Recent Applications of Benzynes and
Indolynes in Organic Synthesis
Trevor Mogg
Nov.10, 2011

Outline








Part I - Benzyne
Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis

Part II – Indolyne
Reactivity and Applications
2

Importance of Benzynes








Benzynes unique, highly reactive intermediate
Useful to create molecules
Traditional methods of preparation use harsh conditions or dangerous precursors
High reactivity requires careful selection of reaction conditions, substrate
Mild method of preparation allows more flexibility
Over last decade, new reactions of benzynes developed
Mild method of preparation extended to generate heteroaromatic indolynes
Useful for preparing biologically active molecules
3

Discovery

First Evidence by Roberts (1953)
= 14 C

Trapping by Wittig (1956)
Roberts et al, JACS, 75, 3290 (1953).
G. Wittig and L.Pohmer, Chem. Ber., 89, 1334 (1956).
via
4

Benzynes




Belong to family of intermediates known as arynes
Di-radical, aromatic, highly reactive species
Properly called didehydrobenzenes – ortho, meta, para
Two non-bonding orbitals outside ring, perpendicular to p system, two electrons between them ortho
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).
Sander et al, Angew Chem. Int. Ed., 2003, p502. meta para
5

Ortho-Benzyne



Reduced overlap of orbitals gives weak p bond
Better described as strained alkyne


Low-lying LUMO – Electrophilic
Readily undergoes pericyclic reactions, nucleophilic addition
Reacts with nucleophiles not normally reactive towards alkynes
K.N. Houk et al, Tet. Lett., 35, 3237 (1979). Sander et al, Angew Chem. Int. Ed., 2003, p502. Roberto Sanz, Org. Prep. Proced. Int.,
40 (3), 215-291 (2008). http://www.bama.ua.edu/~blacksto/CH435_CH531/home.html
. Accessed Oct.20, 2011
6

Preparing Benzyne
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008). 7

Less Common Methods
Cation
Fragmentation
Radicals
Zwitterion
*EXPLOSIVE*
L. Friedman et al, Org.Synth., 48, 12 (1968). Jones, J.Org.Chem. ,1971, p1536.
R.W. Franck et al, JACS, 1968, p.5814. Rees et al, J. Chem. Soc., 1969, p742.
-2 N
2
8


Aryl Anions
Ortho-metalation/elimination

Metal-halogen exchange/elimination


Fluoride induced elimination
Milder base than above methods, better functional group tolerance
Durst et al, Org. Lett., Vol. 1, No.12, 1973 (1999). Suzuki et al, Tet. Lett., Vol.32, No.46, 6735 (1991).
Kobayashi et al, Chem. Lett., 1211 (1983).
9

TMS Triflate



Available from Aldrich – $176 for 5 grams
Several published methods of preparation
One example uses 2-bromophenol as starting material
92%
Kobayashi et al, Chem. Lett., 1211 (1983).
Guitian et al, Synthesis, 2002, p.1454.
80% 65%
10

Regioselectivity

Controlled by Steric and Electronic Effects
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).
K. Suzuki, Tet. Lett., 1991, Vol.32, p6735.
11

Selected Reactions of Benzyne



Nucleophilic Addition




Pericyclic Reactions
[2+2]
[3+2]
[4+2]
Ene
Palladium Catalyzed Reactions
12

Nucleophilic Addition
Buchwald et al, J.Org.Chem., 2000, p5334.
Barrett et al, JACS, 2006, Vol. 128, p14042
53%
65%
13

Nucleophilic Addition
Hiyama et al, Angew. Chem. Int. Ed., 2002, p.3247.
Greaney et al, Angew. Chem. Int. Ed., 2009, p5199.
66%
65%
14

Acyl Alkylation of Benzyne

Insertion of Benzyne into C-C bond
42%
+
Via
53%
Stoltz et al, JACS, 2005, p5341.
15

Acyl Alkylation of Benzyne

Improved selectivity by removal of a -substituent
90%

Ring Expansion
50%
Stoltz et al, JACS, 2005, p5341.
16

Pericyclic Reactions



Benzyne low lying LUMO; readily undergoes pericyclic
Cyclic dienes locked in flat s-cis conformation give [4+2] (e.g. furan, cyclopentadiene)
Some substrates undergo competing [4+2], [2+2], and ene processes
Waali, J. Org. Chem., 1975, p1355. Huisgen, Tet. Lett., 1963, p1017.
Crews, J. Org. Chem., 1973, p522. Braun, J. Org. Chem., 1970, p1208.
17

[2+2] Additions
Liebeskind et al, J.Org.Chem., 1989, p1435.
Hsung et al, Org. Lett., 2009, p.3666.
44%
18
95%

[3+2] Additions
+
Larock et al, J.Org.Chem., 2010, p7381
Larock et al, Org. Lett., 2008, p2409.
58%
R = CH
2
CO
2
Et,
Aryl, Cinnamyl
19

[4+2] Additions
K. Suzuki et al, JACS, Vol.114, No.9, p.3568 (1992).
+
Olofson et al, J.Org.Chem., 1992, p.7122.
68%
20

Intramolecular [4+2] and Ene Additions
Danheiser et al, Org.Lett., 2005, p3917.
Lautens et al, JACS, 2011, Vol.133, p.14200.
21

[4+2] - Dihydronapthalenes
+
R
H
Yield
84%
Br 80%
CO
2
Et 85%
CH
3
0%
48% er > 19:1
First Enantioselective Aryne Diels Alder Reaction
Lautens et al, JACS, 2005, Vol. 127 p15028.
22

Palladium Catalyzed Cyclizations
Yamamoto et al, Angew. Chem. Int. Ed., 2000, p173.
+ 5eq.
Larock et al, J. Org. Chem., 2008, p6679.
Phenanthrene
69%
Fluoren-9-one
75%
23

Palladium p -Allyl Reactions
Cheng et al, Org Lett, 2005, p2921.
Cheng et al, Org. Lett., 2004, p2821.
Cheng et al, Synthesis, 2005, p1693.
R
1
= aryl, allenyl, alkynyl
Yields 66-93%
Cheng et al, Angew Chem. Int. Ed, 2009, p391.
R
2
= aryl, alkyl
Yields 59-92%
24

Outline






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
Part I - Benzyne
Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis

Part II – Indolyne
Reactivity and Applications
25

Total Synthesis: (-)–Quinocarcin


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
Isolated from Streptomyces melunovinuceus
Antitumor, antibiotic properties
Brian Stoltz’s Group, California Institute of Technology
Shortest total synthesis to date (11 steps)
Formed by formal [4+2] annulation of benzyne
(-) - Quinocarcin
Stoltz et al, JACS, 2008, vol.130, p17270.
Zhu, JACS, 2008, Vol.130, p7148.
26

Enamide Synthesis
93%
Stoltz et al, JACS, 2003 p.15000. Stoltz et al, JACS, 2008, p17270. Karmas et al, JACS, 1952 p1580.
74%, 2 steps
69%
27

[4+2] Annulation
60%
Stoltz et al, JACS, 2008, vol.130, p1558. Stoltz et al, JACS, 2008, vol.130, p17270.
28

Completion of (-)-Quinocarcin
99%
Stoltz et al, JACS, 2008, vol.130, p17270.
80%
(-)-Quinocarcin
81%, 2 steps
29

Outline








Part I - Benzyne
Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis

Part II – Indolyne
Reactivity and Applications
30

Part II: Indolynes
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



A heteroaromatic aryne
First indolyne from Igolen and co-workers in1967; nothing in literature until 2007
Keith Buszek and co-workers prepared and trapped three indolynes with furan
Useful to synthesize compounds containing indole rings -> biologically active compounds
Further studies by Buszek and Garg Labs
4,5-Indolyne 5,6-Indolyne 6,7-Indolyne
Reinecke, Tetrahedron, 1982, p427. Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135
Igolen et al, Comptes Rendus des Seances de l’Academie des Sciences, Serie C: Sciences Chimique, Vol. 265, Iss.2, p.110, 1967.
31

Indole TMS Triflate

To study reactivity of 4,5-Indolyne, TMS Triflate was prepared
Garg et al, JACS, 2010, vol.132, p17933.
Garg et al, Org. Lett., 2009, Vol.11, No.4, p1007.
88%
32

Indolyne Reactivity Patterns
Nucleophile
K. Houk, N. Garg et al, JACS, 2010, Vol.132, p.1267.
C5 : C4
12.5 : 1
3 : 1
3.3 : 1
33

Unsymmetrical Aryne Distortions



Pre-distorted ring gives C5 larger internal angle, orbital has electropositive
“p” character
C4 smaller internal angle, orbital has more electronegative “s” character
Attack occurs at flat, electropositive end, relieves ring distortion
Aniline Addition
C
5
C
3a
C
4
C
3a
C
5
C
4
C
3a
K. Houk, N. Garg et al, JACS, 2010, Vol.132, p1267.
34

Regioselectivity Reversal

4,5-Indolyne with Br atom, reversed selectivity
C
5
C
4 C
5
C
4
Garg et al, JACS, 2011, Vol.133, p.3832.
35

Indolactam V




Activator of protein kinase C
Synthesis by Neil Garg’s Group
Demonstrates reversal of normal indolyne selectivity by introducing Br atom
C-N bond formed by nucleophilic attack
Indolactam V
Garg et al, JACS, 2011, Vol.133, 3822.
36

Indolyne Addition
62% (<5% other regioisomer)
Garg et al, JACS, 2011, Vol.133, 3822.
K.Houk, N.Garg et al, JACS, 2010, vol.132, p17933.
37

Completion of Indolactam V
Garg et al, JACS, 2011, Vol.133, 3822.
Nakatsuka et al, Agric. Biol. Chem., 1989, vol.53, p2257.
Indolactam V
Yield Not Given
3:1 Mixture of
Diastereomers
38

(-)-N-methylwelwitindolinone C Isothiocyanate





Isolated from blue-green algae Hapalosiphon welwitschii and
Westiella intricata in 1994
Reverses P-glycoprotein mediated multiple drug resistance to variety of anticancer drugs in human cancer cell lines
Promising for treating drug-resistant tumors
First total synthesis of this compound by Neil Garg’s Group
Intramolecular cyclization via nucleophilic attack on indolyne
(-)-N-methylwelwitindolinone C Isothiocyanate
Garg et al, JACS, 2011, Vol.133 (40), p15797.
Moore et al, JACS, 1994, Vol.116, p9935.
39

Retrosynthesis
Garg et al, JACS, 2011, Vol.133 (40), p15797.
Indolyne Cyclization
40

Indole Substitution
S-Carvone
Garg et al, JACS, 2011, Vol.133 (40), p15797.
Natsume et al, Chem. Pharm. Bull., 1994, Vol.42, p1393. Wang et al, Synlett., 2003, p.2377.
41

Indolyne Cyclization
46%
+
2.5 : 1
Garg et al, JACS, 2011, Vol.133 (40), p15797.
42

Nitrene Insertion
Garg et al, JACS, 2011, Vol.133 (40), p15797.
43

Completion of Target
(-)-N-methylwelwitindolinone C Isothiocyanate
Garg et al, JACS, 2011, Vol.133 (40), p15797.
44

Summary






Benzyne readily undergoes nucleophilic, pericyclic, palladium catalyzed reactions
Mild conditions allows greater variety of substrates to be used, new reactions
Benzyne has been used to complete total synthesis of (-)-
Quinocarcin
Regioselectivity of Indolyne explained through models
Reversal of Indolyne regioselectivity demonstrated through synthesis of Indolactam V
Indolyne has been used to complete first total synthesis of Nmethylwelwitindolinone C isothiocyanate
45

Acknowledgements

Dr. Tony Durst

Durst Lab Members

Chemaphor Members
46

EXTRA SLIDES

Prep of starting material in N-Methylwelwetindolinone C
Isothiocyanate Synthesis
47

Indolynes

Prepared three indolynes
Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135
48

TMS Triflate
Guitian et al, JACS, 1999, p5827.
49

Bromoindole TMS Triflate Synthesis
Garg et al, JACS, 2011, Vol.133, 3822.
Garg et al, JACS, 2010, vol.132, p17933.
50

Pd Cat. Cycle
Cheng Suzuki
Cheng Stille Alkyne
51

Pd Catalytic Cycle
Cheng, Stille Allene coupling Cheng Copper Pd coupling
52

Pd Cat. Cycle
Larock cat. cycle
53

Pd Cat Cycle
Yamamoto cat. cycle
54

Reagents
Comins Reagent dba
Dibenzylidene acetone
Bathophenanthroline dppf
1,1’-bisdiphenylphosphinoferrocene dppp
1,3-bis(diphenylphosphino)propane dppb
Bis(diphenylphosphino)butane
55

Reagents
IBX
2-iodoxybenzoic acid
Dess Martin
HMDS
56