.-Q., Han, K.-L., Zhan, J.-P., and He, G.-Z. (1998). Ab initio
and RRKM calculations of o-benzyne pyrolysis. Chem. Phys. Lett. 288: 33–36.
(b) Moskaleva, L.V., Madden, L.K., and Lin, M.C. (1999). Unimolecular isomerization/decomposition of ortho-benzyne: ab initio MO/statistical theory
study. Phys. Chem. Chem. Phys. 1: 3967–3972. (c) Diau, E.W., Casanova, J.,
Roberts, J.D., and Zewail, A.H. (2000). Femtosecond observation of benzyne
439
440
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
intermediates in a molecular beam: Bergman rearrangement in the isolated
molecule. Proc. Natl. Acad. Sci. U.S.A 97: 1376–1379. (d) Zhang, X., Maccarone,
A.T., Nimlos, M.R. et al. (2007). Unimolecular thermal fragmentation of
ortho-benzyne. J. Chem. Phys. 126: 044312(-1)–044312(-20). (e) Cahill, K.J.,
Ajaz, A., and Johnson, R.P. (2010). New thermal routes to ortho-benzyne. Aust.
J. Chem. 63: 1007–1012. (f) Ajaz, A., Bradley, A.Z., Burrell, R.C. et al. (2011).
Concerted vs stepwise mechanisms in dehydro-Diels–Alder reactions. J. Org.
Chem. 76: 9320–9328. (g) Liang, Y., Hong, X., Yu, P., and Houk, K.N. (2014).
Why alkynyl substituents dramatically accelerate hexadehydro-Diels–Alder
(HDDA) reactions: stepwise mechanisms of HDDA cycloadditions. Org. Lett. 16:
5702–5705. (h) Ghigo, G., Maranzana, A., and Tonachini, G. (2014). o-Benzyne
fragmentation and isomerization pathways: a CASPT2 study. Phys. Chem. Chem.
Phys. 16: 23944–23951. (i) Marell, D.J., Furan, L.R., Woods, B.P. et al. (2015).
Mechanism of the intramolecular hexadehydro-Diels–Alder reaction. J. Org.
Chem. 80: 11744–11754. (j) Skraba-Joiner, S.L., Johnson, R.P., and Agarwal, J.
(2015). Dehydropericyclic reactions: symmetry-controlled routes to strained
reactive intermediates. J. Org. Chem. 80: 11779–11787. (k) Chen, M., He, C.Q.,
and Houk, K.N. (2019). Mechanism and regioselectivity of an unsymmetrical
hexadehydro-Diels–Alder (HDDA) reaction. J. Org. Chem. 84: 1959–1963.
22 Wang, T., Niu, D., and Hoye, T.R. (2016). The hexadehydro-Diels–Alder (HDDA)
cycloisomerization reaction proceeds by a stepwise mechanism. J. Am. Chem.
Soc. 138: 7832–7835.
23 (a) Karmakar, R., Mamidipalli, P., Yun, S.Y., and Lee, D. (2013). Alder-ene reactions of arynes. Org. Lett. 15: 1938–1941. (b) Gupta, S., Lin, Y., Xia, Y. et al.
(2019). Alder-ene reactions driven by high steric strain and bond angle distortion to form benzocyclobutenes. Chem. Sci. 10: 2212–2217. (c) Gupta, S., Xie, P.,
Xia, Y., and Lee, D. (2018). Reactivity of arynes toward functionalized alkenes:
Intermolecular Alder-ene vs. addition reactions. Org. Chem. Front. 5: 2208–2213.
(d) Wang, K., Yun, S.Y., Mamidipalli, P., and Lee, D. (2013). Silver-mediated fluorination, trifluoromethylation, and trifluoromethylthiolation of arynes. Chem.
Sci. 4: 3205–3211. (e) Karmakar, R., Yun, S.Y., Wang, K., and Lee, D. (2014).
Regioselectivity in the nucleophile trapping of arynes: the electronic and steric
effects of nucleophiles and substituents. Org. Lett. 16: 6–9. (f) Karmakar, R.,
Yun, S.Y., Chen, J. et al. (2015). Benzannulation of triynes to generate functionalized arenes by spontaneous incorporation of nucleophiles. Angew. Chem. Int.
Ed. 54: 6582–6586. (g) Ghorai, S. and Lee, D. (2017). Aryne formation via the
hexadehydro Diels–Alder reaction and their Ritter-type transformations catalyzed
by a cationic silver complex. Tetrahedron 73: 4062–4069. (h) Karmakar, R., Le,
A., Xie, P. et al. (2018). Aryne-mediated dearomatization of arylsulfonyl group.
Org. Lett. 20: 4168–4172. (i) Ghorai, S. and Lee, D. (2019). Synthesis of imides,
imidates, amidines, and amides by intercepting the aryne–isocyanide adduct with
weak nucleophiles. Org. Lett. 21: 7390–7393.
24 Wittig, G. and Pohmer, L. (1955). Intermediäre Bildung von dehydrobenzol
(cyclohexadienin). Angew. Chem. Int. Ed. 67: 348–348.
References
25 Kawano, T., Inai, H., Miyawaki, K., and Ueda, I. (2005). Synthesis of indenothiophenone derivatives by cycloaromatization of non-conjugated thienyl tetraynes.
Tetrahedron Lett. 46: 1233–1236.
26 Chen, J., Baire, B., and Hoye, T.R. (2014). Cycloaddition reactions of azide, furan,
and pyrrole units with benzynes generated by the hexadehydro-Diels–Alder
(HDDA) reaction. Heterocycles 88: 1191–1200.
27 Pogula, V.D., Wang, T., and Hoye, T.R. (2015). Intramolecular [4+2] trapping of
a hexadehydro-Diels–Alder (HDDA) benzyne by tethered arenes. Org. Lett. 17:
856–859.
28 Hu, Q., Li, L., Yin, F. et al. (2017). Fused multifunctionalized
isoindole-1,3-diones via the coupled oxidation of imidazoles and tetraynes. RSC
Adv. 7: 49810–49816.
29 Ross, S.P. and Hoye, T.R. (2017). Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products. Nat. Chem. 9:
523–530.
30 Zhang, J., Niu, D., Brinker, V.A., and Hoye, T.R. (2016). The phenol-ene reaction:
biaryl synthesis via trapping reactions between HDDA-generated benzynes and
phenolics. Org. Lett. 18: 5596–5599.
31 Mayr, H. and Ofial, A.R. (2006). The reactivity-selectivity principle: an imperishable myth in organic chemistry. Angew. Chem. Int. Ed. 45: 1844–1854.
32 Bhunia, A., Yetra, S.R., and Biju, A.T. (2012). Recent advances in
transition-metal-free carbon–carbon and carbon–heteroatom bond-forming
reactions using arynes. Chem. Soc. Rev. 41: 3140–3152.
33 Ross, S.P. and Hoye, T.R. (2018). Multiheterocyclic motifs via three-component
reactions of benzynes, cyclic amines, and protic nucleophiles. Org. Lett. 20:
100–103.
34 Arora, S., Zhang, J., Pogula, V., and Hoye, T.R. (2019). Reactions of thermally
generated benzynes with six-membered N-heteroaromatics: Pathway and product
diversity. Chem. Sci. 10: 9069–9076.
35 Chen, J., Palani, V., and Hoye, T.R. (2016). Reactions of HDDA-derived benzynes
with sulfides: mechanism, modes, and three-component reactions. J. Am. Chem.
Soc. 138: 4318–4321.
36 Niu, D., Willoughby, P.H., Baire, B. et al. (2013). Alkane desaturation by concerted double hydrogen atom transfer to benzyne. Nature 501: 531–534.
37 Willoughby, P.H., Niu, D., Wang, T. et al. (2014). Mechanism of the reactions of
alcohols with o-benzynes. J. Am. Chem. Soc. 136: 13657–13665.
38 (a) Hamura, T., Ibusuki, Y., Sato, K. et al. (2003). Strain-induced regioselectivities in reactions of benzyne possessing a fused four-membered ring.
Org. Lett. 5: 3551–3554. (b) Cheong, P.H.Y., Paton, R.S., Bronner, S.M. et al.
(2010). Indolyne and aryne distortions and nucleophilic regioselectivities.
J. Am. Chem. Soc. 132: 1267–1269. (c) Garr, A.N., Luo, D., Brown, N. et al.
(2010). Experimental and theoretical investigations into the unusual regioselectivity of 4,5-, 5,6-, and 6,7-indole aryne cycloadditions. Org. Lett. 12: 96–99.
(d) Bickelhaupt, F.M. and Houk, K.N. (2017). Analyzing reaction rates with
441
442
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
the distortion/interaction-activation strain model. Angew. Chem. Int. Ed. 56:
10070–10086.
Niu, D. and Hoye, T.R. (2014). The aromatic ene reaction. Nat. Chem. 6: 34–40.
Heine, H.W., Hoye, T.R., Williard, P.G., and Hoye, R.C. (1973). Diaziridines
II. The addition of diaziridines to electrophilic acetylenes. J. Org. Chem. 38:
2984–2988.
Arora, S., Palani, V., and Hoye, T.R. (2018). Reactions of diaziridines with benzynes give N-arylhydrazones. Org. Lett. 20: 8082–8085.
Miyawaki, K., Kawano, T., and Ueda, I. (1998). Multiple cycloaromatization of
novel aromatic enediynes bearing a triggering device on the terminal acetylene
carbon. Tetrahedron Lett. 39: 6923–6926.
Nobusue, S., Yamane, H., Miyoshi, H., and Tobe, Y. (2014).
[4.2](2,2′ )(2,2′ )Biphenylophanetriyne: a twisted biphenylophane with a highly
distorted diacetylene bridge. Org. Lett. 16: 1940–1943.
Zhang, M., Shan, W., Chen, Z. et al. (2015). Diels-Alder reactions of arynes in
situ generated from DA reaction between bis-1,3-diynes and alkynes. Tetrahedron
Lett. 56: 6833–6838.
Jung, K. and Koreeda, M. (1989). Synthesis of 1,4-, 2,4-, and
3,4-dimethylphenanthrenes: a novel deoxygenation of arene 1,4-endoxides with
trimethylsilyl iodide. J. Org. Chem. 54: 5667–5675.
Xu, F., Hershey, K.W., Holmes, R.J., and Hoye, T.R. (2016). Blue-emitting arylalkynyl naphthalene derivatives via a hexadehydro-Diels–Alder (HDDA) cascade
reaction. J. Am. Chem. Soc. 138: 12739–12742.
Xu, F., Xiao, X., and Hoye, T.R. (2016). Reactions of HDDA-derived benzynes
with perylenes: rapid construction of novel polycyclic aromatic compounds.
Org. Lett. 18: 5636–5639.
Xiao, X. and Hoye, T.R. (2018). The domino hexadehydro-Diels–Alder reaction
transforms polyynes to benzynes to naphthynes to anthracynes to tetracynes
(and beyond?). Nat. Chem. 10: 838–844.
Mitake, A., Nagai, R., Sekine, A. et al. (2019). Consecutive HDDA
and TDDA reactions of silicon- tethered tetraynes for the synthesis of
dibenzosilole-fused polycyclic compounds and their unique reactivity. Chem.
Sci. 10: 6715–6720.
Heaney, H. and Jablonski, J.M. (1968). Reactions of arynes in the synthesis of
2H-chromens. Chem. Commun. 1139–1139.
(a) Meng, X., Lv, S., Cheng, D. et al. (2017). Fused multifunctionalized
chromenes from tetraynes and α,β-unsaturated aldehydes. Chem. Eur. J. 23:
6264–6271. (b) Wang, T., Oswood, C.J., and Hoye, T.R. (2017). Trapping of
hexadehydro-Diels–Alder benzynes with exocyclic, conjugated enals as a route to
fused spirocyclic benzopyran motifs. Synlett 28: 2933–2935.
Hu, Y., Hu, Y., Hu, Q. et al. (2017). Direct access to fused salicylaldehydes and
salicylketones from tetraynes. Chem. Eur. J. 23: 4065–4072.
Hu, Y., Ma, J., Li, L. et al. (2017). Fused multifunctionalized dibenzoselenophenes from tetraynes. Chem. Commun. 53: 1542–1545.
References
54 Watanabe, T., Curran, D.P., and Taniguchi, T. (2015). Hydroboration of arynes
formed by hexadehydro-Diels−Alder cyclizations with N-heterocyclic carbene
boranes. Org. Lett. 17: 3450–3453.
55 Xiao, X., Wang, T., Xu, F., and Hoye, T.R. (2018). Cu(I)-Mediated bromoalkynylation and hydroalkynylation reactions of unsymmetrical benzynes: complementary
modes of addition. Angew. Chem. Int. Ed. 57: 16564–16568.
56 Thangaraj, M., Bhojgude, S.S., Maneb, M.V., and Biju, A.T. (2016). From insertion to multicomponent coupling: temperature dependent reactions of arynes
with aliphatic alcohols. Chem. Commun. 52: 1665–1668.
57 Zhang, J. and Hoye, T. (2019). R. Divergent reactivity during the trapping of
benzynes by glycidol analogs: ring cleavage via pinacol-like rearrangements vs.
oxirane fragmentations. Org. Lett. 21: 2615–2619.
58 Xu, F., Xiao, X., and Hoye, T.R. (2017). Photochemical hexadehydro-Diels–Alder
(hν-HDDA) reaction. J. Am. Chem. Soc. 139: 8400–8403.
59 Shi, J., Li, Y., and Li, Y. (2017). Aryne multifunctionalization with benzdiyne and
benztriyne equivalents. Chem. Soc. Rev. 46: 1707–1719.
60 Xiao, X. and Hoye, T.R. (2019). A one-pot, three-aryne cascade strategy for naphthalene formation from 1,3-diynes and 1,2-benzdiyne equivalents. J. Am. Chem.
Soc. 141: 9813–9818.
61 Wang, T., Naredla, R.R., Thompson, S.K., and Hoye, T.R. (2016). The
pentadehydro-Diels–Alder reaction. Nature 532: 484–488.
62 Xiao, X., Woods, B.P., Xiu, W., and Hoye, T.R. (2018). Benzocyclobutadienes: an
unusual mode of access reveals unusual modes of reactivity. Angew. Chem. Int.
Ed. 57: 9901–9905.
63 Thompson, S.K. and Hoye, T.R. (2019). The aza-hexadehydro-Diels–Alder reaction. J. Am. Chem. Soc. 141: 19575–19580.
64 Niu, D., Wang, T., Woods, B.P., and Hoye, T.R. (2014). Dichlorination of
(hexadehydro-Diels–Alder generated) benzynes and a protocol for interrogating
the kinetic order of bimolecular aryne trapping reactions. Org. Lett. 16: 254–257.
65 Xu, F., Xiao, X., and Hoye, T.R. (2017). Photochemical hexadehydro-Diels–Alder
reaction. J. Am. Chem. Soc. 139: 8400–8403.
66 Pierson Smela, M. and Hoye, T.R. (2018). A traceless tether strategy for achieving formal intermolecular hexadehydro-Diels–Alder reactions. Org. Lett. 20:
5502–5505.
67 For a summary of these methods, see, for example: (a) Tadross, P.M. and Stoltz,
B.M. (2012). A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112: 3550–3577. (b) Gampe, C.M. and Carreira, E.M. (2012).
Arynes and cyclohexyne in natural product synthesis. Angew. Chem. Int. Ed. 51:
3766–3778. (c) Kitamura, T. (2010). Synthetic methods for the generation and
preparative application of benzyne. Aust. J. Chem. 63: 987–1001.
68 See “Antoine Equation Excel file” at http://hoye.chem.umn.edu/teaching
(accessed 3 January, 2021).
69 http://www.public.asu.edu/~aomdw/MAIP/index.html (accessed 3 January 2021).
70 Maretina, I.A. and Trofimov, B.A. (2000). Diacetylene: a candidate for industrially important reactions. Russ. Chem. Rev. 69: 591–608.
443
444
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry
71 Glen, A.T., Hutchinson, S.A., and McCorkindale, N.J. (1966). Hexa-1, 3,
5-triyne – a metabolite of fomes annosus. Tetrahedron Lett. 4223–4225.
72 Woods, B.P. and Hoye, T.R. (2014). Differential scanning calorimetry (DSC) as a
tool for probing the reactivity of polyynes relevant to hexadehydro-Diels-Alder
(HDDA) cascades. Org. Lett. 16: 6370–6373.
73 https://www.yumpu.com/en/document/read/3619825/dsc-differential-scanning-cl-iaormetry (accessed 3 January 2021).
74 (a) Vandavasi, J.K., Hu, W.-P.P., Hsiao, C.-T.T. et al. (2014). A new approach for
fused isoindolines via hexadehydro-Diels–Alder reaction (HDDA) by Fe(0) catalysis. RSC Adv. 4: 57547–57552. (b) Ghorai, S. and Lee, D. (2018). Silver-catalyzed
cycloaddition reactions. In: Silver Catalysis in Organic Synthesis (eds. C.-J. Li
and X. Bi), 33–83. New York: Wiley-VCH. (c) Karmakar, R., Wang, K.-P.P., Yun,
S.Y. et al. (2016). Hydrohalogenative aromatization of multiynes promoted by
ruthenium alkylidene complexes. Org. Biomol. Chem. 14: 4782–4788. (d) Sieck,
C., Tay, M.G., Thibault, M.-H. et al. (2016). Reductive coupling of diynes at
rhodium gives fluorescent rhodacyclopentadienes or phosphorescent rhodium
2,2′ -biphenyl complexes. Chem. Eur. J. 22: 10523–10532.
445
11
Applications of Benzynes in Natural Product Synthesis
Hiroshi Takikawa 1 and Keisuke Suzuki 2
1
Kyoto University, Graduate School of Pharmaceutical Sciences, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto
606-8501, Japan
2
Tokyo Institute of Technology, Department of Chemistry, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551,
Japan
11.1 Introduction
Complex molecular architectures embedded in bioactive natural products give
us various synthetic issues, requiring innovative approaches for (i) expeditious
skeletal construction, (ii) introduction/management of sensitive functionalities,
and (iii) stereochemical control. Complex polycyclic natural products belong to
such challenging targets, which provide high levels of synthetic difficulties. As one
of the tactical bases to cope with such problems, potential utility of benzynes [1] has
been recognized from the early days, expecting for their inherently high reactivity
and unique characteristics. In recent years, we have witnessed significant advances
along these lines, as reviewed in some recent articles [2].
This chapter is an overview of benzyne chemistry in natural product synthesis [3]. Examples are classified by the reaction patterns, i.e. additions of nucleophiles
(Section 11.3), addition–fragmentation reactions (Section 11.4), [4+2] cycloadditions (Section 11.5), [2+2] cycloadditions (Section 11.6), and ene reactions (Section
11.7). Recent advances, including the multiple use of benzyne, transition metals in
benzyne reactions, and a de novo generation of benzynes from triyne precursors,
are also outlined (Section 11.8).
11.2 General Reactivities of Benzynes
The frontier orbital of benzyne is the unusually low-lying LUMO, leading to the
high electrophilicity (Figure 11.1) [1, 2]. Nonanionic nucleophiles, such as tertiary
amines and even ethers, may add to benzynes (Figure 11.1, (1)) [5]. The resulting
aryl anions can be protonated, giving simple adducts, but trapping with other electrophiles (E+ ) leads to vicinal difunctionalization [6], reminiscent of the 1,4-addition
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
446
11 Applications of Benzynes in Natural Product Synthesis
(1)
E
(3)
Nu then
E+
Nu
H
H
Benzyne
(2)
(4)
Figure 11.1 Four typical reactivities of benzynes: (1) nucleophilic addition; (2) [4+2]
cycloaddition; (3) [2+2] cycloaddition; and (4) ene reaction. Source: Based on Kametani and
Ogasawara [4].
to α,β-enones and enolate trapping. In addition, the formal triple bond of a benzyne
has the ability to undergo pericyclic reactions, including [4+2] cycloadditions, [2+2]
cycloadditions, and ene reactions (Figure 11.1, (2), (3), (4)). Interestingly, benzynes
undergo thermal [2+2] cycloaddition reaction with alkenes or alkynes [7], normally
a symmetry-forbidden process, which can be explained by the frontier molecular
orbital theory [8].
For the benzyne reactions, the choice of the benzyne precursor is critical.
Depending on the reactivity of the reaction partner, one needs to choose a suitable
precursor and associated conditions. Table 11.1 lists four representative methods
for benzyne generation, showing the precursors and the typical reaction conditions
used in natural product synthesis. Aryl halides are the most conventionally used
precursor, which are treated with bases to generate benzyne via deprotonation
followed by β-elimination (no. 1). The halogen–metal exchange reactions are also
exploited, using aryl halides possessing an ortho-leaving group (no. 2). Another
means is the fluoride-induced desilylation of arylsilanes with an ortho-leaving
group (no. 3). Thermolysis of benzenediazonium-2-carboxylates was frequently
used in the early days (no. 4), although special precautions are required owing to
the highly explosive properties.
11.3 Strategies Based on Nucleophilic Additions
to Benzynes
Among the various reactivities of benzynes, additions of nucleophiles have been
most extensively utilized for natural product synthesis. This section will describe
related topics in three parts categorized by the difference in the nucleophilic atoms,
nitrogen nucleophiles (Section 11.3.1), oxygen nucleophiles (Section 11.3.2), carbanions (Section 11.3.3.1), and enamines or enolates (Section 11.3.3.2). Section 11.4
will deal with the addition–fragmentation reaction of benzynes, a sequential process
initiated by the nucleophilic addition.
11.3 Strategies Based on Nucleophilic Additions to Benzynes
Table 11.1
No.
Benzyne precursors used in natural product synthesis.
Benzyne precursor
1
H
Reagent
Applications in natural product syntheses
Amide base RLi
Nucleophilic addition
[4+2] Cycloaddition
[2+2] Cycloaddition
Ene reaction
RLi, RMgX
[4+2] Cycloaddition
[2+2] Cycloaddition
Fluoride ion
Nucleophilic addition
[4+2] Cycloaddition
[2+2] Cycloaddition
Transition-metal-catalyzed reaction
Ene reaction
(Heat)
Nucleophilic addition
[4+2] Cycloaddition
Lv
Lv = F, Cl, Br, I
2
X
Lv
X = Br, I; Lv = Br, OSO2R
3
SiMe3
OTf
4
COO–
N+
N
11.3.1 Additions of Nitrogen Nucleophiles
Addition of nitrogen nucleophiles to benzynes is one of key methods for constructing aza-cycles in alkaloid scaffolds. An early example is the seminal synthesis of
cryptowoline by Kametani and Ogasawara in 1967, featuring an intramolecular benzyne addition of a nitrogen nucleophile for constructing the indoline skeleton of
the dibenzopyrrocoline alkaloids (Scheme 11.1) [4]. By the action of sodium amide
in liquid ammonia, aryl chloride 1 undergoes 1,2-elimination to generate benzyne 2.
The amino group is concurrently deprotonated to give an amido anion, which adds
to the internal benzyne to give indoline 3.
MeO
MeO
MeO
NH
Cl
BnO
NaNH2
O
1
Scheme 11.1
N
N
BnO
NH3 (l)
THF
–40 °C
I
+
H
HO
N
Me
O
O
O
O
O
2
77%
O
O
3
Cryptowoline
Syntheses of dibenzopyrrocoline alkaloids [4].
In 1922, Meyers and coworker reported the asymmetric total synthesis of
(+)-cryptaustoline (Scheme 11.2) [9]. The key transformation is a diastereoselective
alkylation of isoquinoline 4 with benzyl bromide 5 by the assistance of a chiral amidine based auxiliary, which is followed by intramolecular amination of benzyne 6.
447
448
11 Applications of Benzynes in Natural Product Synthesis
It is notable that even a nonanionic nitrogen nucleophile within an amidine can
attack the benzyne species.
MeO
N
BnO
s-BuLi
N
4
N
N
–80 °C
Cl
N
N
R*
R*
s-BuLi
Ot-Bu
Br
Cl
OMe
OMe
OMe
OMe
6
OMe
5
OMe
*
N
R
MeO
+
Li
N+
(1)
OMe
H3O+
BnO
MeO
I
Me
I
+
N
HO
Me
OMe
(2) MeI
58%
OMe
Scheme 11.2
Meyers [9].
N
OMe
OMe
OMe
(+)-Cryptaustoline
Asymmetric synthesis of cryptaustoline. Source: Based on Sielecki and
Another example of an intramolecular benzyne amination is the Iwao synthesis of the makaluvamines, a class of the pyrroloiminoquinone alkaloid
(Scheme 11.3a) [10]. Construction of the pyrroloquinoline skeleton is effected by
using 4-chloroindole 7 as the benzyne precursor and LiNi-PrCy as the base. A similar approach is employed by Tokuyama and coworkers [11], using 4-iodoindoline 8
with an N-Boc-aminoethyl group is treated with LiTMP at −78 ∘ C (Scheme 11.3b).
Importantly, the in situ–generated aryl anion can be trapped with an electrophile.
Indolyne 9 undergoes an intramolecular attack of the carbamate anion and an in
situ chlorination by treatment with Cl(CCl2 )2 Cl, giving the corresponding chloride
10, allowing access to halo congeners, such as isobatzelline C.
Cl
NH2
N
Me
MeO
H
H3O+
LiNi-PrCy
THF, 0 °C
N
Me
MeO
+
HN
HN
H2N
7
N
Me
MeO
78%
N
H2N
Me
O
Makaluvamine A
(a)
I
BocHN
NHBoc
N
CO2Et
MeO
8
(b)
THF
–78 °C
N
CO2Et
MeO
9
N
BocN
Cl(CCl2)2Cl
LiTMP
Cl
Cl
MeO
64%
10
N
CO2Et
N
H2N
O
Me
Isobatzelline C
Scheme 11.3 (a) Syntheses of makaluvamine A. Source: Based on Iwao et al. [10] and (b)
isobatzelline C. Source: Based on Oshiyama et al. [11].
Tokuyama and coworkers expanded such in situ–trapping protocol to the
cross-coupling reactions, as illustrated by the total synthesis of dictyodendrin A, a
11.3 Strategies Based on Nucleophilic Additions to Benzynes
telomerase-inhibitory marine natural product (Scheme 11.4) [12]. Treatment of aryl
dibromide 11 with Mg(TMP)2 ⋅2LiBr allows the formation of arylmagnesium intermediate 12 via addition of the N-Boc-amido anion to the generated benzyne. After
the Mg → Cu transmetalation, Pd-catalyzed coupling with iodo-p-methoxybenzene
gives arylindoline 13. Other bases such as LiTMP and [Me2 Zn(TMP)]Li are less
effective, and Mg(TMP)2 ⋅2LiBr proved to be a suitable base.
MeO
MeO
Br
Br
OMe
Mg(TMP)2 ·2LiBr
OMe
THF
–78 to 0 °C
BocHN Br
OSO3– Na+
HO
NH
BocN
11
MeO2C
MeO
MeO
Br
Br
Cul, –78 °C
OMe
N
Boc
12
Scheme 11.4
OH
N
Mg(TMP)
OMe
p-MeOC6H4I
[Pd(PPh3)4]
–78 °C to rt
N
OH
HO
7
OH
Boc
Dictyodendrin A
93%
13
OMe
Syntheses of dictyodendrin A. Source: Based on Okano et al. [12].
The intermolecular versions of the benzyne reactions have also been used in
alkaloid syntheses, as demonstrated by the Watanabe synthesis of acronycine, an
antitumor acridone alkaloid (Scheme 11.5a) [13]. The annulation of aminoester
14 with bromochromene 15 is achieved via addition of amido anion 16 to the
benzyne 17 followed by cyclocondensation, giving acronycine. Recently, Argade
and coworker reported the related reaction of quinozalinone 18 and silylaryl
triflate 19 in the syntheses of quinazolinone alkaloids (Scheme 11.5b). Anion
20, derived from 18, undergoes an intermolecular addition to benzyne 21, and
subsequent cyclocondensation gives tryptanthrin, which is further converted to
cruciferane [14].
An intermolecular addition of alkylamines to benzyne is less common. In 2011,
Garg and coworkers reported the total synthesis of indolactam V, an alkaloid with an
ansa bridge (Scheme 11.6) [15]. Aminoindole 25 is synthesized by the regioselective
intermolecular addition of dipeptide 22 to indolyne 24, generated from silylaryl triflate 23 and CsF. The enhanced electrophilicity of the C-4 position in 24 is rationalized by the geometrical distortion effect by the bromo group [16].
A recent example of an intermolecular reaction of alkylamines can be found in the
Zhu synthesis of hinckdentine A via the benzyne annulation of an α-aminoimide
(Scheme 11.7) [17]. Treatment of silylaryl triflate 19 with CsF generates benzyne,
which undergoes nucleophilic addition of cyclic α-amino imide 26, followed by
cyclocondensation to give indolinone 27. The reaction of the corresponding α-amino
ester was not fruitful.
449
450
11 Applications of Benzynes in Natural Product Synthesis
O
OMe
NH
O
Me
14
LiNi-PrCy
THF
–78 to –10 °C
OMe
Br
O
OMe
OMe
N
N
O
Me
41%
16
O
O
Me
17
Acronycine
15
(a)
O
NH
OEt
N
18
Me3Si
N
N
MeCN
25 °C
O
O
O
CsF
NaHCO3
O
OEt
N
20
N
N
O
Tryptanthrin
94%
21
O
H
N
OH
Cruciferane
TfO
19
(b)
Scheme 11.5 (a) Syntheses of acronycine. Source: Based on Watanabe et al. [13] and
(b) quinazolinone alkaloids. Source: Based on Vaidya and Argade [14].
Me
N
H
H
N
CO2Me
O
Me
OH
22
CsF
SiMe3
O
4
MeCN
0 °C to rt
TfO
H
N
N
H
Br
Br
23
24
N
H
Scheme 11.6
CO2Me
Me
OH
N
H
H
N
N
H
O
Br
N
H
62%
CO2Me
Me
H
N
N
OH
O
OH
N
H
25
Indolactam V
Synthesis of indolactam V. Source: Based on Bronner et al. [15].
SiMe3
OTf
CsF
O
MeCN
rt
BocN
NH2
26
Br
BocN
NH2
NO2
N
H
38%
27
NH
Br
NO2
NHBoc
Br
N
N
Hinckdentine A
NO2
Scheme 11.7
O
O
O
19
Synthesis of hinckdentine A. Source: Based on Torres-Ochoa et al. [17].
11.3.2 Additions of Oxygen Nucleophiles
This part describes the synthetic strategies based on the addition of oxygen
nucleophiles to benzynes. As benzynes are soft electrophiles, addition of hard
nucleophiles is relatively difficult. Indeed, oxygen nucleophiles have been
little applied to natural product syntheses, which stand in contrast to nitrogen
nucleophiles.
11.3 Strategies Based on Nucleophilic Additions to Benzynes
One of the few examples is Stoltz’s asymmetric synthesis of liphagal, a meroterpenoid (Scheme 11.8) [18]. Benzyne 29, generated from aryl bromide 28, undergoes
nucleophilic addition of an internal alkoxide, giving dihydrobenzofuran 30. Note
that the high reactivity of the benzyne enables the bond formation at a congested
position. By contrast, related attempts via a Cu-catalyzed cyclization failed [19].
MeO
OMe
MeO
MeO
Br
OH
LDA
HO
H
O
OLi
THF
–20 °C
O
OH
H
MeO
MeO
O
83%
H
29
28
Scheme 11.8
30
Liphagal
Synthesis of liphagal. Source: Based on Day et al. [18].
Larock and coworker reported the construction of xanthone structures via the
benzyne reactions with phenolates [20], which is exploited by Moody and coworkers
for the total synthesis of toxyloxanthone B (Scheme 11.9) [21]. Benzyne 33, generated from silylaryl triflate 31, reacts with the phenolate 32 in a regioselective manner, giving xanthone 34, after an intramolecular condensation reaction. Use of NaH
suppresses formation of the byproduct derived from simple protonation after the
addition stage.
MOMO
CO2Me
BnO
OH
OBn
Me3Si
O
NaH
CsF
MOMO
THF
65 °C
BnO
OBn
O
OBn
32
TfO
O
OBn
MOMO
OMe
BnO
40%
33
O
OBn
34
OBn
31
O
OH
O
HO
O
OH
Toxyloxanthone B
Scheme 11.9
Synthesis of toxyloxanthone B. Source: Based on Giallombardo et al. [21].
Knight et al. reported a formal synthesis of vitamin E (Scheme 11.10) [22]. Aminotriazole 35 allows the reaction under nearly neutral conditions, demonstrating the
addition of a nonionized alcohol. After Boc-deprotection in 35, exposure to NIS
under neutral conditions generates benzyne 36, inducing a nucleophilic addition of
an internal hydroxy group. The resulting aryl anion is trapped by NIS, giving aryl
iodide 37.
451
452
11 Applications of Benzynes in Natural Product Synthesis
OH
MeO
OH
N NHBoc
N N
OH
(1) TFA
MeO
MeO
OH
(2) K2CO3;
NIS
63%
(2 steps)
I+
35
I
37
36
Scheme 11.10
Xu [22b].
OH
O
Synthesis of vitamin E core. Source: Knight and Qing [22a]; Knight and
11.3.3 Addition of Carbon Nucleophiles
Benzyne addition of carbon nucleophiles provides opportunities for constructing
densely substituted polycyclic natural products. The carbon nucleophiles are categorized into (a) carbanions, and (b) π-nucleophiles, such as enamines and enolates.
11.3.3.1 Carbanions
An early example is Oppolzer’s synthesis of chelidonine, featuring a benzocyclobutene formation via the benzyne addition of an internal carbanion
(Scheme 11.11) [23]. Upon treatment of bromobenzene 38 with KNH2 , the
α-cyano carbanion attacks the internal benzyne, generated in situ, giving benzocyclobutene 39. After assembly of the D ring unit to afford alkyne 40, heating of
40 triggers pericyclic ring opening to generate quinodimethane 41 that undergoes
an intramolecular [4+2] cycloaddition to give hexacyclic compound 42. Similar
reactions were extensively used for various steroid syntheses by Kametani et al. [24].
O
H
Br
O
O
CN
KNH2
O
NH3 (l)
O
O
O
O
CN
38
Cbz
O
O
40
O
O
MeN
O
O
H
D
H
O
O
73%
41
Scheme 11.11
N
O
O
D
O
O
N
O
N
O
39
Cbz
o-Xylene
120 °C
Cbz
CN
42
OH
Chelidonine
Synthesis of chelidonine. Source: Based on Oppolzer and Keller [23].
In 2006, Barrett and coworkers achieved the asymmetric total synthesis of
ent-clavilactone B by using a benzyne-based three-component coupling (Scheme
11.12) [25]. The benzyne, generated from fluorobenzene 43, reacts with Grignard
reagent 44 to give aryl magnesium 45, which is trapped with epoxyaldehyde 46,
giving epoxyalcohol 47. The synthesis proved the unknown absolute stereochemistry of the natural product. The approach was expanded to a four-component
variant, and exploited in the total synthesis of dehydroaltenuene B, an antibacterial
marine natural product [26].
11.3 Strategies Based on Nucleophilic Additions to Benzynes
O
H
O
ClMg
44
MeO
46
F
O
MeO
n-BuLi
O
THF
–78 °C
MeO
OTBS
MeO
MeO
MgCl
MeO
OH
65%
(d.r. = 1.6 : 1)
47
MeO
MeO
43
45
Scheme 11.12
O
O
OTBS
O
O
ent-Clavilactone B
Synthesis of ent-clavilactone B. Source: Based on Larrosa et al. [25].
𝛑-Nucleophiles: Enamines and Enolates
11.3.3.2
Enamines are suitable for alkaloid syntheses since the nitrogen atom becomes a part
of the target. Kametani et al. reported in 1977 the total synthesis of xylopinine, a
protoberberine alkaloid (Scheme 11.13) [27]. Treatment of bromobenzene 48 with
NaNH2 generates benzyne 49, which undergoes nucleophilic attack of the internal enamine, giving tetracycle 50. A similar scheme is exploited by Kibayashi and
coworkers in the total synthesis of an Amaryllidaceae alkaloid [28].
MeO
MeO
MeO
MeO
N
N
NH3(l)
–33 °C
Br
OMe
OMe
48
N
MeO
NaNH2
15%
H
OMe
49
OMe
MeO
50
N
OMe
OMe
OMe
OMe
Xylopinine
Scheme 11.13 Intramolecular addition in the synthesis of xylopinine. Source: Based on
Kametani et al. [27].
In 2008, Stoltz and coworkers reported the construction of the isoquinoline
skeleton of papaverine, a biosynthetic precursor of the pavine-class opiate natural
products by an annulation of benzynes with N-acyl enamines (Scheme 11.14) [30].
Benzyne 53, generated from silylaryl triflate 51, undergoes nucleophilic addition
of enamide 52, and the subsequent cyclocondensation gives isoquinoline 54. The
strategy was further exploited for the asymmetric total synthesis of (–)-quinocarcin,
a tetrahydroisoquinoline antitumor antibiotic [29]. Note that orthogonal reactivities
SiMe3
MeO
MeO
OTf
51
CO2Me
O
MeO
TBAT
THF
23 °C
CO2Me
O
MeO
N
MeO
CO2Me
N
MeO
53
MeO
MeO
N
OMe
OMe
NH
OMe
70%
54
OMe
OMe
Papaverine
OMe
52
Scheme 11.14
Synthesis of papaverine. Source: Based on Allan and Stoltz [29].
453
454
11 Applications of Benzynes in Natural Product Synthesis
are observed by differentially substituted enamine derivatives, in that reaction of
N-Boc enamines with benzyne gives the corresponding indolines via a formal [3+2]
cycloaddition.
Recently, Guo, He, and coworkers reported the total syntheses of the dictyodendrins, potential compounds for treatment of Alzheimer disease (Scheme 11.15)
[31]. The indole skeleton is constructed by a formal [3+2] cycloaddition of
2-aminoquinone methide 56 and the benzyne intermediate generated from silylaryl
triflate 55 upon treatment with TBAT. Initially, regioselective addition of the
enamine moiety in 56 as a π-nucleophile to the benzyne occurs to give zwitterionic
intermediate 57, whose aryl anion moiety adds to the iminium nitrogen, activated by
the 14-carbonyl group, followed by dehydrogenation to give the desired annulated
product 58, along with the regioisomer 59.
OMe
MeO
+
MeO
TBAT
N
SiMe3
N
THF
60 °C
MeO
H 2N
55
O
MeO
N
H
R1
N
H
50%
(58 : 59 = 4 : 1)
O
O
N
HO
O
OMe
58 (R1 = H, R2 = OMe)
59 (R1 = OMe, R2 = H)
O
OH
HO
N
R2
O
57
OMe
[O]
14
+
H2N
O
MeO
O
N
MeO
H2N
OMe
56
N
O
O
O
OTf
MeO
MeO
MeO
N
H
O
OH
Dictyodendrin F
Scheme 11.15 Annulation of a benzyne in the synthesis of dictyodendrins. Source: Guo
et al. [31a]; Banne et al. [31b].
In the total synthesis of welwitindolinone alkaloid, a marine natural product,
Garg and coworkers used an intramolecular indolyne addition of an enolate,
constructing the bicyclo[4.3.1]decenone skeleton (Scheme 11.16a) [32]. Upon
treatment of bromobenzene 60 with NaNH2 , benzyne 61 undergoes addition of
an internal enolate, giving tetracycle 62. As side product, 63 is formed by an
O-addition. A similar cyclization was used for the total synthesis of tubingensin A,
constructing the characteristic fused ring system with vicinal quaternary carbon
centers (Scheme 11.16b) [33].
11.4 Addition–Fragmentation Reactions
The addition–fragmentation reaction of benzyne is a useful process, which is
initiated by the nucleophilic addition to benzyne followed by reaction of the
11.4 Addition–Fragmentation Reactions
OTBS
H
Br
OTBS
NaNH2
t-BuOH
H
H
H
O
N
Me
+
O
N
Me
61
SCN
O
H
O
N
Me
60
N
Me
62 (33%)
63 (13%)
(a)
OTES
N
MOM
H
O
N
Me
N-Methylwelwitindolinone C
isothiocyanate
OH
O
O
NaNH2
Br
Cl
H
H
THF
23 °C
O
OTBS
TBSO
H
t-BuOH
THF
23 °C
N
H
Tubingensin A
N
MOM
84%
(b)
Scheme 11.16 Synthesis of (a) welwitindolinone alkaloid. Source: Based on Huters et al.
[32] and (b) tubingensin A. Source: Based on Goetz et al. [33].
resulting aryl anion to an internal carbonyl and bond cleavage. In 1967, Caubère
reported a prototype of this sequential process, where simple ketone enolates were
the nucleophiles (Scheme 11.17a) [34]. Later, Guyot and Molho used 1,3-dicarbonyl
compounds in related reactions (Scheme 11.17b) [35]. Benzyne 64, generated from
o-bromoanisole by reaction with NaNH2 , undergoes an attack of malonate anion 65,
concomitantly generated from diethyl malonate. Migration of the ethoxycarbonyl
group followed by hydrolysis gives ester 66, which is converted to the natural
product, melleine [36].
Br
O
O
NaNH2
–
O
O–
–
O
(a)
Br
EtO
MeO
NaNH2
EtO
HMPA
55 °C
O
O
EtO
O
CO2Et
–
OR
O
MeO
64
EtO
65
MeO
R = Et
R = H (66)
O
O
OH
KOH
25% (2 steps)
O
Mellein
(b)
Scheme 11.17 Addition–fragmentation reactions of benzyne with (a) acetone or
(b) diethyl malonate. Source: Caubère [34]; Guyot and Molho [35].
The Danishefsky synthesis of dynemicin A in 1995 [37] used the addition–
fragmentation reaction for annulation to the E-ring. Benzyne 68, generated from
bromobenzene 67, reacts with an enolate of dimethyl malonate to give ester
69 (Scheme 11.18). A suitable set of reaction conditions is established (LiTMP,
THF, −78 ∘ C), giving higher yield compared to the conditions using NaNH2 .
More recently, Lin, Shia, and coworkers exploited this reaction to the synthesis
455
456
11 Applications of Benzynes in Natural Product Synthesis
of fasamycin A [38], where the optimized conditions involve the use of sodium
malonate as a nucleophile and LDA as a base [39].
MOMO
Br
MOMO
MOMO
67
THF
–78 °C
O
OH
OMe
–
O
MOMO
O
HN
CO2H
O
OMe
E
MeO
MOMO
71%
68
O
H
O
O
LiTMP
MeO
MOMO
MeO
O
OMe
OH
69
H
O
OH
Dynemicin A
MeO
Scheme 11.18
Synthesis of dynemicin A. Source: Based on Shair et al. [37a].
The addition–fragmentation strategy is involved as one of the key steps in Kita’s
synthesis of fredericamycin A (Scheme 11.19) [40]. The benzyne, generated from
aryl bromide 70, reacts with the enolate derived from dimethyl malonate to give
regioisomeric esters 71 and 72 (3 : 2 ratio), which are used for the syntheses of
both enantiomers of the natural product, clarifying the hitherto-unknown absolute
configuration.
MeO
OMe
Br
OMe
70
OMe
O
OMe
LiTMP
THF
–78 °C
MeO2C
–
OMe
OMe
MeO2C
+
MeO2C
O
OMe
OMe
71
OMe
O
OMe
MeO2C
OMe
OMe
72
58% (combined yield)
71 : 72 = 3 : 2
OMe
O
O
HO
O
OMe
OMe
OMe
O
OH
HO
O
O
HN
Fredericamycin
Scheme 11.19
Synthesis of fredericamycin A.Source: Based on Kita et al. [40a].
Application of the addition–fragmentation reaction to cyclic substrates provides
the corresponding ring-expanded products, as initially demonstrated by Danheiser
and Helgason in the synthesis of salvilenone, a phenalenone diterpene [36c].
Silylaryl triflates have been extensively exploited as effective benzyne precursors
(Scheme 11.20) [44]. Stoltz and coworkers achieved the total synthesis of curvularin,
a natural product having a benzannulated macrolactone structure (Scheme 11.20a)
[41]. By treating silylaryl triflate 31 and cyclic ketoester 73 with CsF, a regioselective addition proceeds, and subsequent expansion gives macrocyclic lactone
74. In 2016, Iwabuchi and coworkers reported the synthetic study of turkiyenine
11.5 Strategies Based on [4+2] Cycloadditions
(Scheme 11.26) [42]. Treatment of silylaryl triflate 75 and β-ketolactam 76 with
CsF induces a facile addition–fragmentation reaction, giving benzazepineone
77, which is reduced to give the originally proposed structure of turkiyenine.
Recently, Sarpong and coworkers demonstrated the utility of this reaction in the
total synthesis of cossonidine (Scheme 11.20c) [43]. In the presence of β-ketoester
79, silylaryl triflate 78 is treated with CsF, the ketoester anion derived from 79 adds
to benzyne 80 regioselectively to give tricyclic compound 81.
BnO
SiMe3
BnO
OTf
CsF
MeCN
rt
O
BnO
O
BnO
31
O
O
HO
BnO
O
BnO
30%
O
(a)
OH
O
O
O
O
74
O
O
Curvularin
73
Me3Si
O
O
TfO
O
77%
O
O
O
O
O
O
O
O
O
O
77
O
O
(b)
MeN
MeN
O
O
O
O
O
MeCN
rt
MeN
O
O
MeN
CsF
O
O
O
O
O
75
Turkiyenine
(proposed structure)
76
Br
TfO
Me3Si
Br
78
MeO
O
H
O
CsF
O
O
O
MeO
OMe
O
MeCN
70 °C
H
O
Br
OH
OMe
OMe
80
45%
TBSO
H
O
O
81
H
H
OH
N
H H
H
Cossonidine
TBSO
79
(c)
Scheme 11.20 Syntheses of (a) curvularin. Source: Based on Tadross et al. [41], (b)
turkiyenine. Source: Based on Kobayashi et al. [42], and (c) cossonidine. Source: Based on
Kou et al. [43] .
11.5 Strategies Based on [4+2] Cycloadditions
This section describes the [4+2] cycloadditions of benzynes,1 which provide effective
tools for constructing various fused six-membered ring systems. One of the major
issues is the periselectivity, in that the [2+2] and the ene reactions may compete,
1 The mechanism of the [4+2] and [2+2] cycloadditions has been the subject of controversy, i.e.
concerted vs. stepwise. Since the reaction pathway usually depends on arynophiles, it is not
straightforward to discriminate between these mechanisms. In this review, the categorization
follows the original articles.
457
458
11 Applications of Benzynes in Natural Product Synthesis
although the [4+2] cycloaddition is normally the predominant pathway [47]. The
regioselectivity could be controlled by the substituent effect of the benzynes and the
arynophiles [16].
Among the heterocyclic dienes used as arynophiles, furans are the most commonly used. After the benzyne [4+2] cycloadditions, the cycloadducts are easily
aromatized, allowing facile access to fused aromatic ring systems. Early examples
include the syntheses of averufin by Townsend et al. [48], ellipticine by Gribble et al.
[49], and morindaparvin A by Biehl and coworker [50]. A pioneering report on the
intramolecular variant in the syntheses of naphthoquinone natural products by Best
and Wege is worth noting [51].
Suzuki and coworkers reported in 1992 the total synthesis of ent-gilvocarcin M,
an aryl C-glycoside antibiotic (Scheme 11.21) [52, 53]. Iodoaryl triflate 82 having
a sugar moiety is used as the benzyne precursor, which is treated with n-BuLi
in the presence of methoxyfuran 83 (THF, −78 ∘ C), inducing an intermolecular
[4+2] cycloaddition and subsequent aromatization gives naphthol 84 in 88% yield
(regioisomer: 7% yield). The regioselectivity is attributed to the distortion of the
benzyne [16] and the polarization of the furan, both of which are due to the alkoxy
groups. A similar reaction was subsequently applied to the total synthesis of C104,
an aryl C-glycosyl angucyclinone [54]. In 2014, Hosoya, Sumida, and coworkers
reported the synthesis of gilvocarcin aglycon [55], using aryl boronic acid ester with
an ortho-triflate as a leaving group [56].
BnO
I
BnO
H
BnO
OTf
O
BnO
OMe
BnO
OMe
OH
OMe
O
n-BuLi
OBn 82
THF
–78 °C
BnO
H
O
BnO
OMe
OBn
O
OMe
BnO
88%
H
HO
O
BnO
OH
H
O
HO
O
O
OBn
OH
84
ent-Gilvocarcin M
83
Scheme 11.21
Synthesis of ent-gilvocarcin M. Source: Based on Matsumoto et al. [52a].
Brückner and coworker recently reported the asymmetric total syntheses of arizonin B1 using the [4+2] cycloaddition of benzyne and siloxyfuran (Scheme 11.22)
[57]. Treatment of a mixture of bromoaryl tosylate 85 and siloxyfuran 86 with
n-BuLi gives a mixture of regioisomeric cycloadducts 87 and 88 (84 : 16), which
are converged into the naphthalene 89 by treatment with TBAF. More than 10
naphthoquino-γ-lactone analogues were synthesized by this approach [58].
In 2016, MacMillan, DeBrabander, and coworkers reported the isolation and total
synthesis of rifsaliniketal, a biosynthetic congener of rifamycin (Scheme 11.23) [59].
Based on Kinoshita’s report [60], the central naphthoquinone is constructed by a
benzyne [4+2] cycloaddition. The benzyne intermediate, generated from symmetrical dibromide 90, reacts with furan, giving cycloadduct 91. The total synthesis is
completed by an introduction of the side chain after construction of the naphthoquinone skeleton from 91.
11.5 Strategies Based on [4+2] Cycloadditions
OBn OTIPS
OBn
MeO
MeO
Br
O
OH
OBn OH
85
OTs
87
+
OBn
n-BuLi
THF
–78 °C to rt
OTIPS
TBAF
85%
(2 steps)
MeO
O
89
O
O
MeO
MeO
O
O
O
OH
O
(–)-Arizonin B1
86
OTIPS
88
(87 : 88 = 84 : 16)
Scheme 11.22
Synthesis of arizonins B1. Source: Based on Neumeyer and Brückner [57].
O
O
OBn
Br
BnO
Br
90
LDA
THF
–78 °C
O
OBn
OH OH O
OH O
NH
O
BnO
89%
HO
Br
91
HO
O
O
Rifsaliniketal
Scheme 11.23
Synthesis of rifsaliniketal. Source: Based on Feng et al. [59].
In 2017, Suzuki and coworkers used a benzyne–furan [4+2] cycloaddition in the
enantioselective total synthesis of a marine antibiotic, spiroxin C, (Scheme 11.24)
[61]. Upon treatment of a mixture of aryl bromide 92 and furan with LDA at −78 ∘ C,
a [4+2] cycloaddition proceeds to give cycloadduct 93, which is converted to naphthalene 94 by a ring opening by acid treatment.
OMe
OH
Br
OMe
OMe
92
O
LDA
THF
–78 °C
OH
OMe
HCl aq.
O
OMe
93
87%
(3 steps)
O
O
OMe
94
O
O
O
O
Spiroxin C
Scheme 11.24
Synthesis of spiroxin C. Source: Based on Ando et al. [61].
In 2017, Odagi, Nagasawa, and coworkers reported the total synthesis of rishirilide B using a benzyne–furan [4+2] cycloaddition for constructing the tricyclic
framework (Scheme 11.25) [62]. Note that in the reaction of the benzyne from
bromoaryl triflate 95 with furan, two unprotected tertiary alcohols are tolerated. Rishirilide B is synthesized by a regioselective ring opening followed by
deprotection.
459
460
11 Applications of Benzynes in Natural Product Synthesis
HO
CO2t-Bu
OH
TfO
HO
Br
n-BuLi
95
O
O
THF
–78 °C
Scheme 11.25
OH
HO
CO2H
OH
O
68%
(2 steps) Rishirilide B
O
81%
(d.r. = 1 : 1)
O
CO2t-Bu (1) BBr3
i-Pr2O
OH
(2) AlCl3
Synthesis of rishirilide B. Source: Based on Odagi et al. [62].
The use of elaborated furans as an arynophile is attractive for rapid construction of
highly functionalized polycyclic systems. Koert and coworkers reported a synthetic
study of granaticin A, a pyranonaphthoquinone antibiotic, using a benzyne–furan
[4+2] cycloaddition (Scheme 11.26a) [45]. The benzyne, generated from aryl bromide 92, reacts with tricyclic furan 96 having a pyranyl moiety, giving cycloadduct
97 quantitatively. Lewis and coworkers reported the total syntheses of arnottins I
and II (Scheme 11.26b) [46]. Silylaryl triflate 75 is treated with CsF in the presence
of furan having a functionalized aryl group 98, giving cycloadduct 99. Acid treatment
of 99 induces a ring opening and lactonization to give arnottin I. Use of a t-butyl ester
is essential; the yield is low with the corresponding methyl ester.
MeO
Br
MeO
MeO 92
LDA
O
O
O
O
THF
–78 °C
MeO
Quant.
OH OH
OH
O
OH
O
O
O
O
OMe
97
O
Granaticin A
O
O
96
OMe
(a)
O
SiMe3
O
OTf
O
75
O
OMe
OMe
t-BuO
t-BuO
CsF
O
O
64%
O
OMe
O
OMe
OMe
p-TsOH
O
MeCN
23 °C
OMe
99
O
MeOH
50 °C
O
92%
Arnottin I
O
98
(b)
Scheme 11.26 Syntheses of (a) granaticin A. Source: Based on Bartholomäus et al. [45],
and (b) arnottin I. Source: Based on Moschitto et al. [46].
Martin and coworkers exploited an intramolecular benzyne–furan [4+2] cycloaddition for the total synthesis of isokidamycin (Scheme 11.27). A disposable silicon
11.5 Strategies Based on [4+2] Cycloadditions
tether is used to connect a benzyne precursor and a furanyl arynophile [63]. Dibromide 100, flanked by a glycosyl furan, is treated with n-BuLi, to generate a benzyne
species that undergoes a [4+2] cycloaddition to give cycloadduct 101. A four-atom
linker is identified as an appropriate tether length [64]. The tether is cleaved by
treatment of TBAF⋅3H2 O to give, after methylation, naphthalene 102.
Si
O
H
O
OBn
Br
O
Sugar
O
OBn
H
OH
O
O
H
O
O
NMe2
O
MeI, NaH
0 °C
85%
O
OMe OBn
TBAF·3H2O
DMF, 70 °C;
Sugar OMe
Isokidamycin
Sugar OMe
101
Scheme 11.27
O
OMe
Me2N
O
92%
HO
OMe
NMeBoc
100
Si
OBn
O
THF
–25 °C
Br
BnO
O
Si
n-BuLi
102
Synthesis of isokidamycin. Source: Based on O’Keefe et al. [63a].
Among various dienes other than furans in benzyne [4+2] cycloaddition, pyrroles
are useful for the construction of benzo-fused aza-bicyclic skeletons. Based on
the early work of Lautens and coworkers on the asymmetric total synthesis of
(+)-homochelidonine, a phenanthridine alkaloid [65], Coquerel and coworkers
used a benzyne–pyrrole [4+2] cycloaddition in the total synthesis of nomitidine
(Scheme 11.28) [66]. The Lautens intermediate 104 is obtained by the [4+2]
cycloaddition of the benzyne, generated from silylaryl triflate 75, and N-Boc-pyrrole
103. After several steps, the isoquinoline skeleton is constructed by another [4+2]
cycloaddition of aza-diene 105 and benzyne 53. The use of the electron-rich diene
105 is essential; otherwise, the [2+2] cycloaddition of the benzyne with the imine
moiety in 105 would compete. The dimethylamino group also serves as a leaving
group for the aromatization.
Me3Si
O
TfO
O
75
NBoc
Boc
O
N
KF
18-crown-6
O
NBoc
THF
70 °C
O
O
O
88%
104
N
O
N
103
O
MeO
O
N
MeO
53
Scheme 11.28
O
MeO
N
MeO
105
O
N
Nomitidine
Synthesis of nomitidine. Source: Based on Castillo et al. [66].
105
461
462
11 Applications of Benzynes in Natural Product Synthesis
α-Pyrones are often exploited in the benzyne [4+2] cycloaddition. After the
cycloaddition, extrusion of CO2 ensures smooth aromatization to afford the
naphthalene core. In an early report on the syntheses of pyridocarbazole alkaloids
by Moody and coworker, the benzyne [4+2] cycloaddition of a pyranoindolone
is exploited as an arynophile for constructing the isoquinoline skeleton [67].
Cho and coworkers’s synthesis of ningalin D highlights this reaction in alkaloid
syntheses (Scheme 11.29) [68]. The benzyne–pyrone [4+2] cycloaddition followed
by spontaneous aromatization via CO2 extrusion gives naphthalene 106, which is
exploited for the construction of the characteristic biphenylene quinonemethide
framework.
Cl–
+
N
MeO
N
MeO
CO2H
ClCH2CH2Cl
100 °C
O
O
OH
O
MeO
O
MeO
O
HO
OH
Br
HO
OH
N
Br
OH
HO
Br
MeO
O
MeO
Scheme 11.29
HO
MeO
O
–CO2
OH
O
OH
Ningalin D
Br
MeO
106
89%
Syntheses of ningalins D and G. Source: Based on Kim et al. [68].
As a limited example of using cyclopentadiene as an arynophile, Buszek and
coworkers reported the total syntheses of cis-trikentrin B and other related indole
alkaloids (Scheme 11.30) [69]. The characteristic fused-ring structure is constructed
by the [4+2] cycloaddition of indolyne 108, generated from tribromoindole 107,
and cyclopentadiene. It should be noted that the Br–Li exchange only occurred at
the C-7 position, leading to the regioselective formation of 109.
Br
Br
N
7
TBS
Br
107
Br
Br
n-BuLi
N
TBS
Toluene
–78 °C to rt
108
Scheme 11.30
N
H
N
TBS
72%
109
cis-Trikentrin B
Synthesis of trikentrins. Source: Based on Chandrasoma et al. [69a].
Use of cyclohexadienes in benzyne cycloaddition has been rare in natural product
syntheses, due to the periselectivity problem: the [4+2] reactions of carbocyclic
dienes or acyclic dienes are often annoyed by competing [2+2] and ene reactions
[47]. However, the situation is different in the intramolecular variant. In 1995,
11.5 Strategies Based on [4+2] Cycloadditions
Buszek and Bixby reported an intramolecular benzyne [4+2] cycloaddition of
cyclohexadienes in the total synthesis of pseudopterosin aglycon (Scheme 11.31)
[70]. Aryl bromide 110 having a cyclohexadienyl moiety is treated with LDA to
generate benzyne 111 that undergoes an intramolecular [4+2] cycloaddition to give
cycloadduct 112 as a mixture of diastereomers. One of the diastereomers is used for
the synthesis of the aglycon via oxidative cleavage of the double bond.
OMe
OMe
OMe
OH
OMe
OMe
OH
OMe
LDA
Br
O
THF
–78 °C to rt
O
O
O
H
O
O
112 (d.r. = 58 : 42)
111
110
Scheme 11.31
Bixby [70].
71%
Pseudopterosin aglycone
Synthesis of pseudopterosin aglycon. Source: Based on Buszek and
Suzuki reported an intramolecular benzyne–diene [4+2] cycloaddition with broad
substrate scope by using a cleavable silicon tether, which allows an access to various
polycyclic structures (Scheme 11.32) [71]. 2-Bromo-6-(chlorodiisopropylsilyl)phenyl
tosylate 113 serves as an efficient platform for (i) facile attachment of various
arynophiles to the benzyne precursor via a Si—O bond and (ii) facile generation of
benzyne via halogen–metal exchange. For instance, 113 is combined with alcohol
114 having a cyclohexadienyl moiety to give silyl ether 115. Precursor 115, thus
obtained, is treated with Ph3 MgLi, where the desired cycloadduct 116 is obtained.
This strategy is proved to be applicable to various other arynophiles, including
furans, pyrroles, acyclic dienes, and naphthalenes, and is expected to be applied to
complex polycyclic natural product syntheses.
Br
i-Pr2SiCl
113
HO
Imidazole
CH2Cl2
0 °C to rt i-Pr2Si O
80%
OTs
115
114
Scheme 11.32
et al. [71].
NTs
O
Br
OTs
i-Pr2Si
Ph3MgLi
i-Pr2Si
O
O
H
Et2O, 0 °C
i-Pr2Si
O
87%
116
i-Pr2Si
H
O
i-Pr2Si O
Intramolecular Benzyne–Diene [4+2] cycloaddition. Source: Nishii
The benzyne [4+2] cycloaddition is used also in the syntheses of the
aporphine-class alkaloids. Castedo et al. [72] reported the synthesis of an oxoaporphine alkaloid PO-3 (Scheme 11.33) [72c]. Upon refluxing the mixture of methylene
tetrahydroisoquinoline 117 and diazonium carboxylate 118, a regioselective [4+2]
cycloaddition proceeds to give tetracycle 119 after air oxidation. Inspired by
these syntheses, Raminelli and coworkers reported syntheses of nornuciferine
463
464
11 Applications of Benzynes in Natural Product Synthesis
(Scheme 11.33) [73]. When using a silylaryl triflate as a benzyne precursor, no air
oxidation occurs during the benzyne cycloaddition with methylene tetrahydroisoquinoline 117, allowing a rapid access to the characteristic dihydrophenanthrene
skeleton.
MeO
N
MeO
117
CF3
MeO
N
DME
N+
MeO
MeO
MeO
O
N
MeO
CF3
[O]
N
MeO
MeO
O
CF3
O
52%
CO2
119
118
(A)
MeO
MeO
+
N
HO
MeO
O
PO-3
Scheme 11.33
Me
SiMe3
NH
MeO
OTf
Nornuciferine
Syntheses of aporphine alkaloids. Source: Based on Perecim et al. [73a].
In 2017, Jeganmohan and coworker reported the total syntheses of the aristolactam alkaloids such as cepharanone B [74]. The key phenanthrene skeleton
is constructed by the parent benzyne [4+2] cycloaddition with methylene isoindolinone 120 (Scheme 11.34). Note that the introduction of a benzenesulfonyl
group at the methylene moiety in 120 is crucial for securing the periselectivity. The
corresponding isoindolinone without the sulfonyl group gives lower yields of the
product, due to the competing undesired [2+2] cycloaddition [72a, b]. The sulfonyl
group also serves as a leaving group to effect the aromatization.
11.6 Strategies Based on [2+2] Cycloadditions
The benzyne–olefin [2+2] cycloaddition1 constitutes a simple method for the
construction of benzocyclobutenes. Since the final targets seldom contain the
so-generated four-membered rings, the cycloadducts are rather used as synthetic
intermediates, which are useful for constructing polycyclic ring systems via the
pericyclic ring opening – due to inherent strain [75]. In this context, benzocyclobutenones, readily accessible from benzyne [2+2] cycloadditions with a ketene
acetals, are widely used for the synthesis of polyketides as shown in Scheme 11.35,
among which some synthetic uses will be described below [76–82].
In the early days, electron-deficient olefins were employed as arynophiles, and the
[2+2] cycloaddition suffered from low yields and poor regioselectivity [83]. However,
11.6 Strategies Based on [2+2] Cycloadditions
SiMe3
O
OTf
MeO
NPMB
CsF
O
MeO
MeCN
30 °C
MeO
NPMB
SO2Ph
MeO
MeO
O
MeO
PhO2S
120
NH
MeO
MeO
O
MeO
O
MeO
NPMB
Cepharanone B
NPMB
66%
SO2Ph
Scheme 11.34 Syntheses of aristolactam alkaloids. Source: Based on Reddy and
Jeganmohan [74].
RO
R
O
OR
R
+
Ring
expansion
[2+2]
O
OH
HO
OH
O
O
O
O
H
H
O
O
O
H
HO
HO
Estrone derivative
[76a]
OH O
OH
HO
O
OH
OH
O
OH
Scheme 11.35
OH
H
MeO2C
O
O
OH
OH
O
OH
Tetracenomycin C
[82]
CO2Et
Goupiolone A
[80]
HO
O
Cycloinumakiol
[81]
N
H
Euxanmodin B
[76g]
NH2
HN
HN
OH
TAN1085
[76b,e]
O
Defucogilvocarcin M
[76c]
O
O
O
O
HO
O
MeO
OH
OH
O
OH
OMe
O
Aquayamycin
[79]
HO
O
OMe
OH
OH
OH
Nanaomycin D
[78]
O
HO
O
O
Taxodione
[77]
Polycyclic
structures
NMe
Me
Cycloclavine
[76i]
O
N
O
O
OH
N
HN
MeO
OH
O
N
H
OMe
(+)-CC-1065
[90]
The [2+2] cycloaddition strategy.
the situation is different with the use of electron-rich olefins. In 1982, Stevens and
Bisacchi reported that the [2+2] cycloaddition of alkoxybenzynes and ketene acetals
proceeds in high yield and high regioselectivity (Scheme 11.36) [77]. In the presence of NaNH2 , aryl bromide 121 and ketene dimethyl acetal 122 react in THF upon
465
466
11 Applications of Benzynes in Natural Product Synthesis
heating and following acidic workup gave benzocyclobutenone 123. The regioselectivity is rationalized by the benzyne distortion due to the adjacent benzyloxy group
[16]. The addition of anion 124 to 123 gives alcohol 125. Treatment of 125 with
base opens the four-membered ring, giving ketone 126, an intermediate en route to
taxodione.
MeO
MeO
MeO
Br
NaNH2
121
MeO
MeO
THF
Reflux
OMe
MeO
2
H3O+ MeO
MeO
O
HO
O
MeO
123
79%
122
MeO
MeO
MeO
124
O
MeO
Taxodione
t-BuOK
HO
t-BuOH
rt
THF
–78 °C
90%
O
126
125
70%
Scheme 11.36
Synthesis of taxodione. Source: Based on Stevens and Bisacchi [77].
In 1994, Moore and coworkers achieved a total synthesis of nanaomycin D using
benzocyclobutenone 127, prepared by Stevens’ method (Scheme 11.37) [78]. After
converting 127 into the corresponding α-siloxyketone 128 with a dihydropyranyl
moiety, heating followed by acid hydrolysis and oxidation gives pyranonaphthoquinone 130 via quinodimethane intermediate 129. Removal of the methyl group
with AlCl3 gave the target compound.
MeO
Br
MeO
MeO
NaNH2
EtO
O
MeO
EtO OEt
O
H3O+
O
80 °C
OEt
TMSO
128
127
O
OTIPS
MeO
MeO
O
p-Xylene
reflux
OH
O
AlCl3
O
O
(2) PCC
OH
129
Scheme 11.37
O
(1) HCl aq.
O
O
66%
OTIPS
O
130
O
O
O
O
Nanaomycin D
Synthesis of nanaomycin D. Source: Based on Winters et al. [78].
O
11.6 Strategies Based on [2+2] Cycloadditions
In 1995, Suzuki, Matsumoto, Hosoya, and coworkers identified the ketene silyl
acetal (KSA) as an especially reactive arynophile [84]. The reaction with an alkoxybenzyne, generated at −78 ∘ C from an iodoaryl triflate by the action of n-BuLi, allows
regioselective [2+2] cycloaddition. In 2000, the protocol was applied for the first
total synthesis of aquayamycin, an aryl C-glycoside antibiotic (Scheme 11.38) [79].
Benzocyclobutenone 133 is obtained by a [2+2] cycloaddition of KSA 132 and the
benzyne, generated from C-glycosyl substrate 131. Several steps, including a regioselective Baeyer–Villiger oxidation, converts 133 to sulfonylphthalide 134, which is
subjected to a Hauser annulation with enone 135 followed by methylation to give
dimethyl ether 136.
OTf
BnO
BnO
O
I
BnO
131
MeO
OMe
MeO
MeO OMe
Et2O
–78 °C
Sugar
BnO
OMe
KF aq.
n-Bu4NCl
n-BuLi
MeCN
MeO OTMS
OMe
Sugar
OTMS
132
(MeO)2SO2
K2CO3
t-BuOLi
Sugar
O
Sugar
SO2Ph
BnO
134
73%
(2 steps)
OBn
O
BnO
OMe
136
O
TBDPSO
O
O
OBn
O
135
Scheme 11.38
133
TBDPSO
OMe O
O
O
O
BnO
HO
HO
O
HO
OH
OH
O
OH O
Aquayamycin
Synthesis of aquayamycin. Source: Based on Matsumoto et al. [79a].
In 2012, Suzuki and coworkers applied this regioselective benzyne–KSA [2+2]
cycloaddition also to the total synthesis of goupiolone A, a benzotropolone
natural product (Scheme 11.39) [80]. The benzyne, generated from iodoaryl
triflate 137, reacts with the coexisting KSA 138, and hydrolysis gives benzocyclobutenone 139. After conversion of 139 to benzocyclobutene 140 bearing a
cyclopropane moiety, heating in refluxing p-xylene induces a tandem electrocyclic
ring opening–sigmatropic rearrangement to give benzocycloheptadiene 141.
In 2014, Dong and coworkers reported the total synthesis of the proposed structure of cycloinumakiol (Scheme 11.40) [81]. Upon treatment of a mixture of aryl
bromide 141 and enolate 142, generated from THF with n-BuLi [85], with LiTMP, a
[2+2] cycloaddition proceeds to cyclobutenol 143. After elaboration into ketone 144
followed by union with allyl alcohol 145, the resulting benzocyclobutenone 146 is
subjected to a Rh-catalyzed carboacylation of the internal olefin to give ketone 147.
In connection with the synthetic studies on the pyranonaphthoquinone-class
antibiotics such as β-naphthocyclinone by Suzuki and coworkers, a two-step
procedure for the preparation of ortho-methylbenzaldehyde derivatives is devised
467
468
11 Applications of Benzynes in Natural Product Synthesis
O
O
I
OTf
137
TMSO
O
n-BuLi
O
TMSO OMe
THF
–78 °C
OMe
OTBS
O
O
MeCN
–10 °C
O
O
HF aq.
MeO
O
SiMe3
CO2Et
30%
139
(2 steps)
OTBS
OTBS
140
OTBS
138
O MeO
O MeO
p-Xylene
Reflux
CO2Et
82%
TBSO
Scheme 11.39
O
OH O
SiMe3
O
SiMe3
O
BHT
TBSO
141
OH
HO
CO2Et
CO2Et
Goupiolone A
Synthesis of goupiolone A. Source: Based on Fukui et al. [80].
OLi
n-BuLi
rt
OH
142
BnO
BnO
BnO
141
LiTMP
THF, –78 °C
Br
O
O
OH
OH (1) (COCl)2
DMSO, Et3N
OLi
O
(2) Pd(OH)2, H2
[Rh(CO)2Cl]2
P(C6F5)3
THF
75%
144
(3 steps)
143
90%
O
O
O
H
H
[Rh]
THF
130 °C
O
O
66%
147
146
Scheme 11.40
145
DIAD, PPh3
Cycloinumakiol
(proposed structure)
Synthesis of cycloinumakiol. Source: Based on Chen et al. [81a].
(Scheme 11.41) [86]. Benzocyclobutenol 148, prepared via a benzyne [2+2]
cycloaddition with the acetaldehyde enolate 142, is used as a key intermediate,
which undergoes a ring opening [87] by treatment with sodium methoxide to give
benzaldehyde 149.
OLi
142
MeO
O
MeO
MeO
OH
LiTMP
Br
MeO
THF
–78 °C
91% MeO
Scheme 11.41
[86].
NaOMe
H
MeOH
70 °C
Quant. MeO
148
149
OH
O
HO
O
O
CO2Me
O
OAc OH
O
CO2H
β-Naphthocyclinone
Synthesis of ortho-methylbenzaldehydes. Source: Based on Maturi et al.
Hsung and coworkers reported the total synthesis of chelidonine by exploiting the
[2+2] cycloaddition and a ring expansion (Scheme 11.42) [88]. Treatment of a mixture of silylaryl triflate 75 and enamide 150 with CsF gives benzocyclobutene 151,
11.6 Strategies Based on [2+2] Cycloadditions
which is heated at 120 ∘ C inducing electrocyclic ring opening to give the corresponding quinodimethane 152, which undergoes an intramolecular cycloaddition. The
silyl protection of the alkyne is necessary, as the free terminal alkyne undergoes a
nucleophilic addition to the benzyne.
O
OTf
O
SiMe3
O
75
Cbz
O
Cbz
O
N
TIPS
CsF
O
MeCN
rt to 80 °C
O
O
O
N
Cbz
O
O
N
O
151
TIPS
150
O
O
Cbz
Xylene
120 °C
O
N
Cbz
O
O
N
Me
O
O
O
O
O
O
N
O
H
H
65%
152
Scheme 11.42
OH
Chelidonine
Synthesis of chelidonine. Source: Based on Ma et al. [88].
In 2017, Garg and coworkers reported the total synthesis of tubingensin B, an
indole diterpenoid of fungal origin, where the characteristic seven-membered ring
is constructed via a carbazolyne (Scheme 11.43) [89]. Carbazolyne 154, generated
by treatment of aryl bromide 153 with NaNH2 , undergoes intramolecular [2+2]
cycloaddition with the internal silyl enol ether, giving benzocyclobutene 154. Of
particular note is the reactivity difference between the sizes of the ring to be formed.
While the six-membered ring formation gives the addition–protonation product
(vide supra, Scheme 11.16b), the formation of [2+2] cycloadduct 155 is predominant
in the seven-membered ring construction. Rhodium-catalyzed ring opening via
cleavage of the desired C—C bond leads to ketone 156.
OTES
SePh
OTES
SePh
OH
NaNH2
t-BuOH
Br
THF
23 °C
N
MOM
153
PhSe
N
MOM
SePh
MOM
155
154
O
N
47%
OH
[Rh(OH)cod]2
Toluene
100 °C
N
MOM
53%
156
Scheme 11.43
N
H
Tubingensin B
Synthesis of tubingensin B. Source: Based on Corsello et al. [89].
469
470
11 Applications of Benzynes in Natural Product Synthesis
Tokuyama and coworkers reported a convergent total synthesis of CC-1065
(Scheme 11.44) [90]. The left segment, i.e. the cyclopropa[c]-pyrrolo[3,2-e]indol4(5H)-one unit, is constructed from pyrrolotetrahydroquinoline 160 via ring
contraction [91]. The bottom line is a NaBH4 -mediated ring expansion of benzocyclobutenone oxime sulfonate 159, prepared from arylbromide 157 via regioselective
benzyne [2+2] cycloaddition with KSA 158, to give indole 160. Another key point
is the construction of two pyrroroindoline units through a two-directional ring
expansion of bis-oxime derivative 161 (vide infra).
TBSO
Br
BnO
TBSO
EtO
158
LiTMP
OTBS
THF, –78 °C
N
Boc
157
(1) AcOH
THF, H2O
TBSO
EtO
BnO
p-ClC6H4SO2O
N
(2) NH2OH·HCl
Pyridine
54% (3 steps)
OTBS
N
Boc
BnO
159
BnO
NaBH4
OTBS
N
Boc
BocN
DMSO
t-BuOH, 70 °C
BnO
76%
N
Boc
OTBS
EtO
OTBS
N
Boc
160
H2N
N
O
OH
HN
N
O
R
OMe
N
O
O
N
H
OH
OMe
(+)-CC-1065
Scheme 11.44
NH
N
R N
OMe
OMe
161 R = p-ClC6H4SO2O–
Synthesis of (+)-CC-1065. Source: Based on Imaizumi et al. [90].
11.7 Strategies Based on Benzyne–Ene Reactions
While the intermolecular benzyne–ene reaction is often problematic due to the poor
reactivity and periselectivity, two recent alkaloid syntheses circumvented these problems by an intramolecular approach.
Lautens and coworkers reported a formal total synthesis of crinine, an Amaryllidaceae alkaloid (Scheme 11.45) [92], in which the tetrahydroisoquinoline skeleton is
constructed by an intramolecular benzyne–ene reaction. Treatment of aryl bromide
162 with LDA allows formation of benzyne 163, which undergoes intramolecular
ene reaction to afford tetracyclic compound 164. Note that two alkoxy groups on the
benzene ring are essential for the smooth cyclization. Another recent example of this
reaction, reported by Li and coworkers, involves an in situ organization of an alkene
moiety by nucleophilic addition to benzyne followed by a subsequent benzyne generation from 1,2-benzdiyne precursors (vide infra, Scheme 11.51) [93].
11.8 Recent Advances
N
N
Br
N
H
LDA
THF
rt
O
O
50%
H
O
162
H
O
O
H
OH
O
O
163
Scheme 11.45
N
H
O
164
Crinine
Synthesis of crinine. Source: Based on Candito et al. [92].
11.8 Recent Advances
11.8.1 Strategies Based on Multiple Use of Benzyne
Multiple use of benzyne allows for the expeditious assembly of polycycles with
diverse functionalities. In this context, many equivalents of a benzdiyne, a
six-membered carbon ring consisting of two formal C≡C bonds and one C=C
bond, have been widely investigated. Among three benzdiyne equivalents, i.e.
1,4-benzdiyne, 1,3-benzdiyne, and 1,2-benzdiyne equivalents, 1,4-bendiyne has
been well investigated from the dawn of benzyne chemistry as in the pioneering
contribution by Wittig and Härle [94].
1,4-Benzdiyne equivalents started to be exploited in natural product syntheses
from the mid-2000s, as exemplified in an intermolecular dual benzyne–furan [4+2]
cycloaddition in the synthetic study of ent-Sch 47555 by Barrett and coworker
(Scheme 11.46) [95]. Difluorobenzene 165 can be regarded as a formal equivalent to
bis-benzyne. The first cycloaddition is carried out with the benzyne 166, generated
by treatment with n-BuLi in the presence of furan, giving mono-cycloadduct
167 in 80% yield. After glycosylation under the Suzuki conditions [53, 96], aryl
fluoride 168 is treated with n-BuLi for the second cycloaddition with furan to give
cycloadduct 169.
OMe
F
OMe
F
OMe
165
n-BuLi
O
O
THF
–78 to 0 °C
OMe
OMe
F
OMe
O
166
BnO
F
80%
OMe
167
O
O
O
HO
OMe
O
n-BuLi
THF
–78 to 23 °C
O
O
Sugar
OMe OMe
85%
169
HO
O
O
F
OMe OMe
O
168
O
O
O
OH
O
OH
O
Sch 47555
Scheme 11.46 [4+2] Cycloaddition in the synthesis of ent-Sch 47555. Source: Based on
Morton and Barrett [95].
471
472
11 Applications of Benzynes in Natural Product Synthesis
In 2006, Martin and coworkers reported the synthesis of vineomycinone B2
methyl ester, in which iterative intramolecular benzyne–furan [4+2] cycloaddition
is demonstrated (Scheme 11.47) [97]. Upon treatment of tetrabromoarene 170 bearing two furanyl side chains connected by silicon tethers with n-BuLi at −20 ∘ C, two
benzynes are successively generated in one pot, which undergo dual cycloadditions
with two internal furans to give bis-cycloadduct 171.
OBn
BnO
Si
O
H
O
O Br
Si
Br
n-BuLi
OBn
Br O
Br
O
O
Et2O
–20 °C
OPMP
170
O
O
85%
Si
O
Sugar
Si
OBn
OPMP
171
OH
HO
OH
O
O
OH
H
O
OH
CO2Me
Vineomycinone B2 methyl ester
Scheme 11.47
et al. [97a].
Synthesis of vineomycinone B2 methyl ester. Source: Based on Chen
Strategic use of 1,4-benzdiyne to assemble poylicyclic scaffolds was made by
Suzuki in the asymmetric total syntheses of tetracenomycins C and X (Scheme 11.48)
[82]. The strategy utilized a highly selective dual benzyne cycloaddition sequence
comprising a [2+2] and a [4+2] cycloaddition. Bis-tosylate 172 serves as a
1,4-benzdiyne equivalent, allowing sequential generation of two benzyne species,
which are regioselectively trapped with KSA 173 and furan 175, affording, via benzocyclobutene 174, cycloadduct 176. After converting 176 to oxime 177, treatment
with NCS and Et3 N, in the presence of MeOH, induces an oxidative ring opening to
afford naphthonitrile oxide 178 [98], which serves as a useful platform to allow the
total syntheses.
As a synthetic equivalent to allow stepwise generation of two benzyne species in
the Suzuki synthesis of actinorhodin, two distinct benzyne precursors are installed
in the starting material 179 (Scheme 11.49) [99]. The first run exploits the facile
iodine–lithium exchange at low temperature, and the reaction in the presence of
furan gives cycloadduct 180. The second run uses F− -promoted benzyne generation,
and the anion of methyl acetoacetate, generated under the reaction conditions,
undergoes addition–fragmentation sequence to give advanced intermediate
181. Several elaborations, including an enantioselective reduction, Lewis-acidmediated allylation and concomitant ring opening in a regioselective manner, give
nanaomycin-related compound 182. Dimerization allows the first total synthesis of
actinorhodin.
11.8 Recent Advances
OBn
MeO2C
I
I
TsO
OTs
172
MeO
O
OBn
THF
–95 to –20 °C
OTBS
OMe
I
n-BuLi
MeO
175
n-BuLi
OTBS
OBn
MeO2C
–78 °C
TsO
OTBS
MeO
OMe
174
OMe
O
OMe
OMe
173
OBn
MeO2C
OBn
OMe
O
MeO
OMe
44%
NOH
(1) TiCl4, Zn MeO C
2
OTBS (2) HF aq.
176
(3) NH2OH
MeO
Pyridine
69%
OMe
OH
Scheme 11.48
MeOH
CH2Cl2
177
O
MeO2C
MeO
NCS
Et3N
R
O
+
OBn
C
MeO2C
N
O
OMe
MeO
73%
178
OMe
O
OMe
OH
O
OH
R = H Tetracenomycin C
R = Me Tetracenomycin X
Synthesis of tetracenomycins C and X. Source: Based on Sato et al. [82].
OBn
TsO
OTf
O
OBn
I
SiMe3
179
OTf
n-BuLi
OH
OH
182
O
O
O
O
OMe
HO
HO
O
CO2Me
181
53%
O
OBn
O
Scheme 11.49
180
O
O
Toluene
THF, rt
SiMe3
91%
O
OBn
OMe
KF, 18-crown-6
O
THF
–78 °C
O
HO
Actinorhodin OH
O
OH
O
Synthesis of actinorhodin . Source: Based on Ninomiya et al. [99].
Although less investigated than 1,4-benzdiyene equivalents, 1,3-benzdiyne
equivalents have also been applied to natural product synthesis. In the Tokuyama
synthesis of CC-1065 (vide supra, Scheme 11.44) [90], two pyrroloindoline units
were synthesized through a two-directional ring expansion of bis-cyclobutenone
oxime derivative 186 (Scheme 11.50). 1,2-Dibromo-4,5-dimethoxybenzene (183) is
employed as a 1,3-benzdiyne precursor to access to bis-benzocyclobutene 185 via
the double benzyne [2+2] cycloaddition with ketene acetal 184. After conversion
into bis-oxime sulfonate 186, the indole and 2-cyanoindole moieties are constructed
via sequential ring expansion triggered by NaBH4 and KCN, respectively. It should
be noted that the order of two-ring expansions is crucial, in that initial treatment of
186 with KCN affords only a trace amount of the corresponding indole.
473
474
11 Applications of Benzynes in Natural Product Synthesis
MeO
Br
Br
OMe
MeO
OMe THF, reflux
OMe
89%
OMe
183
OMe
Scheme 11.50
OMe
186
THF
t-BuOH, 50 °C
60%
R = p-ClC6H4SO2O–
NH
KCN
OMe
R N
CN
N
OMe
NaBH4
OMe
OMe
185
R
N
H
R
N
OMe
MeO
184
NaNH2
DMSO
N
CH2Cl2, 0 °C
H
73%
OMe
OMe
187
Synthesis of pyrroloindole 187. Source: Based on Imaizumi et al. [90].
1,2-Benzdiyne is a particular class of benzdiynes, where an addition of nucleophiles to a first-generated benzyne triggers a second benzyne generation. Hart and
coworkers first reported a synthetic method for m-terphenyls by the reaction of a
1,2,3-trihalobenzene as 1,2-benzdiyne equivalent with an arylmagnesium reagent
[100]. Initiated by a halogen–metal exchange, a cascade reaction occurs involving
first benzyne generation and nucleophilic addition, second benzyne gene.
Li and coworkers recently reported a related cascade reaction, consisting of a
nucleophilic addition and an intramolecular ene reaction (Scheme 11.51) [93].
Benzyne 190, generated from silylaryl triflate 189 using Cs2 CO3 and crown ether,
undergoes a nucleophilic addition of the sulfonamido anion 191 derived from
amide 188 followed by 1,2-elimination. The second benzyne 192, thus generated,
undergoes an ene reaction to form a spiro structure, embedded in ibutamoren
mesylate, an orphan drug for growth hormone deficiency.
Bz
N
Ms
N
H 188
PhCl
130 °C
OTs
SiMe3
189
Cs2CO3
18-crown-6
OTf
Bz
OTs
N
190 Ms
N
H
N
H
OBn
O
N
O
HN
+
H2N
N
N
191
Bz
Bz
192
Ms
56%
N
Ms
–
N
MeSO3
Ms
Ibutamoren mesylate
Scheme 11.51 Benzyne cascade reaction and the synthesis of ibutamoren mesylate.
Source: Based on Xu et al. [93].
11.8.2 Strategies Based on Transition-Metal-Catalyzed Reactions
Transition-metal catalysis is gaining increasing importance in benzyne chemistry,
allowing rapid assembly of benzo-fused polycycles [2p, q]. Silylaryl triflates have
been mostly used as the benzyne precursor, due to the mild reaction conditions
11.8 Recent Advances
compatible with transition-metal catalysis. Recent applications in natural product
synthesis are discussed below.
A pioneering contribution is in Mori’s total syntheses of taiwanins using a
Pd-catalyzed [2+2+2] cyclization involving a benzyne (Scheme 11.52) [101]. In the
presence of a palladium catalyst, diyne 193 provides the corresponding palladacycle
intermediate 194, which reacts with the benzyne formed from silylaryl triflate 75 by
the action of CsF, giving naphthalene 195.
O
SiMe3
O
OTf
CONMe(OMe)
CONMe(OMe)
75
CsF
Pd2(dba)3
P(o-tol)3
O
(MeO)MeNOC
O
O
[Pd]
O
O
O
O
O
61%
O
O
O
O
Taiwanin C
O
195
194
193
Scheme 11.52
O
O
MeCN
rt
O
O
O
O
O
O
O
Syntheses of taiwanins. Source: Based on Sato et al. [101].
In 2013, Argade and coworker reported the syntheses of justicidin B and retrojusticidin B [102]. The key naphthalene 197 is synthesized using a Pd-catalyzed
[2+2+2] cyclization of a benzyne and diene 196 (Scheme 11.53). Careful choice of
the catalyst/ligand is essential.
MeO
MeO
O
SiMe3
OTf
Pd2(dba)3
IMes·HCl
CsF
OMe
OMe
O
OMe
OMe
MeO
MeO
MeO
O
MeO
66%
O
O
O
197
O
MeO
O
MeCN
Reflux
O
O
O
MeO
O
O
Justicidin B
O
O
Retrojusticidin B
196 O
Scheme 11.53
Argade [102].
Syntheses of retrojusticidin B and justicidin B. Source: Based on Patel and
Among various methods to construct a phenanthridinone skeleton [103], a
Pd-catalyzed annulation of benzynes with o-halobenzamides was developed by
Larock and coworkers in 2012 [104]. Simple benzamides without an ortho halogen
substituent can be used for this Pd-catalyzed C–H activation reaction. In 2014,
Jeganmohan and coworker reported the synthesis of N-methylcrinasiadine. The
benzyne, generated from silylaryl triflate 19, reacts with benzamide 198 to give the
target compound (Scheme 11.54) [105].
Xu, Jiang, and coworkers also reported the synthesis of the phenanthridinone
alkaloids, including N-methylcrinasiadine, by using a Pd-catalyzed three-component
reaction of iodoaniline 199, the benzyne, generated from silylaryl triflate 75, and
carbon monoxide [106]. The same group reported a similar reaction involving a
C–H activation of aniline 200 [107]. A slow generation of the benzyne is crucial,
475
476
11 Applications of Benzynes in Natural Product Synthesis
Pd(OAc)2
CO, TBAI
K2CO3, CsF
OTf
SiMe3
19
H
Me
O
H
N
O
O
MeCN, H2O
100 °C
80%
Pd(OAc)2
t-BuCO2H
K2S2O8
CsF
O
MeCN
100 °C
Me
N
CuF2·2H2O
Pd(OAc)2
Cu(OAc)2
CO, KOAc, KI
O
O
30%
N-Methylcrinasiadine
I
Me
199
Me3Si
O
O
TfO
75
DMF, MeCN
100 °C
198
78%
H
Me
Scheme 11.54
NH
NH
200
Pd-catalyzed benzyne reactions toward N-methylcrinasiadine [105–107]
since the C–H activation step is rate determining CuF2 ⋅2H2 O is the most effective
fluoride source.
Recently, similar annulations have been exploited, such as the Zhang synthesis
of isocryptolepine (Scheme 11.55) [108]. The key skeleton in tetracycle 202 is
constructed by the Cu-catalyzed cycloaddition of the benzyne, generated from
silylaryl triflate 19, and indole-3-carboxamide 201, having a directing group (MQ:
5-methoxy-8-quinolyl) for C–H activation.
Me3Si
TfO
19
O
O
CsF
Cu(OAc)2
TBAI, O2
MQ
NH
DMF, MeCN
100 °C
62%
MQ
N
N
MOM
202
Me
N
N
Isocryptolepine
N
MOM
201
Scheme 11.55 [4+2] Cycloaddition in the synthesis of isocryptolepine. Source: Based on
Zhang et al. [108].
Larock and coworker reported the syntheses of 9-fluorenylidenes and
9-phenanthrenes by a Pd-catalyzed benzyne annulation via Heck-type reaction
[109]. Functional-group compatibility is demonstrated by the Yao–Zhang synthesis
of tylophorine (Scheme 11.56) [110].
Gogoi and coworkers reported the total synthesis of flemichapparin C, an
analogue of coumestans, using a Pd-catalyzed oxidative annulation (Scheme 11.57)
[111]. The target compound is directly synthesized by the migratory insertion of the
11.8 Recent Advances
MeO
MeO
OMe
OMe
MeO
SiMe3
OTf
MeO
Pd(dba)2
dppm, CsF
EtO2C
I
CO2Et
Toluene, MeCN
110 °C
N
MeO
MeO
N
Boc
MeO
OMe
46%
Boc
N
OMe
Tylophorine
OMe
Scheme 11.56
Synthesis of tylophorine. Source: Based on Yao et al. [110].
palladium enolate 204, generated from coumarin 203, and the benzyne, generated
from silylaryl triflate 75, followed by the intramolecular C—O bond formation.
Me3Si
O
Pd(OAc)2
Cu(OAc)2 ·H 2O
CsF, NaOAc
O
TfO
75
OH
MeO
O
MeCN
120 °C
O PdOAc
O
MeO
O
O
O
204
O
203
O
OAc
Pd
OH
O
O
O
O
MeO
O
O
MeO
67%
O
O
Flemichapparin C
Scheme 11.57 Palladium-catalyzed reaction toward flemichapparin C. Source: Based on
Neog et al. [111].
11.8.3 Benzyne Generation via Hexadehydro-Diels–Alder Reaction
Conventional methods of benzyne generation involve a release of two adjacent
substituents from a benzenoid, while a conceptually distinct approach has emerged
in late 1990s, involving an intramolecular hexadehydro-Diels–Alder reaction of
triyne precursors (Scheme 11.58). After the early report by Ueda, Johnson, and
coworkers [113], the potential of this unique method remained underscored until
Hoye et al. [114] and Lee and coworkers [115] expanded the scope and utility. This
section describes two natural product syntheses, exploiting this method of benzyne
generation.
477
478
11 Applications of Benzynes in Natural Product Synthesis
In 2016, Hoye and coworker reported the synthesis of koenidine using
hexadehydro-Diels–Alder cascade (Scheme 11.58) [112]. Carbazolyne 207,
generated from triyne 205, reacts with aldehyde 206 to form oxa-cyclobutene 208.
Ring opening followed by 6π-electrocyclization gives carbazole 209.
Lee and coworker applied this approach to the total synthesis of selaginpulvilin C,
a phosphodiesterase-4 inhibitor (Scheme 11.59) [116]. Upon oxidation of tetrayne
TMS
MeO
TMS
TMS
N
Ts
205
MeO
MeO
O
ClCH2CH2Cl
100 °C
O
N
Ts
MeO
N
Ts
207
206
TMS
TMS
TMS
+
O
O
O
N
Ts
N
Ts
N
Ts
208
TMS
O
MeO
MeO
TBAF
THF
80 °C
N
Ts
209
Scheme 11.58
O
MeO
MeO
85%
(2 steps)
N
H
Koenidine
Synthesis of koenidine. Source: Based on Wang and Hoye [112].
Ar
O
O
OH
MnO2
Cyclooctane
MeO
MeO
MeO
Ar
25 °C
210
211
OMe
SiEt3
SiEt3
SiEt3
212
H
H
OH
OMe
OH
HO
O
MeO
29%
SiEt3
213
Scheme 11.59
H
HO
CH3
H
Selaginpulvilin C
Syntheses of selaginpulvilins. Source: Based on Karmakar and Lee [116].
References
210 with MnO2 , the resulting ketone 211 allowed facile generation of benzyne 212
that undergoes an unusual hydrogen transfer from cycloalkanes [117] to give the
fluorenone 213. A similar approach was applied to the formal synthesis of selaginpulvilin D [118].
References
1 Hoffmann, R.W. (1967). Dehydrobenzene and Cycloalkynes. New York: Academic
Press.
2 (a) Pellissier, H. and Santelli, M. (2003). Tetrahedron 59: 701–730. (b) Wenk,
H.H., Winkler, M., and Sander, W. (2003). Angew. Chem. Int. Ed. 42: 502–528.
(c) Sanz, R. (2008). Org. Prep. Proced. Int. 40: 215–291. (d) Kitamura, T.
(2010). Aust. J. Chem. 63: 987–1001. (e) Wentrup, C. (2010). Aust. J. Chem.
63: 979–986. (f) Yoshida, H., Ohshita, J., and Kunai, A. (2010). Bull. Chem.
Soc. Jpn. 83: 199–219. (g) Bhunia, A., Yetra, S.R., and Biju, A.T. (2012).
Chem. Soc. Rev. 41: 3140–3152. (h) Wu, C. and Shi, F. (2013). Asian J. Org.
Chem. 2: 116–125. (i) Dubrovskiy, A.V., Markina, N.A., and Larock, R.C.
(2013). Org. Biomol. Chem. 11: 191–218. (j) Pérez, D., Peña, D., and Guitián,
E. (2013). Eur. J. Org. Chem.: 5981–6013. (k) Miyabe, H. (2015). Molecules
20: 12558–12575. (l) Yoshida, S. and Hosoya, T. (2015). Chem. Lett. 44:
1450–1460. (m) García-López, J.-A. and Greaney, M.F. (2016). Chem. Soc.
Rev. 45: 6766–6798. (n) Karmakar, R. and Lee, D. (2016). Chem. Soc. Rev. 45:
4459–4470. (o) Idiris, F.I.M. and Jones, C.R. (2017). Org. Biomol. Chem. 15:
9044–9056. (p) Shi, J., Li, Y., and Li, Y. (2017). Chem. Soc. Rev. 46: 1707–1719.
(q) Feng, M. and Jiang, X. (2017). Synthesis 49: 4414–4433. (r) Dhokale, R.A.
and Mhaske, S.B. (2018). Synthesis 50: 1–16. s Roy, T. and Biju, A.T. (2018).
Chem. Commun. 54: 2580–2594.
3 (a) Tadross, P.M. and Stoltz, B.M. (2012). Chem. Rev. 112: 3550–3577.
(b) Gampe, C.M. and Carreira, E.M. (2012). Angew. Chem. Int. Ed. 51:
3766–3778. (c) Goetz, A.E., Shah, T.K., and Garg, N.K. (2015). Chem. Commun. 51: 34–45. (d) Takikawa, H., Nishii, A., Sakai, T., and Suzuki, K. (2018).
Chem. Soc. Rev. 47: 8030–8056.
4 Kametani, T. and Ogasawara, K. (1967). J. Chem. Soc. C: 2208–2212.
5 (a) Wolthuis, E., Bouma, B., Modderman, J., and Sytsma, L. (1970). Tetrahedron
Lett. 11: 407–408. (b) Richmond, G.O. and Spendel, W. (1973). Tetrahedron Lett.
14: 4557–4560.
6 Chapdelaine, M.J. and Hulce, M. (1990). Org. React. 38: 225–653.
7 For explanation by invoking pseudo-excitation effect, see;(a)Hayes, D.M. and
Hoffmann, R. (1972). J. Phys. Chem. 76: 656–663. (b) Epiotis, N.D. (1974).
Angew. Chem. Int. Ed. Engl. 13: 751–828.
8 (a) Woodward, R.B. and Hoffmann, R. (1965). J. Am. Chem. Soc. 87: 395–397.
(b) Woodward, R.B. and Hoffmann, R. (1969). Angew. Chem. Int. Ed. Engl. 8:
781–932.
9 Sielecki, T.M. and Meyers, A.I. (1992). J. Org. Chem. 57: 3673–3676.
479
480
11 Applications of Benzynes in Natural Product Synthesis
10 Iwao, M., Motoi, O., Fukuda, T., and Ishibashi, F. (1998). Tetrahedron 54:
8999–9010.
11 (a) Oshiyama, T., Satoh, T., Okano, K., and Tokuyama, H. (2012). Tetrahedron 68: 9376–9383. (b) Oshiyama, T., Satoh, T., Okano, K., and Tokuyama, H.
(2012). RSC Adv. 2: 5147–5149.
12 Okano, K., Fujiwara, H., Noji, T. et al. (2010). Angew. Chem. Int. Ed. 49:
5925–5929.
13 Watanabe, M., Kurosaki, A., and Furukawa, S. (1984). Chem. Pharm. Bull. 32:
1264–1267.
14 Vaidya, S.D. and Argade, N.P. (2013). Org. Lett. 15: 4006–4009.
15 Bronner, S.M., Goetz, A.E., and Garg, N.K. (2011). J. Am. Chem. Soc. 133:
3832–3835.
16 (a) Cheong, P.H.-Y., Paton, R.S., Bronner, S.M. et al. (2010). J. Am. Chem. Soc.
132: 1267–1269. (b) Medina, J.M., Mackey, J.L., Garg, N.K., and Houk, K.N.
(2014). J. Am. Chem. Soc. 136: 15798–15805, and references therein.
17 Torres-Ochoa, R.O., Buyck, T., Wang, Q., and Zhu, J. (2018). Angew. Chem. Int.
Ed. 57: 5679–5683.
18 Day, J.J., McFadden, R.M., Virgil, S.C. et al. (2011). Angew. Chem. Int. Ed. 50:
6814–6818.
19 Carril, M., SanMartin, R., Tellitu, I., and Domínguez, E. (2006). Org. Lett. 8:
1467–1470.
20 Zhao, J. and Larock, R.C. (2005). Org. Lett. 7: 4273–4275.
21 Giallombardo, D., Nevin, A.C., Lewis, W. et al. (2014). Tetrahedron 70:
1283–1288.
22 (a) Knight, D.W. and Qing, X. (2009). Tetrahedron Lett. 50: 3534–3537.
(b) Knight, D.W. and Xu, Q. (2016). Heterocycles 93: 647–672.
23 Oppolzer, W. and Keller, K. (1971). J. Am. Chem. Soc. 93: 3836–3837.
24 (a) Kametani, T., Nemoto, H., Ishikawa, H. et al. (1977). J. Am. Chem. Soc. 99:
3461–3466. (b) Kametani, T., Matsumoto, H., Nemoto, H., and Fukumoto, K.
(1978). J. Am. Chem. Soc. 100: 6218–6220. (c) Kametani, T., Suzuki, K., and
Nemoto, H. (1979). J. Chem. Soc., Chem. Commun.: 1127–1128. (d) Kametani,
T., Suzuki, K., and Nemoto, H. (1981). J. Am. Chem. Soc. 103: 2890–2891.
(e) Kametani, T., Suzuki, K., and Nemoto, H. (1982). J. Org. Chem. 47:
2331–2342. (f) Nemoto, H., Nagai, M., Fukumoto, K., and Kametani, T. (1985).
Tetrahedron Lett. 26: 4613–4616. (g) Nemoto, H., Nagai, M., and Fukumoto,
K. (1986). J. Chem. Soc., Perkin Trans. 1: 1621–1625. (h) Nemoto, H., Nagai,
M., Moizumi, M. et al. (1988). Tetrahedron Lett. 29: 4959–4962. (i) Nemoto, H.,
Nagai, M., Moizumi, M. et al. (1989). J. Chem. Soc., Perkin Trans. 1: 1639–1645.
25 Larrosa, I., Da Silva, M.I., Gómez, P.M. et al. (2006). J. Am. Chem. Soc. 128:
14042–14043.
26 Soorukram, D., Qu, T., and Barrett, A.G.M. (2008). Org. Lett. 10: 3833–3835.
27 Kametani, T., Sugai, T., Shoji, Y. et al. (1977). J. Chem. Soc., Perkin Trans. 1:
1151–1155.
28 Iida, H., Yuasa, Y., and Kibayashi, C. (1979). J. Org. Chem. 44: 1074–1080.
29 Allan, K.M. and Stoltz, B.M. (2008). J. Am. Chem. Soc. 130: 17270–17271.
References
30 Gilmore, C.D., Allan, K.M., and Stoltz, B.M. (2008). J. Am. Chem. Soc. 130:
1558–1559.
31 (a) Guo, J., Kiran, I.N.C., Gao, J. et al. (2016). Tetrahedron Lett. 57: 3481–3484.
(b) Banne, S., Reddy, D.P., Li, W. et al. (2017). Org. Lett. 19: 4996–4999.
32 Huters, A.D., Quasdorf, K.W., Styduhar, E.D., and Garg, N.K. (2011). J. Am.
Chem. Soc. 133: 15797–15799.
33 Goetz, A.E., Silberstein, A.L., Corsello, M.A., and Garg, N.K. (2014). J. Am.
Chem. Soc. 136: 3036–3039.
34 Caubère, P. (1967). Bull. Soc. Chim. Fr.: 3451–3457.
35 Guyot, M. and Molho, D. (1973). Tetrahedron Lett. 14: 3433–3436.
36 (a) Caubère, P., Derozier, N., and Loubinoux, B. (1971). Bull. Soc. Chim. Fr.:
302–307. (b) Caubère, P., Guillaumet, G., and Mourad, M.S. (1971). Tetrahedron Lett. 12: 4673–4676. (c) Danheiser, R.L. and Helgason, A.L. (1994). J. Am.
Chem. Soc. 116: 9471–9479.
37 (a) Shair, M.D., Yoon, T.Y., and Danishefsky, S.J. (1995). Angew. Chem. Int.
Ed. Engl. 34: 1721–1723. (b) Shair, M.D., Yoon, T.Y., Mosny, K.K. et al. (1996).
J. Am. Chem. Soc. 118: 9509–9525.
38 Huang, J.-K., Lauderdale, T.-L.Y., Lin, C.-C., and Shia, K.-S. (2018). J. Org.
Chem. 83: 6508–6523.
39 Bauta, W.E., Lovett, D.P., Cantrell, W.R. Jr., and Burke, B.D. (2003). J. Org.
Chem. 68: 5967–5973.
40 (a) Kita, Y., Higuchi, K., Yoshida, Y. et al. (1999). Angew. Chem. Int. Ed. 38:
683–686. (b) Kita, Y., Higuchi, K., Yoshida, Y. et al. (2001). J. Am. Chem. Soc.
123: 3214–3222.
41 Tadross, P.M., Virgil, S.C., and Stoltz, B.M. (2010). Org. Lett. 12: 1612–1614.
42 Kobayashi, H., Sasano, Y., Kanoh, N. et al. (2016). Eur. J. Org. Chem.: 270–273.
43 Kou, K.G.M., Pflueger, J.J., Kiho, T. et al. (2018). J. Am. Chem. Soc. 140:
8105–8109.
44 (a) Tambar, U.K. and Stoltz, B.M. (2005). J. Am. Chem. Soc. 127: 5340–5341.
(b) Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A. (2005). Chem. Commun.: 3292–3294. (c) Ebner, D.C., Tambar, U.K., and Stoltz, B.M. (2009). Org.
Synth. 86: 161–171.
45 Bartholomäus, R., Bachmann, J., Mang, C. et al. (2013). Eur. J. Org. Chem.:
180–190.
46 Moschitto, M.J., Anthony, D.R., and Lewis, C.A. (2015). J. Org. Chem. 80:
3339–3342.
47 (a) Huisgen, R. and Knorr, R. (1963). Tetrahedron Lett. 4: 1017–1021. (b) Wittig,
G. and Dürr, H. (1964). Justus Liebigs Ann. Chem. 672: 55–62. (c) Crews, P. and
Beard, J. (1973). J. Org. Chem. 38: 522–528. (d) Waali, E.E. (1975). J. Org. Chem.
40: 1355–1356.
48 Townsend, C.A., Davis, S.G., Christensen, S.B. et al. (1981). J. Am. Chem. Soc.
103: 6885–6888.
49 Gribble, G.W., Saulnier, M.G., Sibi, M.P., and Obaza-Nutaitis, J.A. (1984). J. Org.
Chem. 49: 4518–4523.
50 Khanapure, S.P. and Biehl, E.R. (1989). J. Nat. Prod. 52: 1357–1359.
481
482
11 Applications of Benzynes in Natural Product Synthesis
51 Best, W.M. and Wege, D. (1981). Tetrahedron Lett. 22: 4877–4880.
52 (a) Matsumoto, T., Hosoya, T., and Suzuki, K. (1992). J. Am. Chem. Soc. 114:
3568–3570. (b) Hosoya, T., Takashiro, E., Matsumoto, T., and Suzuki, K. (1994).
J. Am. Chem. Soc. 116: 1004–1015.
53 For a recent review on total syntheses of aryl C-glycoside natural products,
see:Kitamura, K., Ando, Y., Matsumoto, T., and Suzuki, K. (2018). Chem. Rev.
118: 1495–1598.
54 (a) Matsumoto, T., Sohma, T., Yamaguchi, H. et al. (1995). Synlett: 263–266.
(b) Matsumoto, T., Sohma, T., Yamaguchi, H. et al. (1995). Tetrahedron 51:
7347–7360.
55 Sumida, Y., Harada, R., Kato-Sumida, T. et al. (2014). Org. Lett. 16: 6240–6243.
56 Sumida, Y., Kato, T., and Hosoya, T. (2013). Org. Lett. 15: 2806–2809.
57 Neumeyer, M. and Brückner, R. (2017). Eur. J. Org. Chem.: 2512–2539.
58 Neumeyer, M., Kopp, J., and Brückner, R. (2017). Eur. J. Org. Chem.:
2883–2915.
59 Feng, Y., Liu, J., Carrasco, Y.P. et al. (2016). J. Am. Chem. Soc. 138: 7130–7142.
60 (a) Nakata, M., Kinoshita, M., Ohba, S., and Saito, Y. (1984). Tetrahedron Lett.
25: 1373–1376. (b) Nakata, M., Wada, S., Tatsuta, K., and Kinoshita, M. (1985).
Bull. Chem. Soc. Jpn. 58: 1801–1806.
61 (a) Ando, Y., Matsumoto, T., and Suzuki, K. (2017). Synlett 28: 1040–1045.
(b) Ando, Y., Hanaki, A., Sasaki, R. et al. (2017). Angew. Chem. Int. Ed. 56:
11460–11465.
62 Odagi, M., Furukori, K., Takayama, K. et al. (2017). Angew. Chem. Int. Ed. 56:
6609–6612.
63 (a) O’Keefe, B.M., Mans, D.M., Kaelin, D.E. Jr., and Martin, S.F. (2010). J. Am.
Chem. Soc. 132: 15528–15530. (b) O’Keefe, B.M., Mans, D.M., Kaelin, D.E. Jr.,
and Martin, S.F. (2011). Tetrahedron 67: 6524–6538.
64 Kaelin, D.E. Jr., Sparks, S.M., Plake, H.R., and Martin, S.F. (2003). J. Am. Chem.
Soc. 125: 12994–12995.
65 McManus, H.A., Fleming, M.J., and Lautens, M. (2007). Angew. Chem. Int. Ed.
46: 433–436.
66 Castillo, J.-C., Quiroga, J., Abonia, R. et al. (2015). Org. Lett. 17: 3374–3377.
67 May, C. and Moody, C.J. (1984). J. Chem. Soc., Chem. Commun.: 926–927.
68 Kim, J.-Y., Kim, D.-H., Jeon, T.-H. et al. (2017). Org. Lett. 19: 4688–4691.
69 (a) Chandrasoma, N., Brown, N., Brassfield, A. et al. (2013). Tetrahedron Lett.
54: 913–917; For related studies of the [4+2] cycloaddition of indolyne and
furan, see:(b)Buszek, K.R., Luo, D., Kondrashov, M. et al. (2007). Org. Lett.
9: 4135–4137; (c) Buszek, K.R., Brown, N., and Luo, D. (2009). Org. Lett. 11:
201–204. (d) Chandrasoma, N., Pathmanathan, S., and Buszek, K.R. (2015).
Tetrahedron Lett. 56: 3507–3510.
70 Buszek, K.R. and Bixby, D.L. (1995). Tetrahedron Lett. 36: 9129–9132.
71 Nishii, A., Takikawa, H., and Suzuki, K. (2019). Chem. Sci. 10: 3840–3845.
72 (a) Castedo, L., Guitián, E., Saá, J.M., and Suau, R. (1982). Tetrahedron Lett. 23:
457–458. (b) Atanes, N., Castedo, L., Guitián, E. et al. (1991). J. Org. Chem. 56:
References
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
2984–2988. (c) Saá, C., Guitián, E., Castedo, L., and Saá, J.M. (1985). Tetrahedron Lett. 26: 4559–4560.
(a) Perecim, G.P., Rodrigues, A., and Raminelli, C. (2015). Tetrahedron Lett.
56: 6848–6851; (b) Rossini, A.F.C., Muraca, A.C.A., Casagrande, G.A., and
Raminelli, C. (2015). J. Org. Chem. 80: 10033–10040.
Reddy, M.C. and Jeganmohan, M. (2017). Chem. Sci. 8: 4130–4135.
(a) Klundt, I.L. (1970). Chem. Rev. 70: 471–487. (b) Oppolzer, W. (1978). Synthesis: 793–802. (c) Thumme, R.P. (1980). Acc. Chem. Res. 13: 70–76. (d) Mehta, G.
and Kotha, S. (2001). Tetrahedron 57: 625–659.
(a) Pellissier, H. and Santelli, M. (1996). Tetrahedron 52: 9093–9100.
(b) Ohmori, K., Mori, K., Ishikawa, Y. et al. (2004). Angew. Chem. Int. Ed.
43: 3167–3171. (c) Takemura, I., Imura, K., Matsumoto, T., and Suzuki, K.
(2004). Org. Lett. 6: 2503–2505. (d) Mori, K., Tanaka, Y., Ohmori, K., and
Suzuki, K. (2008). Chem. Lett. 37: 470–471. (e) Mori, K., Ohmori, K., and
Suzuki, K. (2009). Angew. Chem. Int. Ed. 48: 5633–5637. (f) Ben, A., Hsu,
D.-S., Matsumoto, T., and Suzuki, K. (2011). Tetrahedron 67: 6460–6468.
(g) Takahashi, N., Kanayama, T., Okuyama, K. et al. (2011). Chem. Asian J.
6: 1752–1756. (h) Yamaguchi, S., Takahashi, N., Yuyama, D. et al. (2016). Synlett
27: 1262–1268. (i) Deng, L., Chen, M., and Dong, G. (2018). J. Am. Chem. Soc.
140: 9652–9658.
(a) Stevens, R.V. and Bisacchi, G.S. (1982). J. Org. Chem. 47: 2393–2396.
(b) Stevens, R.V. and Bisacchi, G.S. (1982). J. Org. Chem. 47: 2396–2399.
Winters, M.P., Stranberg, M., and Moore, H.W. (1994). J. Org. Chem. 59:
7572–7574.
(a) Matsumoto, T., Yamaguchi, H., Hamura, T. et al. (2000). Tetrahedron Lett.
41: 8383–8387. (b) Yamaguchi, H., Konegawa, T., Tanabe, M. et al. (2000).
Tetrahedron Lett. 41: 8389–8392. (c) Matsumoto, T., Yamaguchi, H., Tanabe, M.
et al. (2000). Tetrahedron Lett. 41: 8393–8396.
Fukui, N., Ohmori, K., and Suzuki, K. (2012). Helv. Chim. Acta 95: 2194–2217.
(a) Chen, P.-H., Savage, N.A., and Dong, G. (2014). Tetrahedron 70: 4135–4146.
(b) Xu, T. and Dong, G. (2014). Angew. Chem. Int. Ed. 53: 10733–10736.
Sato, S., Sakata, K., Hashimoto, Y. et al. (2017). Angew. Chem. Int. Ed. 56:
12608–12613.
South, M.S. and Liebeskind, L.S. (1982). J. Org. Chem. 47: 3815–3821.
(a) Hosoya, T., Hasegawa, T., Kuriyama, Y. et al. (1995). Synlett: 177–179.
(b) Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K. (1995). Tetrahedron Lett. 36: 3377–3380. (c) Hosoya, T., Hamura, T., Kuriyama, Y. et al. (2000).
Synlett: 520–522.
Fleming, I. and Mah, T. (1975). J. Chem. Soc., Perkin Trans. 1: 964–965.
Maturi, M.M., Ohmori, K., and Suzuki, K. (2018). Chimia 72: 870–873.
Choy, W. and Yang, H. (1988). J. Org. Chem. 53: 5796.
Ma, Z.-X., Feltenberger, J.B., and Hsung, R.P. (2012). Org. Lett. 14: 2742–2745.
Corsello, M.A., Kim, J., and Garg, N.K. (2017). Nat. Chem. 9: 944–949.
Imaizumi, T., Yamashita, Y., Nakazawa, Y. et al. (2019). Org. Lett. 21:
6185–6189.
483
484
11 Applications of Benzynes in Natural Product Synthesis
91 Okano, K., Tokuyama, H., and Fukuyama, T. (2006). J. Am. Chem. Soc. 128:
7136–7137.
92 (a) Candito, D.A., Panteleev, J., and Lautens, M. (2011). J. Am. Chem. Soc. 133:
14200–14203. (b) Candito, D.A., Dobrovolsky, D., and Lautens, M. (2012). J. Am.
Chem. Soc. 134: 15572–15580.
93 (a) Shi, J., Qiu, D., Wang, J. et al. (2015). J. Am. Chem. Soc. 137: 5670–5673.
(b) Xu, H., He, J., Shi, J. et al. (2018). J. Am. Chem. Soc. 140: 3555–3559.
94 Wittig, G. and Härle, H. (1959). Liebigs Ann. Chem. 623: 17–34.
95 (a) Morton, G.E. and Barrett, A.G.M. (2005). J. Org. Chem. 70: 3525–3529.
(b) Morton, G.E. and Barrett, A.G.M. (2006). Org. Lett. 8: 2859–2861.
96 (a) Matsumoto, T., Katsuki, M., and Suzuki, K. (1988). Tetrahedron Lett. 29:
6935–6938. (b) Ben, A., Yamauchi, T., Matsumoto, T., and Suzuki, K. (2004).
Synlett: 225–230.
97 (a) Chen, C.-L., Sparks, S.M., and Martin, S.F. (2006). J. Am. Chem. Soc. 128:
13696–13697. (b) Sparks, S.M., Chen, C.-L., and Martin, S.F. (2007). Tetrahedron
63: 8619–8635.
98 Takikawa, H., Sato, S., Seki, R., and Suzuki, K. (2017). Chem. Lett. 46:
998–1000.
99 Ninomiya, M., Ando, Y., Kudo, F. et al. (2019). Angew. Chem. Int. Ed. 58:
4264–4270.
100 (a) Du, C.J.F., Hart, H., and Ng, K.K.D. (1986). J. Org. Chem. 51: 3162–3165.
(b) Du, C.J.F. and Hart, H. (1987). J. Org. Chem. 52: 4311–4314.
101 Sato, Y., Tamura, T., and Mori, M. (2004). Angew. Chem. Int. Ed. 43: 2436–2440.
102 Patel, R.M. and Argade, N.P. (2013). Org. Lett. 15: 14–17.
103 (a) Mohanakrishnan, A.K. and Srinivasan, P.C. (1995). J. Org. Chem. 60:
1939–1946. (b) Kleppinger, R., Lillya, C.P., and Yang, C. (1997). J. Am. Chem.
Soc. 119: 4097–4102. (c) Padwa, A., Dimitroff, M., Waterson, A.G., and Wu, T.
(1998). J. Org. Chem. 63: 3986–3997. (d) Furuta, T., Kitamura, Y., Hashimoto,
A. et al. (2007). Org. Lett. 9: 183–186. (e) Bernardo, P.H., Fitriyanto, W., and
Chai, C.L.L. (2007). Synthesis: 1935–1939. (f) Rajeshkumar, V., Lee, T.-H., and
Chuang, S.-C. (2013). Org. Lett. 15: 1468–1471.
104 Lu, C., Dubrovskly, A.V., and Larock, R.C. (2012). J. Org. Chem. 77: 8648–8656.
105 Pimparkar, S. and Jeganmohan, M. (2014). Chem. Commun. 50: 12116–12119.
106 Feng, M., Tang, B., Wang, N. et al. (2015). Angew. Chem. Int. Ed. 54:
14960–14964.
107 Feng, M., Tang, B., Xu, H.-X., and Jiang, X. (2016). Org. Lett. 18: 4352–4355.
108 Zhang, T.-Y., Liu, C., Chen, C. et al. (2018). Org. Lett. 20: 220–223.
109 (a) Worlikar, S.A. and Larock, R.C. (2009). Org. Lett. 11: 2413–2416.
(b) Worlikar, S.A. and Larock, R.C. (2009). J. Org. Chem. 74: 9132–9139.
110 Yao, T., Zhang, H., and Zhao, Y. (2016). Org. Lett. 18: 2532–2535.
111 Neog, K., Borah, A., and Gogoi, P. (2016). J. Org. Chem. 81: 11971–11977.
112 Wang, T. and Hoye, T.R. (2016). J. Am. Chem. Soc. 138: 13870–13873.
113 (a) Miyawaki, K., Suzuki, R., Kawano, T., and Ueda, I. (1997). Tetrahedron Lett.
38: 3943–3946. (b) Bradley, A.Z. and Johnson, R.P. (1997). J. Am. Chem. Soc.
References
114
115
116
117
118
119: 9917–9918; For a review, see: (c) Holden, C. and Greaney, M.F. (2014).
Angew. Chem. Int. Ed. 53: 5746–5749.
(a) Hoye, T.R., Baire, B., Niu, D. et al. (2012). Nature 490: 208–211.
(b) Hoffmann, R.W. and Suzuki, K. (2013). Angew. Chem. Int. Ed. 52:
2655–2656.
Yun, S.Y., Wang, K.-P., Lee, N.-K. et al. (2013). J. Am. Chem. Soc. 135:
4668–4671.
Karmakar, R. and Lee, D. (2016). Org. Lett. 18: 6105–6107.
Niu, D., Willoughby, P.H., Woods, B.P. et al. (2013). Nature 501: 531–534.
Shankar, B. and Baire, B. (2017). Org. Biomol. Chem. 15: 5908–5911.
485
487
Index
a
abnormal addition-elimination (AEa )
mechanism 360, 361
acetophenone-derived sulfonium salts
169
acetylene dicarboxylates 171
actinorhodin 473
acylalkylation, of arynes 126
9-acyl-9H-fluorenes 124
addition-elimination (AEn ) mechanism
360
addition-fragmentation reactions 455
AgF 183
AgOTf-catalyzed reaction of
2-alkynylbenzaldoximes with
arynes 260, 261
3-alkoxy-2-naphthol 126
alkynylbenzaldehyde 239
alkynyllithium catalyzed aryne generation
326
1-allyl-2-alkynylbenzene derivatives
227
amino benzotriazole 11
aminocyanation, of arynes
with N-cyanoanilide 118
aminosulfinylation, of arynes 114
aminotriazole anion 389
ammonium ylide 269
aniline synthesis 111
anthranilic acid derivatives 10
aporphine alkaloids 464
aquayamycin 467
aristolactam alkaloids 465
arizonins B1 459
arnottin 460
aroylacetonitriles 153
1-aroyl-3,4-dihydroisoquinolines 299
arylation reactions 17
9-aryldihydrophenanthrenes 15
2-aryl-2H-indazole 74
aryl(mesityl)iodonium tosylate 320
aryl ketone O-acetyloximes 215, 217
3-(arylsulfonyl)-2H-chromene-2-ols
168
aryl vinyl sulfides 102
aryne
amination reactions 114
natural product synthesis 21
possible reactivity modes of 13
arylation reactions 17
insertion reactions 17
MCC 18, 19
molecular rearrangements 18–19
pericyclic reactions 14–16
transition metal-catalyzed reactions
18
[2+2] aryne cycloadditions 30–31
[2+2+2] aryne cycloadditions 31–32
[4+2] aryne cycloadditions 29–30
aryne cycloaddition reactions 28
[2+2] aryne cycloadditions 30–31
[2+2+2] aryne cycloadditions 31–32
[4+2] aryne cycloadditions 29–30
aryne dipolar cycloaddition 69, 70
aryne generation methods 28
catalytic 323–326
Modern Aryne Chemistry, First Edition. Edited by Akkattu T. Biju.
© 2021 WILEY-VCH GmbH. Published 2021 by WILEY-VCH GmbH.
488
Index
aryne generation methods (contd.)
ortho-deprotonative elimination
aryliodonio group 321
HOTf 320
LDAM 317, 319
PhCl-LiTMP system 317, 318
Uchiyama’s conditions 319
ortho-difunctionalized precursors
Knochel’s aryne precursors 323
photoinduced aryne generation
methods 323
silyl-based or OTf-based
difunctionalized aryne precursors
322
Suzuki’s o-iodoaryl triflate 322
strategy 316
2,3-aryne intermediate 12
aryne-mediated synthesis, of functional
polyarenes
acenes, synthesis of 32–41, 43
carbon nanostructures 58–60, 62
helicenes, synthesis of 54–58
perylene derivatives, synthesis of 43,
46, 47
π-extended starphenes, synthesis of
48–54
triptycenes, synthesis of 48
aryne multifunctionalization
1,2-benzdiyne 336–342
1,4-benzdiyne 345–349
1,3-benzdiynes 342–345
1,3,5-benztriyne 349–351
benzyne insertion, C–H
functionalization cascade
351–353
aryne regioselectivity
electronic effect 330–335
intermolecular aryne reactions 327
small ring-fused arynes 335–336
steric effect 327–330
arynes 1
characterization of 3–5
cycloadditions of 47
electrophilicity of 4
history of 1–3
Kobayashi’s fluoride induced aryne
generation 12–13
methods of 9
from anthranilic acids 10
deprotonation, of aryl halides 9
fragmentation, of amino
benzotriazoles 10
HDDA 11
metal-halogen exchange/elimination
10
from ortho-borylaryl triflates
11–12
Pd(II)-catalyzed C–H activation
strategy 12
ortho-arynes
of heterocycles 6–7
with substitution 5–6
with oxaziridines 82
photochemistry of 4
transformations 128–129
aryne trifunctionalization 351, 353
aryne-triggered rearrangements 267
aryne-triggered Sommelet–Hauser
rearrangement of tertiary benzylic
amines 271
aryne-triggered [1,2]-Stevens
rearrangement
benzylic thioethers 275
of benzylic thioethers 276
of tertiary amines 269
1,2,3,4-tetrahydroisoquinolines 269,
270
aryne-triggered [2,3]-Stevens
rearrangement
of allylic thioethers 277
of cyclic allylic amines 273
of propargylic thioethers 276, 277
of tertiary allylic amines 272
of tertiary propargylic amines 274
arynic triple bonds 36
arynophiles 111
atomic force microscopy (AFM) 27
Au-bearing pyrylium cation 93
Au-catalyzed cyclotrimerization of arynes
197–198
Index
azacyclic allene 399
aza-HDDA reaction 430
azanickelacycle 224
aza-ortho-quinone methides 162
2-azidoacrylates 98
azomethine imines 83
azomethineylides 160
b
1,2-benzdiyne
aryne trifunctionalization through
Grob fragmentation 341
diamination reactions with TPBT
reagent 339
domino aryne nucleophilic-ene cascade
339
naphthyne from 1,2-benzdiyne-HDDA
cascade 340
process and equivalents 337
σ-bond insertion of N–Si and S–Si
bonds 342
3-silylbenzyne 343
TPBT with protected thiobenzamides
338, 474
1,3-benzdiynes
equivalents 473
Ikawa-Akai’s 343, 344
Kitamura’s hybrid 344
Suzuki’s strategy 343
1,4-benzdiynes 1, 7
actinorhodin 345, 346
bis(sulfonyloxy)diiodobenzene 345,
346
1,4-bis(trimethylsilyl)phenyl
2,5-bis(triflate) 346, 347
equivalents 471
Ikawa-Akai’s 348, 349
Kitamura’s hybrid 349
nanographenes 347, 348
vineomcinone B2 methyl ester 350
benzenediazonium 2-carboxylate 10, 33,
60, 296, 446
benzene thiol 133
benzocyclobutene synthesis 122–123
1,3-benzodithiol-2-imine 136
benzo[d][1,2,3]thiadiazole 1,1-dioxide
10
2,3-benzofuranyne 362–363
4,5-benzofuranyne 78
benzo-fused carbocycles 1
benzophenone O-perfluorobenzoyl
oximes 215, 217
benzothiadiazole dioxide 10, 11
2,3-benzothiophyne 361, 363
1,2,3-benzotriazin-4-(3H)-ones 222
benzoxaphosphole derivatives 175
benzoxazoles 230, 231
1,3,5-benztriyne
Suzuki’s synthesis of hexaredialene
351, 353
Suzuki’s synthesis of TCBBs 352
Suzuki’s synthesis of tetraketone 350
2-benzyl-3-hydroxy-1,4-naphthoquinone
126
benzyne 2
cycloisomerization 409–410
dimerization of 31
benzyne-ene reaction 470
Bergman cyclization 9
Bettinger’s synthesis, of undecacene 41
biaryl synthesis 121
bicyclohexene 8
biphenylene-based starphenes 52, 53
1,2-bis(trifluoromethylation) 249
bisanthene 43, 46
bis(pinacolato)diboron onto indolynes
379
bismuthosulfanylation, of arynes 138
bis(trimethylsilyl)naphthalenes 43
bis-tosylate 472
boronic esters 192, 325, 329
2-bromobenzofuran 362
3-bromobenzofuran 2, 361, 363
3-bromo-2-chloropyridine 366
1-bromocyclohexene 398
5-bromoindole 369
7-bromoindole derivative 371
2-bromophenylboronic ester 192
3-bromo-4-(phenylsulfinyl)pyridine
368
489
490
Index
c
carbazole-containing alkaloid
mahanimbine 414
carbazolyne 384, 414, 469, 478
carboamination, of N-benzoylanilide
117
carbodiimide-derived aza-ortho-quinone
methide 163
carbodiimides 162, 163
carbolithiation, of arynes 121, 122
carbon-carbon triple bond 2, 5, 14, 171,
267, 280, 436
carbon nanohorns 61, 62
carbon nanotubes, by aryne
cycloadditions 60–61
carbon nucleophiles
carbanions 452
enamines and enolates 453–454
carboxylic acids 82, 129, 155, 156, 285
catalytic aryne generation methods
alkynyllithium catalyzed aryne
generation 326
Pd-catalyzed aryne generation 324
Pd-mediated aryne generation from
benzoic acids 324–325
Pd-mediated aryne generation from
methyl 2-bromobenzoates 325
Pd-mediated aryne generation from
o-bromoaryl boronic esters 325
C–B, C–I, or C–Cl bond formation,
transformations 142
cesium fluoride 126
4-CF3 -thiobenzonitrile 242
C60 -graphene hybrids 63
chelidonine 452, 461, 468, 469
chiral α-bromoamide 99
1-chlorocyclohexene 388
4-chloroindole derivative 369
2-chloro-3,4-pyridyne 89
C–H/N–H annulations
copper 224
Ni-catalyzed denitrogenative/
annulation 222
palladium-catalyzed arynes 215–222
palladium-catalyzed carbocyclization
201–215
cine-substitution via addition-ringopening-elimination-ring-closure
(ANRORC cine) 361
cine-substitution via addition-substitution-elimination (ASE) 361
cine-substitution via trans-halogenation
(BCHD) 361
(±)-Cis-trikentrin A 384
14
C labelling 3
cloverphenes 49, 51, 186, 187
cobalt-, rhodium- and palladiumcatalyzed corbonylative cycloaddition of benzynes 255–260
copper-catalyzed arynes
Ar–Sn bond Addition 244–246
B–B bond addition 244
1,2-bis(trifluoromethylation) 249–251
C–Br bond addition 249
CuCF3 238
multi-component reactions
copper-catalyst 235, 236
[(IPr)CuCl]-catalyzed synthesis of
isocoumarins 236–237
terminal alkynes and activated
alkenes 236
P–H bond addition 253–255
sp C–H bond addition 247
three-component coupling
carboamination 230–233
copper(I) acetylide 232
o-alkynyl aryl iodides 238
vinylaziridines 232
copper-mediated C–H/N–H annulation
reaction
of benzamides 224, 225
of indolobenzamides and arynes 225
cossonidine 457
coumestans 220, 476
C–P bond formation, transformations
140–142, 143
crinine 470, 471
cryptaustoline 447, 448
Index
Curtius-type rearrangement 273, 274,
275
curvularin 456, 457
α-cyanoketones 124
2-cyanophenylstannane 245
cyclic alkyne 4, 385
cyclic amines 157, 294, 421
cyclic 1,3-dipoles 70, 71, 90–92
cyclic ketones 124, 126, 396
cycloaddition
Au(I)-catalyzed benzannulation of
o-alkynyl(oxo)benzenes with
arynes 198, 201
hetarynes 375–380
nickel-catalyzed arynes 193
palladium 184–193
of 4,5-pyrimidyne 374
[2+2] cycloaddition 16, 393
aquayamycin 467
of (+)-CC-1065 470
chelidonine 469
cycloinumakiol 468
goupiolone A 468
nanaomycin D 466
ortho-methylbenzaldehydes 468
polyketides 464
taxodione 466
tubingensin B 469
[2+2+2] cycloaddition 28
[4+2] cycloadditions
aporphine alkaloids 464
aristolactam alkaloids 465
arizonins B1 459
arnottin 460
ent-gilvocarcin M 458
ent-Sch 47555 471
granaticin A 460
intramolecular Benzyne-Diene 463
isocryptolepine 476
isokidamycin 461
ningalins D and G 462
nomitidine 461
pseudopterosin aglycon 463
rifsaliniketal 459
rishirilide B 460
spiroxin C 459
trikentrins 462
vineomycinone B2 methyl ester 472
cycloaddition reactions 5
[2+2] cycloaddition 393–394
cycloalkynes
Diels–Alder Reaction 393, 394
1,3-dipoles 394
[2+2] cycloaddition reactions 15
[3+2] cycloaddition reactions 16
1,2-cycloalkadienes reactions
[2+2] cycloaddition reaction 401
Diels–Alder reaction 400–401
1,3-dipolar cycloaddition 401–402
cycloalkynes
alkenylation reactions 395
allenic intermediate 386–387
14
C-labelled l-chlorocyclohexene with
phenyllithium 386
cycloaddition reactions
[2+2] cycloaddition 393–394
Diels–Alder Reaction 393, 394
1,3-dipoles 394
cycloheptyne 387
cyclohexyne 387
cyclopentyne 387
dodecahydrotriphenylene from
1,2-dibromocyclohexene 385
fluoride induced cyclohexyne
generation
cyclohexenynone 392–393
3,4-oxacyclohexyne 391
2,3-piperidyne 392
3,4-piperidyne 392
insertion reactions 395–396
phenyllithium with
l-chlorocyclohexene 385–386
reactivity and isolability of 384
traditional methods of
aminotriazoles fragmentation 389
base induced 1,2 elimination
388–389
1,2-bishydrazzones oxidation 390
diazirine fragmentation 390
491
492
Index
cycloalkynes (contd.)
metal-halogen exchange/elimination
389
vinylidenecarbenes rearrangement
390, 391
trapping of 386–387
cycloheptyne 386, 387, 388, 389, 390
cyclohexyne 384, 385, 386, 387, 388, 389,
390, 391, 393, 394, 395, 396, 397,
400
cycloinumakiol 467, 468
cyclopentadienone 20, 29, 42, 43, 58,
347, 426
cyclopentyne 385, 386, 387, 389, 390, 391
cyclotrimerization
gold-catalyzed self-trimerization of
arynes 197, 200
nickel-catalyzed arynes 193
palladium 184–193
d
dehydrogenation 33, 34, 43, 57, 89, 99,
454
dehydrohalogenation, of aryl halides 27,
316, 318, 368
3,4-Dehydro-1,5-naphthyridine 362,
373, 374
2,3-dehydropyridine-N-oxides 362
1,2-diallylated benzenes 226
diaroylmethanes 153
diaryl sulfoxides or sulfilimines 304
diazo compounds 72, 75
dibenzophospholederivative, synthesis of
122
dibenzopyrrocoline alkaloids 447
dibenzosultams 222
1,2-diborylarene 243
1,2-dibromobenzene 141
1,4-dibromobenzene 36
1,2-dibromocyclohexene 385
dibromoindole 369–370
dibromoisobenzofuran 35
2,3-dibromonaphthalene 34, 35
1,3-dicarbonyl compounds 124
1,2-didehydrobenzene diradicals 409
2,3-didehydronaphthalene 34
Diels–Alder (D–A) reactions 3, 7, 27
of tropones 15
diepoxypentacene 36
difluorobenzene 471
difunctionalization, of arynes 118, 119,
132, 144, 231, 278–303
1,2-difunctionalization of arynes
formal insertion of arynes into
carbon-carbon bonds
cyclic ketone 278
1,3-diketones 281
β-ketoesters 279, 280
α-lithiated malonate/an α-lithiated
nitrile 279
malonates and 1,3-diketones
279–280
N-tosylacetimidates/N-tosylacetimidamides 283
α-substituted ketones 281–282
formal insertion of arynes into
carbon-heteroatom bonds
acyl-oxygen and acyl-halogen
&sigma;-bonds 285
C–P and C–S bonds 286
ethoxyacetylene 287
imidazolidines 287
imides, ureas, and cyanamides 284
secondary amides 283
tertiary amides 284, 285
formal insertion of arynes into
heteroatom-heteroatom bonds
288
vicinal formation 289
1,8-difurylnaphthalene 46
dihalide pyridine precursor 366
2,3-dihydro-1H-indazole 298
dihydroisoquinolinium N-oxide 86, 87
9,10-dihydrophenanthrenes 187, 190
diiodobenzenes, pyrolysis of 3
dimethyl acetylenedicarboxylate (DMAD)
32, 55, 185, 187, 430
1,2-dimethylenecyclobutane 33
dimethyl maleate 39, 161
Index
dinaphthocoronene tetracarboxdiimide
204
2-diphenyliodonium carboxylate 28
1,3-diphenylphenanthrofuran 41
1,2-diphosphinobenzene derivatives 141
1,3-dipolar cycloaddition 16
1,7-dipolar cycloaddition 72
1,3-dipolar cycloaddition reactions 29,
70, 71
cycloaddition, of arynes 95–97
cycloaddition, with dipoles 92–95
[3+2] dipolar cycloaddition reactions,
cyclic 1,3-dipoles
arynes, with Münchnones 92
arynes, with sydnones 90–92
[3+2] dipolar cycloaddition reactions,
linear 1,3-dipoles
arynes with azides 75–79
arynes, with azomethine imines and
ylides 83, 84
arynes, with nitrile imines 80
arynes, with nitrile oxides 79–80
arynes, with nitrones 80–83
arynes, with pyridinium N-imides
87–89
arynes, with pyridinium N-oxides
85–87
arynes, with pyridinium Ylides
89–90
with diazo compounds 72–75
formal cycloaddition reactions 97
hydrazone-derived N–N–C systems
99–103
N–C–C systems 97, 99, 100
1,3-dipolar cycloadditions (1,3-DC) 70
dipolarophiles 16, 69, 80, 83, 90, 394
dipolar variant 93
1,3-dipoles 70, 394
3,6-di-2-pyridyl-1,2,4,5-tetrazine 35
diselenide 427–428
distal vinylic position 102
1,2-disubstituted arenes 150
2,4-disubstituted benzothiazole 338
diverse transformations 123
diynamide 414
DMSO-derived textit-ortho species 171
1-dodecanethiol 133
domino aryne generation 19
domino HDDA 426
domino Heck spirocyclization 211, 213
double helicene, Synthesis of 55
dynemicin A 455, 456
e
6π-electrocyclization 478
electron-deficient alkynes 32, 153, 154,
185, 424
electronic effect
3-borylbenzynes 332
3,4-pyridyne 333, 334
regiocomplementary [3+2]
cycloaddition 332, 333
reversing regioselectivity on
4,5-indolyne 333, 334
silyl groups 331
substituted benzynes and hetarynes
330, 331
electron-withdrawing groups 75, 77,
159, 207, 229, 301, 305
elimination-addition (EA) mechanism
360
elusive bimolecular HDDA reaction
433–434
enal trapping 427
enamines 97, 98, 446, 452, 453–454
ent-clavilactone B 453
epoxynaphthalene 14, 27, 35
2-ethoxybenzofuran 1, 362
eupolauramine 21, 380, 382, 383
f
few-layer graphene (FLG) 62
final cyclization 46
five-membered hetarynes 7, 359, 361
five-membered heterocycles 70, 80, 361,
365
flash vacuum thermolysis (FVT)
experiment 363
flemichapparin C 220, 476, 477
fluoride induced cyclohexyne generation
493
494
Index
cyclohexenynone 392–393
3,4-oxacyclohexyne 391
2,3-piperidyne 392
3,4-piperidyne 392
fluoride induced elimination 10
azacyclic allene 399
cycloalkatriene generation 400
oxacyclic allene 399–400
α-fluoro-β-amino acid derivatives 153
3-fluoro-2-iodophenyl triflate 133
formal insertion of arynes
carbon–carbon bonds
cyclic ketone 278
β-ketoesters 279, 280
malonates and 1,3-diketones 279,
280
α-substituted ketones 281, 282
carbon–heteroatom bonds
acyl–oxygen and acyl–halogen
σ-bonds 285
C–P and C–S bonds 286
ethoxyacetylene 287
imidazolidines 287
imides, ureas, and cyanamides
284
secondary amides 283
tertiary amides 284, 285
heteroatom–heteroatom bonds
C–P and C–S bonds 286
N–O bonds 289, 290
organophosphorus acids and
sulfinamides 288, 289
phosphoryl amides 288
[1,3]-rearrangement 289
formamide 427–428
fragmentation, of amino benzotriazoles
10
fredericamycin A 456
free radical explanation 2
fullerobenzyne precursor 60
g
Garg–Houk’s study 328–329
gold/copper-catalyzed sp C–H bond
Addition 247
goupiolone A 467–468
granaticin A 460
Gribble’s bisaryne synthesis, of tetracenes
37
Gribble’s synthesis, of tetracenes 35
Grob fragmentation 12, 340–341
guanacastepenes O and N 396, 397
h
halobenzene 2, 9, 316, 319, 324, 336
halogen–metal exchange reactions 446
3-halopyridine 365, 367
Hamura’s synthesis, of substituted
pentacene 36, 39, 53
Hart’s bisaryne synthesis, of
dodecamethyltetracene 37
Hart’s synthesis, of epoxyacenes 38
Heck-type coupling of benzynes 228
helical corannulene trimers 57
helicene synthesis 91
(±)-herbindole A 384
herbindole B 413–414
hetarynes 114
abnormal addition–elimination (AEa )
mechanism 360, 361
addition–elimination (AEn ) mechanism
360
cycloaddition reaction 375
elimination–addition (EA) mechanism
360
five-membered 359, 361
indolyne
herbindole 384
lysergic acid synthesis 383
trikentrin 384
insertion reaction 379–380
nucleophilic addition reactions
377–379
pyridine
ellipticine synthesis 382
eupolauramine 382, 383
(S)-Macrostomine 382
perlolidine synthesis 381
six membered 359, 361
Index
heterocycles 1, 6–7, 21, 30, 70, 80,
97, 150, 157, 159, 163–165, 237,
257, 273, 301, 317–318, 361, 365,
369
heterocyclic helicenes 57
hetero-Diels–Alder reaction 93
hexabenzotriphenylene, synthesis of
54–55
hexacene 33–34, 39, 426
hexadehydro Diels–Alder (HDDA)
reaction 1, 11, 114, 149
Ag- and B-promoted carbene chemistry
412–413
aryne formation 315, 428
aza-HDDA variant 431
benzyne cycloisomerization 409, 410
classical vs. HDDA benzyne chemistries
431
Cu(I)-Catalyzed hydro- and
halocupration 428
de novo arene ring construction
413–414
diselenide 427
diynophile 434
domino 426
elusive bimolecular HDDA reaction
433
enal 427
examples of 411–412
formamide 427
half-life measurements 437–438
intramolecular 424
Lee group 416, 417
naphthynes via double 424, 425
natural products
colchicine and quinine 420
phenol 419
new mechanistic insights
dearomatizing ene reaction 424
diaziridine 424
dihydrogen transfer reactions
422–423
silyl ether 424
thioamides 424
three component reactions 421–422
NHC-borane trapping 427
nucleophilic trapping agent 432
4π- and 2π-components 407, 408
perylene 426
[4π+2π] cycloaddition reactions,
aromatic dienes 416, 417
pristine reaction conditions 435
reaction conditions
temperature, pressure, and alkyne
stability 436–437
tolerance for water and oxygen
435–436
substrate concentration 437
substrate design 434
trapping agents 433
triyne to benzyne 415
unanticipated transformation 411
hexaphenyltetrabenzopentacene 41
highest occupied molecular orbital
(HOMO) 4–5, 29, 41, 183, 415
1H-indazoles 72–75
3H-indazoles 72–74
Hückel theory 4, 8
hydrazonyl chlorides 80, 99–100
4-hydroxycoumarins 220
i
ibutamoren mesylate 339, 474
Ikawa-Akai’s
1,3-benzdiyne strategy 344
1,4-benzdiyne strategy 348, 349
3-imidopyridinium 94
3-imidopyridinium species 72, 94
imine oxides 80
iminoesters 260
6,7-indoline 57
indolinyne generation 375
2,3-indolyne 361
4,5-indolyne 78
2,3-indolyne generation 363
4,5-indolyne generation
5-bromoindole 369
4-chloroindole derivative 369
dibromoindole 369–370
silyltriflate precursor 370
495
496
Index
5,6-indolyne generation 370
6,7-indolyne generation
7-bromoindole derivative 371–372
dichloroindole precursor 371
proton-lithium exchange 371
insertion reactions 17
of arynes 118, 140, 153, 280
insertion reactions, of aryne intermediates
amination and related transformations
formation of C–N and C–C bonds
116–118
formation of C–N and C–H bonds
111–115
formation of C–N and C–Mg bonds
115–116
formation of C–N and C–S, C–P,
C–Cl, or C–Si bonds 118–121
bond formation, with nucleophilic
carbons
acylalkylations and related
transformations 124–128
benzocyclobutene synthesis, [2+2]
cycloaddition 122–123
transformations, carbometalation
121–122
transformations, C–C and C–H bond
formations 128–129
etherification, and transformations
129, 132, 133
in situ generated nitrile oxides 80
intramolecular arylation 114
intramolecular benzyne–diene [4+2]
cycloaddition 463
intramolecular N-arylation 117
iodine-magnesium exchange 114
2-(2-iodophenoxy)-1-substituted
ethanones 204
1-iodo-2-(2-(phenylethynyl)benzyloxy)
benzenes 204
isobenzofuran 35, 39–40, 52, 290, 386
isochromen-6-ones 204
α-isocyanoacetamides 152
β-(2-isocyanophenyloxy)acrylates 290
isokidamycin 460–461
isolable cyclic 1,3-dipole 90
isopropylmagnesium chloride
(i|i-PrMgCl) 116, 322
isoquinolinium N-oxides 86–87
3,4-Isoquinolyne 373
isotopomers, of phthalic anhydride 3
isoxazolone 392
j
justicidin B 192, 475
k
Kelly’s synthesis, of molecular ratchet
48
ketene dithioacetals 102–103
ketene silyl acetals (KSAs) 123, 321, 340,
343, 350–351, 467, 470, 472
ketene silyl acetyls (KSAs) 340
β-ketophosphonic acid diester 127
ketoxime-derived nitrones 83
Kitamura’s hybrid 1,3-benzdiyne
equivalent 344
Kitamura’s hybrid 1,4-benzdiyne
equivalent 349
Kitamura’s synthesis, of substituted
tetracenes 45
Kita’s synthesis of fredericamycin A
456
Knochel’s aryne precursors 323
Kobayashi method 267, 269
Kobayashi’s aryne 183, 391
Kobayashi’s fluoride induced aryne
generation 12–13
Kobayashi’s method 13, 29, 36, 39, 46,
149, 315, 321, 331, 340, 347, 354
Kobayashi-typed benzdiyne precursor
95
koenidine 478
l
Larock’s group 201, 215
laserflash photolysis (LFP) 5
LiBr elimination 363
liphagal 451
2-lithio-3-bromo-1-phenylsulfonylindole
363
Index
lithium di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2 Zn(TMP)Li)
319
lithium diisopropylamide (LDA) 317,
319, 320, 336, 372, 459, 463, 470
lithium 2,2,6,6-tetramethylpiperidide
(LiTMP) 317–318, 449, 455, 467
lithium tetramethylpiperidide (LTMP)
38
lowest unoccupied molecular orbital
(LUMO) 4–6, 13, 29, 111, 183,
434, 445
low-valent titanium 41
lysergic acid synthesis 383
m
(S)-macrostomine 382
makaluvamines 369, 380, 384, 448
m-benzyne 8
2-mercaptobenzothiophenes 103
mesogenic tetrabenzopentaphenes 50
mesoionic rings 70
metal bound benzyne 4–5
metal-halogen exchange/elimination 10,
326, 389
metallacyclopropenes 5
metal-metal (or) metal-carbon bond
arynes
copper-catalyzed Ar–Sn bond Addition
244–246
copper-catalyzed B–B bond addition
244
copper-catalyzed C–Br bond addition
249
copper-catalyzed P–H bond addition
253–255
copper-mediated1,2-bis(trifluoromethylation) 249–251
gold/copper-catalyzed sp C–H bond
addition 247–248
palladium-catalyzed C–Sn bond
addition 240–241
palladium-catalyzed Sn–Sn/Si–Si bond
Addition 241
platium-catalyzed boron–boron bond
addition 243–244
sp C–H bond Addition 247
meta-methoxyaniline derivatives 113
3-methoxybenzyne 113
4-methoxybenzyne 95
4-methylbenzenesulfonate 372
methyl 2-bromobenzoates 191, 324, 325
(trimethylsilyl)methylmagnesium
chloride 119
Michael acceptor 95, 97
Michaelis–Arbuzov-type reactions 141
microporous polymers 48
molecular gyroscope 48
molecular rearrangements 13–14, 18,
21, 267–310, 393, 400
molecular rearrangements triggered
1,2-difunctionalization of arynes
278–303
four-component reactions with three
aryne molecules 308–309
monofunctionalization of arynes
nitrogen nucleophiles 268–275
sulfur nucleophiles 275–278
three-component reactions with two
aryne molecules
of 4-hydroxycoumarins 306, 307
nitriles 306
oximes 306, 308
thioureas 306, 307
1,2,3-trifunctionalization of arynes
303–305
3-morpholinobenzyne 114
Müllen’s synthesis, of pentacene 33
multicomponent couplings (MCCs) 14,
18
reactions of arynes 183, 184
multicomponent reactions 149
carbon nucleophile-based
multicomponent reactions
active methylenecompounds 153
isocyanide 150–152
classification of 150
halogen nucleophile-based 177–179
nitrogen nucleophile-based
497
498
Index
multicomponent reactions (contd.)
amine 153, 155–159
diazene 164–165
imine 159–163
N-heteroarene 163–164
nitrite 165
oxygen nucleophile-based
cyclic ether 172–173
dimethylformamide 165–169
sulfoxide 169–172
trifluoromethoxide 173–174
phosphorus nucleophile-based
174–175
sulfur nucleophile-based 176–177
multisubstituted naphthalenes 153
Münchnone 70–71, 92
n
N-alkoxyamides 114
N-alkoxybenzsulfonamides 222
N-alkoxy oxyindoles 99
N-aminotriazolo-pyridine 366, 368
nanaomycin D 466
nanographene 50–51, 57, 345, 347, 348,
353
1,2-naphthalyne 91
2,6-naphthodiyne synthon 42
2,3-naphthyne 34
naphthynes 6, 34, 36, 40, 49, 340,
424–426, 428–429
N-aryl-2-acylpyrrolidines 273
N-arylation
of amines 17
with arynes 126
of N–H sulfoximine 114
reaction 113
natural bond orbital (NBO) 76, 78
natural product synthesis
addition–fragmentation reaction
454––457
1,3-benzdiyne equivalents 473
1,4-benzdiyne equivalents 471
benzyne–ene reaction 470–471
benzyne generation via hexadehydroDiels–Alder reaction 477–479
benzyne precursors 447
[2+2] cycloadditions 446, 464–470
[4+2] cycloadditions 446, 457–464
ene reactions 446
nucleophilic additions to benzynes
carbon 452–454
nitrogen 447–450
oxygen nucleophiles 450–452
transition-metal catalyzed reactions
474–477
N-benzoyloxymorpholine 116
N-benzoylquinolinium imides 93
N-benzyl-N-tosylenamide 123
N-boc-2-methyleneglycine derivatives
97
1,n-dipolar cycloaddition 69
1,n-dipoles 69, 70
Neckers’s synthesis, of hexacene 34
N2 extrusion 35, 39, 43
NHC-borane trapping 427–428
Ni-catalyzed denitrogenative/annulation
222–223
nickel-catalyzed arynes
cycloaddition
activated alkenes and alkynes 197,
200
with alkynes/eneynes 197
of enynes and arynes 196, 199
3,4-pyridyne with 1,3-diynes 195,
198
with unactivated alkenes 196, 199
cyclotrimerization
with allenes 194, 196
with diynes 195
three-component coupling 230
ningalins D and G 462
nitrile imines 16, 70–71, 80, 99, 102, 394
nitrile oxides 16, 70, 77–80, 394, 401
nitrogen nucleophiles
acronycine 450
aryne-triggered Sommelet–Hauser
rearrangement of tertiary benzylic
amines 269, 271
aryne-triggered [2,3]-Stevens
rearrangement 273
Index
benzye-induced [1,4]-rearrangement
270, 271
cryptaustoline 448
Curtius-type rearrangement 273, 275
dibenzopyrrocoline alkaloids 447
dictyodendrin A 449
textit-benzyl glycinate 270
of hinckdentine A 450
indolactam V 450
isobatzelline C 448
makaluvamine A 448
quinazolinone alkaloids 450
(aminomethyl)silane 268
three-component reaction of pyridines,
arynes and isatins 275
triethylamine 268
nitrones 16, 70–71, 78, 80–83, 85, 87,
308, 331, 376, 394, 401–402
N-methoxybenzamides 217, 219
N-methylcrinasiadine 476
N-methyltetrahydroquinoline 157
N-monosubstituted hydrazones 101
N-monosubstituted hydrazonyl chlorides
99
N,N-dialkylanilines 157
N,N-dimethylaniline 114
N,N-dimethylhydrazone 118
N,N-dimethylhydrazonyl chlorides 100
nomitidine 461
non-anionic nucleophiles 445
1,3,8-nonatriyne 409
non-zwitterionic amphiphiles 70
N—O single bond 85
N-substituted-N-(2-halophenyl)
formamides 209
N-substituted phenanthridinones 209
N-tosylhydrazones 75, 101
N-tosylisoquinolinium imides 89
N-(trifluoroacetyl)anilides 118
Nuckolls’s synthesis, of substituted
pentacenes 45
nucleophilic addition reactions 332, 370,
375, 378–379, 402
hetarynes 377
nucleophilic C–C bond formation 122
nucleophilic organophosphorus
compounds 140
nucleophilic organosulfur compounds
133
nucleophilic substitution reaction 2, 360
N-vinyl-α,β-unsaturated nitrones 81
o
O allyl migration 172
o-aminoarylsilanes 119
O-arylation, with arynes 82
o-benzoxazolylhydroxylamines 230
o-benzyne 4
o-dihaloaryls 27
o-haloaryl sulfonates 321
o-iodoaryl sulfonates 116
o-iodoaryl triflates 114, 123, 321
one-pot transformation 35, 39
one-pot tricyclic phenanthridinones
217
organolithium reagents 179–180
organometallic reagents 10, 225, 227
organonitrogen compounds 114, 116
organophophorus compounds 140–142
ortho-formyl diaryl ethers 169
ortho-methylbenzaldehydes 468
ortho-olefinated biphenyls 190
ortho-quinoid species 170
ortho-quinone methide 168, 169
ortho-silyl aryltriflates 183
ortho-(trifluoromethoxy)aryl anion 173
ortho-(trimethylsilyl)phenyl triflate 183
o-silylaryltriflates 50, 111, 119, 133
o-silylaryl triflate-type 3-sulfanylaryne
precursors 138
o-siylphenyl triflate 321
o-transpositioned ketones 93
o-(trimethylsilyl)phenyl triflate 28
oxacyclic allene 399–400
3,4-oxacyclohexyne 387, 391
oxidative photocyclization reactions 55
3-oxidopyridinium dipole 72
oxonium Claisen rearrangement 172,
304, 351
499
500
Index
oxygen nucleophiles 165–174, 284, 446,
450–452
oxysulfanylations, of aryne intermediates
132, 135
p
paddle-wheel nanostructures 59–60
palladacycloheptadiene 190
palladium-catalyzed arynes
ArS–CN addition 241–243
co-cyclization 185
C–Sn bond addition 240–241
ctrimerization of (2-bromophenyl)
boronic esters 192
in C–X annulations
aryl ketone O-acetyloximes 215, 217
benzophenone O-perfluorobenzoyl
oximes 215
dibenzosultams 222
N-acylcarbazoles 215, 216
N-methoxybenzamides 217, 219
N-methyl benzylamines 221
one-pot tricyclic phenanthridinones
217, 219
ortho-halobenzamides 216
phenanthridinones 221
phthalimides 222, 223
quinolinones 218, 220
cycloaddition
with alkynes 186
allylic chlorides or alkynes 188
benzodiynes 188
benzoic acids 191, 192
cloverphene 186, 187
conjugated dienes 192
indole-based conjugated trimers
192
methyl 2-bromobenzoates 191
substituted diynes 188, 189
cyclocarbonylation
1H-inden-1-ones 259
cyclotrimerization 185
allenes 190
bicyclic alkene 187, 188
carbon-carbon π-components 185
cloverphene 187
coupling of alkenes 190
substituted indole based arynes 192
Pd(0) oxidation state 184
Sn–Sn/Si–Si bond addition 241
three-component coupling
with allylic epoxides and terminal
alkynes 228
allylic halides and alkynyl stannanes
226
arynes, isocyanides and
cyanoformates 230, 231
arynes, terminal alkynes, and vinyl
cyclopropanedicarboxylate 229,
230
bis-allylation 226
Heck-type coupling 228, 229
Sonogashira type coupling 227
Stille and Suzuki coupling reactions
227
three-component reaction
carbon monoxide and 2-iodoanilines
259
palladium-catalyzed carbocyclization
aromatic halides with arynes 202, 203
arynes with allyl-substituted
iodocyclohexenones and
iodofuranones 209
arynes with propargylic carbonates
207
biscarbocyclization reactions 206
carbopalladation of arynes with
iodo-aryl-alkenes 213, 214
chemoselective [3+2] spiroannulation
of 2-halobiaryls with arynes 216
(diarylmethylene)cyclopropa[b]naphthalenes with arynes 206
dinaphthocoronene tetracarboxdiimide
204
domino Heck spirocyclization 211,
212
2-halobiaryls with arynes 201, 202
indolo-[1,2-f ]phenanthridines 203
2-iodobenzyl-3-phenylpropiolates 204
Index
2-(2-iodophenoxy)-1-substituted
ethanones 204
N-(2-halophenyl)formamides with
arynes 210
N-(2-phenylallyl)sulphonamides with
arynes 210, 212
o-halobenzaldehydes with arynes 203
ortho-halostryrenes with arynes 210,
211
polycyclic dibenzocoronene
bis(dicarboximide) 204
substituted o-halostyrenes with arynes
208
three-component coupling of aromatic
halides with alkynes and arynes
202, 204
three component coupling of aromatic
iodides with
bicyclic/heterobicyclic alkenes and
arynes 203, 205
palladium-catalyzed [2+2+2]
cocyclotrimerization 32, 49
palladium-catalyzed cocyclotrimerization,
of arynes 49
palladium-catalyzed cyclotrimerization,
of indolynes 57
papaverine 238, 453
Pascal’s synthesis, of twisted substituted
pentacene 42
p-benzyne intermediates 8
Pd-catalyzed aryne generation 324, 325
Pd-mediated aryne generation
from benzoic acids 325
from methyl 2-bromobenzoates 325
from o-bromoaryl boronic esters 325
Peña’s synthesis, of decacene 40
pentahelicene 56
1,3-pentanedione 126
Pérez–Peña synthesis, of benzo-fused
substituted acenes 44
Pérez’s synthesis 58
pericyclic reactions 13–15, 315, 339, 446
perlolidine 380–381
perylene 43, 45–47, 426
perylenebisimides (PBIs) 46, 47
π-extended starphenes, synthesis of
49–52, 54
3,4-phenanthryne 91
phenyl(2-(trimethylsilyl) phenyl)
iodonium triflate 10–11
phenylpropiolic acid 408
phenylsulfanylation, of arynes 135
1-phenylsulfonyl-2,3-indolyne 363
3-(phenylthio)benzyne 114
(2-aminoaryl)phosphine oxides 288
α-phosphinylacetonitrile 127
photoinduced aryne generation methods
323
photoinitiated benzenediazonium
carboxylates decomposition 3
platinum-catalyzed boron-boron bond
addition 243–244
P–Li bonds 140
polycyclic aromatic compounds 19–20,
54, 185, 188, 201, 345
polycyclic aromatic hydrocarbons (PAHs)
19–20, 29–31, 48–55, 57–58, 204,
345–346, 353–354, 393–394
polycyclic aryne precursors 187
polycyclic dibenzocoronene
bis(dicarboximide) 204
porous triptycene-based molecules 48
possible reactivity modes of
arylation reactions 17
insertion reactions 17
MCC 18, 19
molecular rearrangements 18–19
pericyclic reactions 14–16
transition metal-catalyzed reactions
18
prefluoroalkoxylation–bromination
reactions 174
proton-lithium exchange 371
pseudopterosin aglycon 463
pyrazolo[5,1-a]isoquinolines 239–240
2,3-pyridine dicarboxylic anhydride 7
pyridinium N-oxides 71, 85–87, 96
1,2-pyridyne 362
2,3-pyridyne 377
dihalide pyridine precursor 366
501
502
Index
2,3-pyridyne (contd.)
3-halopyridine 365–366
N-aminotriazolo-pyridine 366
3-(trimethylsilyl)pyridin-2-yl
trifluoromethanesulfonate 367
pyridyne-N-oxides generation
374–375
3,4-pyridynes 7, 378, 380
3-bromo-4-(phenylsulfinyl)pyridine
368
3-halopyridine 367–368
N-aminotriazolo-pyridine 368
thermolysis of diazonium carboxylates
367
4-trialkylsilyl-3-pyridyl triflate 368,
369
4,5-pyrimidyne 77, 373
α-pyrones 462
pyrroloindole 474
3,4-pyrrolynes 364
q
quinolynes generation
5,6- and 7,8-dehydroquinolines 372
3,4-isoquinolyne 373
7,8-quinolyne 372, 373
3,4-quinolyne from halo derivatives
372
r
regioselective amination, of pyridynes
114
regioselectivity
in aryne reactions 3
rationales 78
of unsymmetrical benzyne 77
resonance stabilization energies (RSE)
415, 434
retro-D–A reaction 33, 35, 37–39
retrojusticidin B 192, 475
retro-6π electrocyclization 94
Rickborn’s synthesis
of pentacene 37
of tetracene 35
rifsaliniketal 458–459
rishirilide B 459–460
Ritter-type reactions 416
s
scanning tunnelling microscopy (STM)
40, 50, 53
Schlüter’s synthesis, of epoxyacenes 38
selaginpulvilin C 414, 478
selaginpulvin C 413–414
1,3-sigmatropic-like rearrangement 86
1,3-sigmatropic rearrangement 83
silver-catalyzed [3+2] cycloaddition of
arynes 74, 260–261
silylamination, of arynes 119, 121, 141
silylaryl triflates 70, 114, 119, 138, 267,
269–270, 272–273, 275–276,
279–281, 283, 285–290, 292,
294–295, 298–299, 301, 303–306,
309, 321, 345, 449, 451, 453–454,
456–457, 460–461, 464, 468,
474–477
3-silylbenzyne 77
silyl ether 351, 411, 423–424, 428, 463
silylmethyl Grignard reagent 114, 121,
133, 322
silylphosphination, of arynes 141, 143
silyl-protected carboxylic acids 285
silyltriflate precursor 370, 372, 378, 391,
393
singlet-triplet splitting 3, 8
six membered hetarynes 7, 359, 361
small ring-fused arynes 335–336
Sommelet–Hauser rearrangement
269–271
Sonogashira type coupling 227–228
sp2 -hybridization 70
spiropalladacycle 212
spiroxin C 459
S-silyl sulfides 136
starphenes 48–54
steric effect
3-alkyl groups on arynes 327, 328
boronic esters 329
Garg–Houk’s study 329
silyl 328
Index
trimethylsilyl (TMS) group 328
[1,2]-Stevens rearrangement 268
strained cyclic allenes
1,2-cycloalkadienes generation
base induced 1,6-elimination 397
cyclopropylidenes rearrangement
398
fluoride induced elimination
398–400
via pyrolysis of ketene 398
1,2-cycloalkadienes reactions 400
styrenes, reaction of 15
α-substituted α-diazophosphonate 74
sulfanylation
hydrosulfanylation, of arynes 133, 135
transformations, C–S and C–C bond
formations 135
transformations, C–S and C–X bond
formations 136, 138, 140
sulfanylation reactions, of arynes 133
sulfanyl magnesiations, of arynes 136
sulfur 102–103, 170, 176–177, 275–278,
299, 302–304, 306, 363, 426, 434
sulfur nucleophiles
aryne-triggered [1,2]-Stevens
rearrangement 275
aryne-triggered [1,2]-Stevens
rearrangement of benzylic
thioethers 276
aryne-trigger [2,3]-Stevens
rearrangement of allylic thioethers
276, 277
aryne-trigger [2,3]-Stevens
rearrangement of propargylic
thioethers 276, 277
benzyne-triggered [2,3]-Stevens
rearrangement of allylic thioethers
276, 277
superior electrophile 183
Suzuki–Miyaura C–C coupling 46
Suzuki–Miyaura cross-coupling reactions
243, 379
Suzuki’s 1,3-benzdiyne strategy 343
Suzuki’s synthesis of hexaredialene 351,
353
Suzuki’s synthesis of TCBBs 352
Suzuki’s synthesis of tetraketone 350
sydnone 70–71, 78, 90–92
symmetrical tetraynes 412, 424, 426, 432
t
taiwanins 188–189, 475
tandem aryne cycloadditions 47
tandem [4+2]/[2+2] cycloaddition 16
tandem HDDA/TDDA 426
taxodione 466
terminal alkynes 18, 75, 113, 162,
227–232, 235–239, 247–248, 251,
253, 437, 469
α-(tert-butoxycarbonylamino)acrylic acid
methyl ester 118
tert-butyldimethylsilyl (TBDMS) group
329
tert-butylisocyanide 159
tetrabenzoheptaphenes 187
tetrabenzopentaphenes 49–50
1,2,4,5-tetrabromobenzene 40
tetrabutylammonium
difluorotriphenylsilicate (TBAT)
13, 141, 283, 454
tetrabutyl ammonium fluoride (TBAF)
13, 42–43, 50, 59, 62, 79–80, 85,
126, 155, 271, 458
tetrabutyl ammonium iodide (TBAI)
172–173, 224
tetrabutylammonium
triphenyldifluorosilicate (TBAT)
13, 141, 283–284, 454
tetracenes 33–35, 39, 43, 45
tetracenomycins C and X 472, 473
tetrachlorothiophenedioxide 33
tetradehydrobenzenes 7
tetradehydro-Diels–Alder (TDDA)
reaction 408–409, 411, 426, 435
tetraepoxydecacene 39–40
tetrahydrofuran (THF) 13, 85, 135, 163,
172–173, 241, 345, 409, 422, 435,
455, 458, 465, 467
tetrahydroisoquinoline skeleton 470
503
504
Index
tetrahydro naphthalenes via Diels–Alder
reaction 394
1,2,3,6-tetrahydropyridine-2-carboxylate
273
1,2,4,5-tetraiodobenzene 194
β-tetralone 124
2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) 40
tetramethylpyrrole 36
tetra-n-butylammonium fluoride 183
tetraphenylcyclopentadienone (TPCPD)
29, 37, 366, 393, 424, 425
tetraphenyltetrabenzoheptacene 41, 42
thiacycloalkyne 387
thianaphthene-2,3-dicarboxylic acid
anhydride 363
thianthrene 136
3,4-thiophyne 364
thioxantone synthesis 133
Thummel’s synthesis 33
tosylhydrazine 164, 165, 239–240
toxyloxanthone B 451
transition metal-catalyzed reactions 18,
149, 183–261, 315, 354, 474–477
transition metal catalyzed
three-component coupling
reactions
copper 230–239
Ni-catalyzed arynes 230
palladium-catalyzed arynes 225–230
silver 239–2407
4-trialkylsilyl-3-pyridyl triflate 368, 369
tricarbonyl compound 126
tricyclobutabenzene (TCBB) 350–352
tridehydrobenzenes 7
triepoxypentacene 39
triflones 303–304
trifluoroacetic acid (TFA) 36, 155–156
2-(trifluoroacetylamino)pyridine 114
trifluoromethoxide anion 173
trifluoromethoxylation–bromination
products 173
3-(triflyloxy)aryne intermediate 119
3-triflyloxy arynes 12, 136
3-triflyloxybenzyne 114, 303
triflyloxy (OTf) group 319
triflyloxy (OTf)-substituted
benzocyclobutenones 179, 180
1,2,3-trifunctionalization, of aromatic ring
172
1,2,3-trifunctionalization of arynes 303
trikentrins 462
trimerization 2
2-(trimethylsilyl)aryl triflates 12, 149
trimethylsilyl (TMS) group 173,
319–322, 328, 337, 339, 344–345,
348
2-(trimethylsilyl)-1,3-phenylene
bis(trifluoromethanesulfonate)
(TPBT) 1, 337
3-(trimethylsilyl)pyridin-2-yl
trifluoromethanesulfonate 367
triphenylene 2, 12, 31, 52, 185, 191–192,
197, 202, 324
triphenylphosphine 114, 118, 159, 303
triple bond 2–5, 36, 69, 77, 171–172, 180,
267, 280, 286, 321, 330, 333, 370,
384, 424, 431, 436, 446
triptycene sensors, for explosives 49
triscoranylene, synthesis of 57
triyne precursors 445, 477
tubingensin A 381, 384, 454–455
tubingensin B 381, 384, 469
turkiyenine 456–457
tylophorine 210, 476, 477
u
Uchiyama’s conditions 319
ultra-high vacuum (UHV) 27, 39–40, 53
urea insertion onto hetarynes 379
UV spectra 3
v
vicinal carbon
carbon/carbon–carbon bond-forming
reactions of arynes 289–292
carbon/carbon–heteroatom
bond-forming reactions of arynes
acyl hydrazides 298, 299
Index
1-aroyl-3,4-dihydroisoquinolines
299, 300
aryl sulfonamides 299, 300
aryne-triggered aza-Claisen
rearrangement of tertiary allylic
amines 293, 294
aryne-triggered propargyl Claisen
rearrangement 294, 295
diazo compounds 296, 297
N-hydroxyindoles 295
nitrosoarenes 296
pyridine N-oxides 298
thioamides 296, 297
three-component reaction of arynes,
tertiary aromatic amines, and
carbon dioxide 301, 302
three-component reaction of arynes,
tertiary aromatic amines, and
carbonyl compounds 301
heteroatom/carbon–heteroatom
bond-forming reactions of arynes
302
vineomycinone B2 methyl ester
348–350, 472
vinylogous quinolinium imides 93
vinyl sulfoxides 302–303
1-vinyl-1,2,3,4-tetrahydroisoquinolines
273
vitamine E core 452
w
welwitindolinone alkaloid 454–455
Woodward–Hoffmann rules 30–31, 122
Wudl’s synthesis
of benzo-fused substituted heptacene
43
of heptacene 38
Wurtz reaction 2
x
X-ray crystallography 4, 212, 222, 363
xylopinine 453
z
Zhang’s synthesis, of dodecatwistacene
42
zwitterionic 2, 10, 70, 103, 136, 162,
267–268, 303, 421, 454
505