Organofluorine Chemistry
Organofluorine Chemistry
Synthesis and Applications
V. Prakash Reddy
Department of Chemistry, Missouri University of Science
and Technology, Rolla, MO, United States
Elsevier
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To My Parents and Teachers
Contents
Preface
1.
2.
xi
Nucleophilic reactions in the synthesis of
organofluorine compounds
1
1.1 Introduction
2
1.2 Reagents for nucleophilic fluorinations
2
1.3 Nucleophilic deoxyfluorination
3
1.4 Nucleophilic fluorination of pyridines and diazines
8
1.5 Nucleophilic gem-difluorination of carbonyl compounds
10
1.6 Nucleophilic fluoroalkylations
12
1.7 Nucleophilic trifluoromethylthiolation
31
1.8 Trifluoromethoxylations
31
References
35
Electrophilic reactions in the synthesis of
organofluorine compounds
43
2.1 Introduction
43
2.2 Reagents for electrophilic fluorination
44
2.3 Enantioselective electrophilic fluorination
48
2.4 Electrophilic fluorination in the synthesis of α-fluorinated
amino acids
53
2.5 Electrophilic fluoroalkylation
54
2.6 Electrophilic trifluoromethylthiolation and
trifluoromethoxylation
61
2.7 Synthetic methods for trifluoromethylthiolation
63
2.8 Difluoromethylthiolation
68
References
70
vii
viii
Contents
3.
4.
5.
Free-radical reactions in the synthesis of
organofluorine compounds
75
3.1 Introduction
75
3.2 Reagents for the free-radical trifluoromethylation
77
3.3 Decarboxylative fluoroalkylation
78
3.4 β-Amino-fluoroalkylation of alkenes
80
3.5 Fluoroalkylation using sodium triflinate (Langlois reagent)
82
3.6 Photoredox-catalyzed S-fluoroalkylation and arylation
94
3.7 Radical fluoroalkylation of enolates
96
References
98
Organotransition metal catalysis in the
synthesis of organofluorine compounds
103
4.1 Introduction
104
4.2 Pd-catalyzed fluorination of aryl halides and triflates
105
4.3 Transition metal catalyzed C H fluorination
106
4.4 Au(I)-catalyzed hydrofluorination of alkenes and alkynes
114
4.5 Ni-catalyzed fluoroalkylation of aromatics
116
4.6 Ag(II)-catalyzed oxidative ring-opening fluorination of cyclic
amines
121
4.7 Ag(I)-catalyzed decarboxylative fluorination
123
4.8 Cu(I)-mediated dediazoniative difluoromethylation
124
4.9 Fluoroalkylation of arylboronic acids and esters
125
4.10 Cu(I)-catalyzed fluoroalkylation of aryl halides
126
4.11 Ni-catalyzed trifluoromethylthiolation
127
4.12 Pd(II)-catalyzed (amino)trifluoromethoxylation
129
References
131
Pharmaceutical applications of
organofluorine compounds
133
5.1 Introduction
134
5.2 Antibacterial pharmaceuticals
141
Contents
6.
ix
5.3 Antidiabetic pharmaceuticals
146
5.4 Anti-Alzheimer pharmaceuticals
152
5.5 Anti-HIV pharmaceuticals
163
5.6 Antimalarial pharmaceuticals
165
5.7 Anticancer pharmaceuticals
167
5.8 Antiviral pharmaceuticals
185
5.9 Fluorinated pharmaceuticals for cardiovascular diseases
195
5.10 Antiinflammatory pharmaceuticals
199
5.11 Antidepressants
202
References
204
Synthesis and applications of 18F-labeled compounds
215
6.1 Introduction
216
6.2 Synthetic methods for radiofluorination
220
6.3 Sharpless click reactions for positron emission tomography
tracers
225
6.4 Staudinger ligation reactions for positron emission tomography
tracers
232
6.5 Radiofluorination via aromatic nucleophilic substitution
235
6.6 Transition metal mediated radiofluorination
243
6.7 Radiofluorination via diaryliodonium salts
250
18
6.8 Enzymatic fluorination reactions for [ F]-labeled positron
emission tomography tracers
256
6.9 Positron emission tomography tracers in Alzheimer’s
disease
258
6.10
7.
18
F-positron emission tomography tracers in cancer
diagnosis
264
References
271
Materials applications of organofluorine compounds
279
7.1 Introduction
280
7.2 Fluorinated surfactants
280
x
Contents
Index
7.3 Fluoropolymers
286
7.4 Fluorinated π-conjugated polymeric materials in photovoltaic
devices
289
7.5 Fluorinated poly(aryl thioethers) in organic electronic
materials
298
7.6 Polymer electrolytes
300
7.7 Fluorinated ionomers as proton-exchange membranes
in fuel cells
304
7.8 Fluorinated carbon nanoparticles and nonaqueous
electrolytes in lithium- and lithium-ion batteries
307
7.9 Fluorinated hyperbranched dendrimers: synthesis and
applications
308
7.10 Fluorinated compounds in drug delivery and magnetic
resonance imaging
310
7.11 Organofluorine liquid crystal materials
313
7.12 Organofluorine compounds in high-energy materials
313
References
321
329
Preface
This book is focused on modern synthetic methods for the incorporation of fluorine and
fluoroalkyl moieties into organic compounds, and on the pharmaceutical and materials
applications of organofluorine compounds. It is hoped that this book would serve as a text
book for the specialized graduate-level courses in organofluorine chemistry as well as a reference book for industrial and academic scientists involved in the drug design, materials
chemistry, and organofluorine chemistry. Rapid advances in the efficient synthetic methods
of organofluorine compounds contribute to their ever-increasing application in diverse areas,
including the design of materials, pharmaceuticals, agrochemicals, and a wide range of consumer goods. Notably, fluoropolymers, which include poly(tetrafluoroethylene), poly(vinylidene fluoride), poly(vinyl fluoride), and Nafion, a perfluorinated ion-exchange membrane,
are integral parts of chemical industry.
Chapters 1 4 are focused on the synthetic methods for the fluorinations, fluoroalkylations, fluoroalkoxylations, and fluoroalkylthiolations. The synthetic methods are broadly classified to include nucleophilic, electrophilic, free-radical, and organotransition
metal catalyzed/mediated reactions. Emphasis is placed on those reactions that are of
broad significance in the synthesis of fluorinated pharmaceuticals, positron emission tomography (PET) imaging agents, and materials.
Chapter 1, Nucleophilic reactions in the synthesis of organofluorine compounds, outlines
a variety of commercially available nucleophilic fluorination reagents, including DAST,
DeoxoFluor, XtalFluor, PhenoFluor, and FluoLead. Nucleophilic trifluoromethylations,
difluoromethylations, trifluoromethoxylations, and trifluoromethylthiolations have been
widely used in the design of pharmaceuticals and materials. Deoxyfluorination of alcohols,
phenols, and carboxylic acids can be achieved with a variety of commercially available
reagents, including PhenoFluor, PyFluor, XtalFluor, DAST, and related reagents.
Nucleophilic fluorinating reagents of broader scope are being continually developed as taskspecific reagents in the synthesis of pharmaceutically interesting compounds. There is
emerging interest in the enantioselective nucleophilic fluorinations and trifluoromethylations. Enantioselective trifluoromethylation, in some cases, can be achieved with up to 93%
enantioselectivity using cinchonidine-based chital catalysts.
Chapter 2, Electrophilic reactions in the synthesis of organofluorine compounds, outlines
various electrophilic reagents, such as Selectfluor and NFSI, and electrophilic fluoroalkylations,
fluoroalkylthiolations, and fluoroalkoxylations, focusing on electrophilic trifluoromethylation,
trifluoromethylthiolations, and difluoromethylthiolation reactions. Electrophilic trifluoromethylation of a wide variety of alkynes, aromatics, amines, and alcohols has found applications in
the synthesis of pharmaceuticals. Electrophilic difluoromethylation of alcohols provides access
to the corresponding difluoromethoxy compounds, and these reactions can be used in the
xi
xii
Preface
late-stage modification of pharmaceuticals. Recent progress in the enantioselective electrophilic
fluorination of aldehydes, amides, allylsilanes, and enolsilyl ethers is also outlined, focusing on
the reactions that are of broad scope in the design of pharmaceuticals.
Chapter 3, Free-radical reactions in the synthesis of organofluorine compounds, covers
free-radical reactions in the fluorinations and fluoroalkylations. Commercially available
Togni’s or Umemoto’s reagents, originally developed for the electrophilic trifluoromethylations, can be used in the free-radical trifluoromethylation, under photoredox or organometallic catalysis. Free-radical reactions, such as decarboxy-trifluoromethylation and
difluoromethylations, mediated by organometallic catalysts, are useful in the late-stage modification of pharmaceuticals. There is emerging interest in the free-radical trifluoromethylations using the cost-effective Langlois reagent, using organometallic catalysts and under
photoredox conditions. Organotransition metal catalyzed fluorination and fluoroalkylations
are an emerging area that has broad applicability in the synthesis of pharmaceuticals, agrochemicals, materials, and PET tracers.
Chapter 4, Organotransition metal catalysis in the synthesis of organofluorine compounds, outlines a variety of transition metal catalyzed reactions, such as Pd(0)-catalyzed
fluorination and trifluoromethoxylation of aromatics, Mn(III)-catalyzed mono-fluorinations,
Ni(I)-catalyzed fluoroalkylation and trifluoromethylthiolation of aromatics, and Ag(I)-catalyzed decarboxylative fluorination of carboxylic acids. The transition metal catalyzed reactions provide an attractive route for the late-stage modification of pharmaceuticals and in
the synthesis of the 18F-labeled PET tracers.
Chapter 5, Pharmaceutical applications of organofluorine compounds, and Chapter 6,
Synthesis and applications of 18F-labeled compounds, focus on the medical and pharmaceutical applications. Incorporation of fluorine or fluoroalkyl groups as bioisosteres in the lead
compounds has emerged as the major focus of drug design efforts. Fluorine-containing pharmaceutical candidates, in general, exhibit enhanced potency, bioavailability, and metabolic
stability, as compared to their nonfluorinated analogs. Numerous blockbuster drugs, including the cholesterol-lowering drug atorvastatin (Lipitor) and drugs for the treatment of hepatitis C, such as sofosbuvir (Sovaldi), are fluorine-containing compounds. Furthermore, PET
using 18F-labeled compounds afford access to noninvasive monitoring of the disease progression and to follow the effectiveness of the drug candidates.
Chapter 5, Pharmaceutical applications of organofluorine compounds, outlines the drug
design using organofluorine chemistry, focusing on the recently FDA-approved drugs, and
widely prescribed pharmaceuticals, for treating various diseases, including diabetes, cardiovascular diseases, Alzheimer’s disease (AD), various cancers, and bacterial (malaria) and
viral infections (HIV). Fluorine-containing compounds play a key role in the design of pharmaceuticals. Structural modification of pharmaceutically interesting compounds through
introduction of fluorine, fluoroalkyl, fluoroalkoxy, or fluoroalkylthio moieties enhances their
metabolic stability, bioavailability, and potency. In 2018 alone nearly one-third of the FDAapproved drugs are organofluorine compounds. Fluorine-containing pharmaceuticals are
used in the treatment of a wide variety of diseases, including diabetes (sitagliptin), malaria
(e.g., mefloquine), HIV infections (e.g., bictegravir), antiviral agents (e.g., sofosbuvir, a
Preface
xiii
nucleotide analog inhibitor of the HCV NS5B RNA-polymerase3 inhibitor, for the treatment
of hepatitis C), antibacterial agents (e.g., fluoroquinolones and tetracyclines), cancer (e.g.,
afatinib, dacomitinib, and lorlatinib), cardiovascular diseases (e.g., ezetimibe and atorvastatin), and as inti-inflammatory agents (e.g., celecoxib, a selective COX-2 inhibitor, to treat
rheumatoid arthritis). Fluorine-containing compounds have emerging interest as pharmaceutical candidates to treat AD. Although several clinical trials using organofluorine drug
candidates (and other drug candidates), as BACE-1 inhibitors, γ-secretase inhibitors, and
γ-secretase modulators have not been successful to date, a fluorinated selective BACE-1
inhibitor, CNP540, is currently undergoing clinical trials for its efficacy in preventing AD in
individuals susceptible to the development of AD.
Chapter 6, Synthesis and applications of 18F-labeled compounds, outlines the recent
progress in the synthesis and applications of the 18F-PET tracers in the diagnosis of various
diseases, including the AD and cancers. Synthetic methods using the late-stage radiofluorinations have significantly contributed to the advancement of this area. 18F-labeled PET tracers,
in combination with magnetic resonance imaging (MRI), PET/MRI, are emerging as alternative to the widely used PET/computed tomography (PET/CT), a technique that requires
patients to be exposed to hazardous X-ray radiation, in the diagnosis and monitoring of the
disease progression in various cancers, Alzheimer’s disease, and cardiovascular diseases.
Furthermore, in some cases, the PET/MRI provides superior imaging of the sites of lesions
over that of the PET/CT scans. PET/MRI can be used in probing the blood brain barrier of
pharmaceuticals, a key feature for a drug to be active in the neurological disorders. 18F-PET/
MRI imaging of the lung cancers, including adenocarcinoma, squamous cell carcinoma, and
small-cell lung carcinoma, is indispensable in monitoring the effectiveness of the various
chemotherapeutic agents. Until recently, 2-[18F]-fluoro-2-deoxy-D-glucose is the only FDAapproved 18F-PET imaging agent, for the clinical diagnosis of AD, cancers, and other glucose
metabolism linked lesions. Emerging, efficient synthetic methods for the late-stage radiofluorination are now being adapted for the synthesis of various disease-specific 18F-PET
agents. For example, FDA-approved 18F-PET imaging agents, florbetapir (Amyvid), florbetaben (Neuraceq), and flutemetamol (Vizamyl), show high specificity for binding to the Aβ plaques and are now widely used in the clinical diagnosis of the AD patients. On the other
hand, flortaucipir (AV-1451) shows substantial selectivity in its binding to the neurofibrillary
tangles and is useful to distinguish AD from other neurodegenerative diseases, such as
behavioral variant frontotemporal dementia, Parkinson’s disease with or without cognitive
impairment, and vascular dementia. The latter PET imaging agent is also useful in the diagnosis of the chronic traumatic encephalopathy, also called traumatic brain injury, as demonstrated in the PET scans of the football players with concussion symptoms. Fluciclovine is an
18
F-PET tracer that is used the diagnosis of prostate cancer.
Chapter 7, Materials applications of organofluorine compounds, outlines synthesis and
applications of a wide range of organofluorine-based materials. Numerous materials, biomaterials, smart materials, liquid crystal displays, solar cells, fuel cells, and numerous consumer
goods are fluorine-containing compounds. For example, fluorinated ionomers, such as
Nafion-H and fluorinated versions of poly(ether sulfone) and poly(imide) materials, are
xiv
Preface
extensively used as proton-exchange membranes in fuel cells. Fluorinated π-conjugated
polymeric materials have found applications in the design of photovoltaic devices. For example, the all-organic solar cells, consisting of fluorinated materials, afford power conversion
efficiencies, as high as 13.1%. Furthermore, fluoropolymers have been used as photoresist
materials in the 157 nm lithography, as they are transparent at this wave length.
Perfluorinated nanomaterials also have medicinal applications. For example, the oxygenenriched fluorinated hydrocarbon and polymeric nanomaterials are being developed for use
in the photodynamic therapy of cancer. Fluorinated dendrimer amphiphiles are finding
applications as probes for 19F MRI probes and in drug delivery.
I am grateful for the continued encouragement and support of the editors and editorial
staff, in particular, Dr. Kostas Marinakis and Ms. Michelle Fisher, during the preparation of
the manuscript. I appreciate Ms. Swapna Praveen, Sr. Copyrights Coordinator, for her advice
and help in getting copyright permissions, and Ms. Maria Bernadette Vidhya Bernard J,
Project Manager, for patiently reviewing the manuscript and for incorporating many corrections. I thank Professor G. K. Surya Prakash (University of Southern California) for careful
reading of many chapters and for his valuable suggestions and corrections. I also thank
Professor Jinbo Hu (Shanghai Institute of Organic Chemistry) for his helpful comments on
one of the chapters. I thank all my friends, faculty colleagues, and my graduate students for
their encouragement. Some of the cutting-edge advances in the synthesis of organofluorine
compounds may have been inadvertently omitted due to the sheer number of the everincreasing publications in this area in the recent years, although every effort is made to
include the synthetic methods that are of broad applicability for the design of pharmaceuticals and materials. I hope the readers will find this book useful and appreciate their suggestions and corrections for future editions.
1
Nucleophilic reactions in the
synthesis of organofluorine
compounds
Chapter Outline
1.1 Introduction ..................................................................................................................................... 2
1.2 Reagents for nucleophilic fluorinations ........................................................................................ 2
1.3 Nucleophilic deoxyfluorination...................................................................................................... 3
1.4 Nucleophilic fluorination of pyridines and diazines .................................................................... 8
1.5 Nucleophilic gem-difluorination of carbonyl compounds......................................................... 10
1.6 Nucleophilic fluoroalkylations ..................................................................................................... 12
1.6.1 Nucleophilic difluoromethylation of aldehydes ............................................................... 12
1.6.2 RuppertPrakash reagent (CF3SiMe3) for trifluoromethylation..................................... 13
1.6.2.1 Enantioselective trifluoromethylation......................................................................... 14
1.6.2.2 Synthesis of trifluoromethyl ketones.......................................................................... 16
1.6.2.3 Trifluoromethylation of imines................................................................................... 18
1.6.3 Fluoroacetone hydrates for the nucleophilic fluoroalkylations ...................................... 18
1.6.4 Trifuoromethylations using fluoroform (CHF3)................................................................. 19
1.6.5 Borazine-mediated trifluoromethylation and difluoroalkylation................................... 23
1.6.6 N-Trifluoromethylation of amines ..................................................................................... 26
1.6.7 Tetrakis(dimethylamino)ethylene-mediated fluoroalkylations....................................... 28
1.6.7.1 Trifluoromethylation of acyl chlorides........................................................................ 29
1.6.7.2 Synthesis of gem-(difluoromethyl)thioethers ............................................................. 30
1.7 Nucleophilic trifluoromethylthiolation ....................................................................................... 31
1.8 Trifluoromethoxylations............................................................................................................... 31
1.8.1 Trifluoromethyl benzenesulfonatemediated vicinal
(bromo)trifluoromethoxylation.......................................................................................... 33
1.8.2 Trifluoromethyl benzoatemediated trifluoromethoxylation ....................................... 34
References............................................................................................................................................. 35
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00001-8
© 2020 Elsevier Inc. All rights reserved.
1
2
Organofluorine Chemistry
1.1 Introduction
Nearly one-third of the pharmaceuticals are fluorinated compounds. Often a single fluorine
at the strategic site modulates the pharmacokinetic properties of the pharmaceuticals.
18
F-labeled compounds are used as the state-of-the-art positron emission tomography (PET)
tracers in the diagnosis of cancers, cardiovascular diseases, and neurodegenerative diseases.
Furthermore, fluorinated compounds are increasingly used in the design of novel materials
for a broad range of applications, including photovoltaic solar cells and energy storage
devices. Polyfluorinated compounds (fluorous compounds) are used in the 19F nuclear magnetic resonance (19F-NMR) imaging (also called as 19F-magnetic resonance imaging,
19
F-MRI), and as recyclable fluorous catalysts, fluorous solvents, and fluorous stationary
phases, in organic synthesis. Early synthetic methods for nucleophilic fluorinations relied on
hydrogen fluoride (HF) and its amine complexes [e.g., Olah’s reagent, pyridinium poly
(HF; PPHF), and sulfur tetrafluoride (SF4)]. There are currently many safer and more effective fluorinating reagents that have wide functional group tolerance and that would afford
high regio- and stereoselectivity. These selective fluorinating agents are invaluable in the
synthesis of complex fluorine-containing organic compounds. Nucleophilic fluoroalkylations,
especially gem-difluoromethylation and trifluoromethylation, are widely used in the design
of functional materials and pharmaceuticals because of the unique and favorable physicochemical and pharmacokinetic properties of these fluoroalkyl compounds.
gem-Difluoromethylene (CF2) moiety is isopolar and, to some extent, isosteric with
respect to oxygen, and thus the gem-difluoromethyl (CHF2) and difluoromethylene
(CF2) moieties serve as bioisosteres of alcohols and ethers, respectively, in the drug
design applications. It is also a lipophilic bioisostere of SH and CH3 when attached to the
aryl or alkyl moieties. The CF2H is a hydrogen-bond donor as well as acceptor, and the
lipophilicity of the compounds is dramatically enhanced when this moiety is introduced
adjacent to the ether, sulfoxide, and sulfone moieties.1,2 The trifluoromethyl moiety is
bioisosteric with respect to the tert-butyl and isopropyl groups and is used, for example, in
the design of γ-secretase inhibitors.3 Many of the nucleophilic reagents for fluorination and
fluoroalkylation are now commercially available. This chapter aims to give a comprehensive
coverage of the nucleophilic fluorinations and fluoroalkylations that have broad scope in the
design of pharmaceuticals, agrochemicals, and materials.
1.2 Reagents for nucleophilic fluorinations
A variety of reagents for nucleophilic fluorination are now commercially available.
Deoxyfluorination of alcohols and gem-difluoromethylation of carbonyl compounds can be
achieved by reagents, such as DAST ((diethylamino)sulfur trifluoride),4 Morpho-DAST
(morpholinosulfur trifluoride),4 Deoxo-Fluor [bis(2-methoxyethyl)aminosulfur trifluoride],57
XtalFluor-E [(diethylamino)difluorosulfinium tetrafluorobrate],8 XtalFluor-M (morpholinodifluorosulfinium tetrafluoroborate),8 FluoLead ((4-tert-butyl-2,6-dimethylphenyl)sulfur
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
Cyanuric fluoride
3
Ishikawa's reagent
FIGURE 1–1 Selected commercially available reagents for the transformation of the carbonyl compounds to the
gem-difluoromethyl and -methylene compounds.
trifluoride).9 PhenoFluor [1,3-bis(2,6-diisoproylphenyl)-2,2-difluoro-4-imidazoline]10 and
PyFluor (2-pyridinesulfonyl fluoride)11 reagents are useful for selective deoxyfluorination of
alcohols in the presence of carbonyl functional groups. Other reagents that are useful in the
deoxyfluorinations include Petrov’s reagent (1,1,2,2-tetrafluoroethyl-N,N-dimethylamine),
cyanuric fluoride, Ishikawa’s reagent (N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine), and
3,3-difluoro-1,2-diarylcyclopropenes (Fig. 11).12,13
DAST and Deoxo-Fluor reagents are widely used for the deoxyfluorination of alcohols in
the synthesis of numerous biologically and pharmaceutically interesting fluorine-containing
compounds.14 Deoxyfluorination reactions using DAST are usually carried out at a low
temperature to avoid the decomposition of the reagent. Similarly, carbonyl groups are
effectively gem-difluorinated at a relatively low temperature.15 (Trifluoromethyl)trimethylsilane
(CF3SiMe3; RuppertPrakash reagent) is widely used for the nucleophilic trifluoromethylation
of carbonyl compounds, including aldehydes, ketones, imines, and esters (vide infra).16,17
1.3 Nucleophilic deoxyfluorination
Nucleophilic deoxyfluorination of alcohols can be achieved using various commercially available reagents such as DAST, Deoxo-Fluor, Morpho-DAST, XtalFluor-E, XtalFluor-M, PyFluor,
and PhenoFluor. Deoxo-Fluor is relatively more thermally stable as compared to DAST and
is the preferred reagent over DAST when high temperatures are required for the reactions.
4
Organofluorine Chemistry
F
iPr
OH PhenoFluor/toluene
iPr
N
CsF (3 equiv)
N
F F
iPr iPr
110 ºC
89%
PhenoFluor
Selected examples:
F
N
O
Me
N
N
F
N
N
F
N
F
58%
34%
78%
93%
FIGURE 1–2 PhenoFluor-mediated deoxyfluorination of phenols.
Selective fluorinating reagents, especially those that can be used in the stereoselective deoxyfluorination of alcohols, are of great importance for the synthesis of pharmaceutical compounds. Among several such reagents recently developed, PhenoFluor and PyFluor are of
broad scope in the deoxyfluorination of alcohols, although DAST is still widely used for deoxyfluorination reactions.18 XtalFluor reagents (XtalFluor-E and XtalFluor-M) show improved
selectivity in deoxyfluorination reactions, compared to DAST, as the elimination byproducts
are minimized. Similar to that of DAST and Deoxo-Fluor-mediated deoxyfluorination reactions, the XtalFluor reagentmediated deoxyfluorination of alcohols proceed through a SN2
mechanism, with predominant inversion of configuration.14
PhenoFluor was originally discovered by Ritter and coworkers for the deoxyfluorination
of phenols.19,20 Phenols as well as heteroaryl phenolic compounds were deoxyfluorinated to
their corresponding fluorinated compounds using this reagent. To overcome the moisture
instability of this reagent, toluene solutions of this reagent can be used for the deoxyfluorinations (Fig. 12).
PhenoFluor can also be used for the deoxyfluorination of primary and secondary alcohols, using slightly different conditions as for the phenols.21 Addition of Hunig’s base, in
these reactions, shortens the reaction time, and potassium fluoride (KF) minimizes the elimination products from the aliphatic alcohols. Deoxyfluorinations of secondary alcohols using
PhenoFluor proceed in high yields with inversion of configuration.21 Although these deoxyfluorinations proceed at 0 C to room temperature, elimination products are formed as
minor byproducts. However, at 80 C in toluene, the elimination reaction is suppressed, and
the reaction proceeds in high yields to give the corresponding deoxyfluorination products.
A variety of pharmaceutically interesting compounds, such as morphine, galantamine, testosterone, and epi-androsterone, could be stereoselectively transformed into their corresponding fluorinated products with the inversion of configuration in high yields and with high
stereoselectivity (Fig. 13). PhenoFluor provides access to the late-stage fluorination of pharmaceuticals and is suitable for the preparation of 18F-labeled compounds for the PET.
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
FIGURE 1–3 PhenoFluor-mediated deoxyfluorination of alcohols.
5
6
Organofluorine Chemistry
Doyle and coworkers have developed 2-pyridinesulfonyl fluoride (PyFluor) as a low-cost
nucleophilic fluorinating reagent for the fluorination of primary and secondary alcohols.
PyFluor is conveniently prepared on a multigram scale via the oxidation of 2-mercaptopyridine with sodium hypochlorite (NaOCl), followed by the halide anion exchange of the resulting 2-pyridylsulfonyl chloride, using potassium bifluoride (KHF2). Deoxyfluorination of
alcohols using PyFluor reagent, in the presence of a sterically crowded base, such as 1,8diazabicyclo-[5.4.0]undec-7-ene (DBU), gives the alkyl fluorides in high yields and with high
diastereoselectivity.11 Elimination reactions are minimized using the sterically crowded
amines, such as DBU or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD). Various biologically interesting fluorinated compounds, including 2-deoxy-2-fluoro-D-glucose and its
18
F-labeled analog, could be synthesized in a one-pot procedure. The 18F-labeled PyFluor
reagent, [18F]PyFluor, used in the radiofluorinations was synthesized through the reaction of
the 18F-labeled KF with the 2-pyridylsulfonyl chloride, in situ (Fig. 14A).11 The reaction
proceeds through the intermediate formation of the 2-pyridylsulfonate ester (1), through SN2
reaction pathway, with the in situ generated DBUHF providing the nucleophilic fluoride
anion. Elimination reactions are minimized using the DBU or MTBD reagents, as compared
to the other amine-based reagents.
Among other related nucleophilic reagents for the deoxyfluorination, N-tosyl-p-chlorobenzene-sulfonimidoyl fluoride (SulfoxFluor) has dramatically high reactivity (1030 min at
RT) and similar mechanism as that of the PyFluor, and is also readily synthesized in large
scale from the N-Tosyl-p-chlorobenzenesulfonimidoyl chloride (Fig. 14B).22
Sanford and coworkers have developed an operationally simple method for the deoxyfluorination of phenols using the relatively inexpensive reagent combination of sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (Me4NF). This reagent achieves the
deoxyfluorinations under mild conditions, often at room temperature, and in high yields
(Fig. 15).23 These deoxyfluorination reactions proceed through the formation of the aryl
fluorosulfonate intermediates. This synthetic method was demonstrated to be applicable for
the synthesis of pharmaceutically interesting compounds, such as MPPF [20 -methoxyphenyl(N-20 -pyridinyl)-p-fluorobenzamide-ethylpiperazine], a serotonin 1A receptor ligand.
DAST and related reagents, such as Deoxo-Fluor and XtalFluor reagents, can be used for
the conversion of carboxylic acids to the corresponding acid fluorides.2426 DAST and
Deoxo-Fluor are thermally not as stable as XtalFluor and can decompose violently under
some circumstances. These reagents, however, are used widely for the deoxyfluorination of
alcohols, carboxylic acids, and gem-difluorination of carbonyl compounds. On the other
hand, the aminodifluorosulfinium tetrafluoroborate salts—XtalFluor-E and XtalFluor-M—
are crystalline salts that show enhanced thermal stability over DAST and Deoxo-Fluor and
do not react violently with water, unlike DAST. XtalFluor-E is conveniently synthesized
through the reaction of the DAST with BF3Et2O. XtalFluor, in the presence of Et3N3HF,
transforms carboxylic acids into the corresponding acid fluorides in high yields (Fig. 16).26
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
(A)
(B)
FIGURE 1–4 Deoxyfluorination reactions mediated by PyFluor(A), and SulfoxFluor (B).
FIGURE 1–5 Deoxyfluorination of phenols using SO2F2 and Me4NF.
7
8
Organofluorine Chemistry
FIGURE 1–6 Deoxyfluorination of carboxylic acids using XtalFluor reagents.
Prakash and coworkers have achieved the deoxyfluorination of carboxylic acids to the
corresponding acyl fluorides, using a reagent combination of triphenylphosphine (Ph3P), Nbromosuccinimide (NBS), and Et3N3HF, under mild reaction conditions, in high yields.
Through this efficient and cost-effective synthetic procedure, pharmaceuticals with a carboxylic acid functional group, such as ibuprofen, naproxen, and ketoprofen, were transformed
to the corresponding acid fluorides in high yields. The acid fluorides could be transformed,
in situ, to their corresponding amide derivatives in a one-pot procedure.27 The acyl fluorides
have numerous synthetic applications, including their conversions to trifluoromethylarenes,
ketones, aldehydes, amides, esters, and hydrocarbons (Fig. 17).2733
The above deoxyfluorination reactions may proceed through the transiently formed acyloxyphosphonium salt (2), the identity of which was confirmed by NMR spectroscopy. The
latter acyloxyphosphonium salt, 2, is presumably protonated by Et3N3HF to give the dicationic intermediate 3, which upon nucleophilic substitution by the fluoride anion would give
the acyl fluoride (Fig. 17).27
1.4 Nucleophilic fluorination of pyridines and diazines
Fluorinated heterocycles are ubiquitous in agrochemicals, pharmaceuticals, and materials.
Hartwig has developed a broadly applicable synthetic method for the ortho-fluorination of
pyridines and diazines using Ag(II)F2.34 These fluorination reactions have a broad scope and
a range of pyridines and diazines, including quinolines, pyrazines, pyrimidines, and pyridazines, have been regioselectively fluorinated in moderate to high yields. Pharmaceutically
interesting compounds, such as 4, 5, and 6, could be synthesized in moderate to high yields
through this aryl-fluorination (Fig. 18). This reaction tolerates both electron-donating and
electron-withdrawing substituents, such as ketone, ester, amide, amine, and nitrile moieties,
in pyridines and diazines.34
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
9
for example
D
R′
R′
R′
R′
for example
K
N
I
FIGURE 1–7 Deoxyfluorination of carboxylic acids to the acid fluorides.
A proposed mechanism involves complexation of AgF2 to pyridine nitrogen, followed by
intramolecular transfer of fluoride to the ortho-position and then AgF2-mediated rearomatization. The reaction mechanism resembles that of Chichibabin reaction, a reaction involving
ortho-amination of pyridines by NaNH2 (Fig. 18).34
10
Organofluorine Chemistry
FIGURE 1–8 ortho-Fluorination of pyridines and diazines using AgF2.
1.5 Nucleophilic gem-difluorination of carbonyl compounds
gem-Difluorination of carbonyl compounds can be achieved using nucleophilic fluorinating
reagents, such as DAST, Deoxo-Fluor, and XtalFluor. XtalFluor-E and XtalFluor-M reagents,
synthesized from the corresponding dialkylaminosulfur trifluorides, are crystalline compounds and are relatively more stable and moisture-sensitive than the conventional fluorinating agents, DAST and Deoxo-Fluor. When used in the presence of Et3N.3HF, these
reagents transform aldehydes and ketones into the corresponding gem-difluoro compounds.8
Ester moieties and the N-benzyloxycarbonyl (Cbz) protecting groups are unaffected under
the reaction conditions (Fig. 19). XtalFluor reagents can also be used for the transformation
of alcohols to the alkyl fluorides, and carboxylic acids to the acid fluorides, under similar
reaction conditions (vide supra).8
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
N SF3
11
F
HBF4 .OEt2
N
BF 4
S
F
-HF
XtalFluor-E
DAST
96%
F
O
XtalFluor-E
F
Et 3 N.3HF, Et3 N, DCM
RT, 24 h
91%
O
F
XtalFluor-E
N
Cbz
O
F
O
Cbz =
N
Cbz
Et3 N.3HF, Et3 N, DCM
RT, 24 h
91%
F
O
F
1. 6 N HCl/60 °C/5 h
DAST, neat
F
OH
OEt
OEt
N
Cbz
0 °C to RT
N
Cbz
F
O
7
O
2. NaHCO3 /THF
RT, 24 h
N
H
O
8
9
64%
81%
SF3
FluoLead
O
PPHF (1.7 equiv)
DCM, RT, 24 h
F F
70%
FluoLead, 100 °C, 3 h
PhCO2 H
PhCF3
FIGURE 1–9 gem-Difluorination of carbonyl compounds and trifluoromethylation of carboxylic acids; Cbz 5
carbobenzyloxy.
Peptides consisting of fluorinated proline moieties, such as the 3,3-gem-difluoroproline 9,
can act as selective enzyme inhibitors, with favorable pharmacokinetics.35 Toward this goal, the
N-carbobenzyloxy-3,3-gem-difluoroproline 9 was synthesized through the DAST-mediated
deoxy-gem-difluorination of the 3-prolinone derivative 7, followed by hydrolysis of the ester
moiety and deprotection of the N-benzyloxycarbonyl (Cbz) protecting group (Fig. 19).
12
Organofluorine Chemistry
25 °C, 4 h
25 °C, 4 h
FIGURE 1–10 gem-Difluorination of carbonyl compounds using sulfuryl fluoride.
FluoLead (Fig. 11) has relatively higher thermal stability and is stable up to 100 C.
FluoLead achieves transformation of carbonyl compounds to the gem-difluoro compounds at
0 C to room temperature, in high yields.9 Reaction of carboxylic acids with FluoLead at high
temperatures (50 C100 C) gives the corresponding trifluoromethyl compounds (Fig. 19).
The transformation of the carbonyl compounds to the gem-difluoro compounds can also
be achieved using the abundantly available sulfuryl fluoride (SO2F2) as the fluorinating agent.
Thus reaction of benzaldehydes and α-ketoesters with sulfonyl fluoride, in the presence of
tetrabutylammonium fluoride (TBAF), at room temperature, gives the corresponding gemdifluoro compounds (Fig. 110).36
The 1,3-dithiolanes, hydrazones, or oxime derivatives of the carbonyl compounds could
be transformed into their corresponding gem-difluoro compounds, using PPHF, in the presence of an electrophilic reagent such as NBS or nitrosonium tetrafluoroborate (NOBF4).37
Thus reaction of the 1,3-dithiolanes with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (or
NBS),38 sulfuryl chloride fluoride (SO2ClF),39 nitrosonium tetrafluoroborate (NOBF4),40 or
Selectfluor,41 in PPHF, gives the corresponding gem-difluoro compounds. The dithioketals
were transformed into the corresponding gem-difluoro compounds by reaction with p-iodotoluene difluoride.42 The gem-difluoro compounds can also be synthesized through the reaction of the hydrazone derivatives of carbonyl compounds with NBS in PPHF,43 or through
the reaction of the oximes with NOBF4 in PPHF (Fig. 111).44
1.6 Nucleophilic fluoroalkylations
1.6.1 Nucleophilic difluoromethylation of aldehydes
The difluoromethylation of carbonyl compounds could be achieved using CHF2TMS and CsF
in a polar solvent such as dimethylformamide (DMF).45,46 Activation of CHF2TMS for difluoromethylation of carbonyl compounds requires somewhat harsher conditions than for the
CF3TMS. Difluoromethyl moiety, similar to the trifluoromethyl group, alters the pharmacokinetic properties of the drug candidates. In an attempt to synthesize a wide range of derivatives of the insecticide tebufenpyrad for screening the antiangiogenic potential, the pyrazole
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
13
FIGURE 1–11 gem-Difluorination of carbonyl compounds.
FIGURE 1–12 Difluoromethylation of pyrazole aldehyde in the synthesis of tebufenpyrad analogs, as potential
antiangiogenic agents.
aldehyde moiety was difluoromethylated using this reagent (Fig. 112). Various difluoromethylated as well as poly-fluoroalkylated derivatives, thus synthesized, exhibited the desired
antiangiogenic effect, although their undesired mitochondrial inhibition activity precluded
their use as medicinal agents.47
1.6.2 RuppertPrakash reagent (CF3SiMe3) for trifluoromethylation
Trifluoromethylation of aldehydes and ketones using the trifluoromethyltrimethylsilane
(CF3TMS; RuppertPrakash reagent) is widely used in the synthesis of the α-trifluoromethyl
alcohols.16,4850 The CSi bond in CF3TMS is labile and therefore in situ generation of the
14
Organofluorine Chemistry
CF3 SiMe3 /Bu4N + F –
O
R
R′
F3 C OSiMe 3
R′
R
THF; 1–24 h, RT
F3 C OH
Aq. HCl
+ Me 3 SiCl
R′
R
R/R′ = H. alkyl, aryl
Mechanistic outline:
F
CF3 SiMe3
CF3
Me Si Me
F Me
R
O
CF3
O
Me Si
R′
O
R
10
Me
Me
R′
R
F3 C O
R
R′
R′
CF3
11
F3 C OSiMe 3
CF3 SiMe3
R′
R
12
Commonly used fluoride sources for the activation of CF3TMS:
Me
N
Bu4NF
CsF
F
S
N
N
F
F
Me
Si
Me
TASF
Ph
Bu4 N+
Si
F
Ph
Ph
TBAT
FIGURE 1–13 Trifluoromethylation of carbonyl compounds using CF3TMS.
trifluoromethyl anion can be achieved using various anionic reagents, including CsF, TBAF
(Bu4NF), tetrabutylammonium difluorotriphenylsilicate, and tris(dimethylamino)sulfonium
difluorotrimethylsilicate (TASF) (Fig. 113). The mechanism of the reaction involves formation of a negatively charged penta-coordinated silicon species (10) upon activation by the
fluoride anion (or other anionic activators such as tetrabutylammonium acetate). The
SiCF3 bond is now elongated and weakened so that the trifluoromethanide anion (CF2
3 ) is
readily transferred to the electrophilic carbonyl carbon to give the intermediate 11. The
intermediate 11, in turn, acts as a source of the CF2
3 anion and is regenerated continually as
the reaction proceeds. Thus catalytic amounts of the anionic activators (e.g., F2) are sufficient to achieve the trifluoromethylations.
1.6.2.1 Enantioselective trifluoromethylation
Moderate enantioselectivities of the trifluoromethylation reactions could be
achieved using cinchonidine-derived sterically crowded catalysts such as 1315.51,52
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
15
Cinchonidine-based chiral catalysts:
CF3
O
F–
Br
N
O
N
Br
CF3
N
CF3
OH
OH
N
N
F3C
OH
N
CF3
CF3
13
14
15
OMe
Me
O
O
Ar
O
CF3TMS (2 equiv)
Chiral catalyst 15
F3 C
Me
OMe
OTMS
O
O
DCM, –50 °C
OMe
OMe
16
17
97% (92% ee)
CJ-17,493
(NK-1 receptor
antagonist)
FIGURE 1–14 Enantioselective trifluoromethylation.
The cinchonidine catalyst, 15, however, gives 92% enantioselectivity in the trifluoromethylation of the ketone moiety in compound 16, to give 17, an intermediate for the
synthesis of the Pfizer’s neurokinin-receptor antagonist, CJ-17,493 (Fig. 114).53
Shibata and coworkers showed that the cinchonidine-derived catalyst 18 gives up to
50% enantioselectivity in the trifluoromethylation of the alkynyl ketone 20, using
CF3TIMS (RuppertPrakash reagent) and tetramethylammonium fluoride (Me4NF) as the
trifluoromethylating agent, to give compound 21. Chiral resolution of 21, followed by
reduction of the nitro moiety, and then reaction with p-nitrophenyl chloroformate gives
the anti-HIV drug Efavirenz in 88% overall enantioselectivity. The enantioselectivity could
be improved to up to 99% by simple recrystallization (Fig. 115).52 Shibata and coworkers
have later shown that a slightly modified cinchonidine-based catalyst 19 exhibited substantially higher enantioselectivity for the trifluoromethylation of compound 20, by up to
93%.54
16
Organofluorine Chemistry
H
CF3
N
Br
N
Br
CF3
CF3
OBu
OH
N
N
CF3
F3C
18
CF3
19
O
NO2
1. Chiral resolution
2. Fe/AcOH
Cl
Me3 SiCF3 (2.0 equiv)
NO2
Me4 NF, DCM
–60 °C
20
OH
F 3C
18 or 19 ; 10 mol%
Cl
21
88%; 50% ee for catalyst 18
93% ee for catalyst 19
NO2
O
F 3C
OH
Cl
Cl
O
23
F3C
NO2
Cl
NH 2
22
+
O
N
H
O
HO
Efavirenz, 88%
(anti-HIV drug)
FIGURE 1–15 Enantioselective trifluoromethylation for the synthesis of Efavirenz.
1.6.2.2 Synthesis of trifluoromethyl ketones
Although Grignard reactions of esters usually give the corresponding tertiary alcohols,
because the intermediate ketones are too reactive with the Grignard reagents, the Grignard
reactions of ethyl trifluoroacetate (24) almost exclusively give the aryl trifluoromethyl
ketones. The tetrahedral intermediate 25 is stable under the reaction conditions, because of
the strong electron-withdrawing effect of the trifluoromethyl group, and the trifluoromethyl
ketones (26) are formed only during the aqueous workup of the reaction mixture. Therefore
tertiary alcohols are not formed as the major products in the trifluoromethylation of esters
(Fig. 116).55 Ethyl fluoroacetate, with a single fluorine on the methyl group, also gives the
corresponding fluoromethyl ketone as the predominant product. The aryl Grignard reagents
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
17
FIGURE 1–16 Grignard reaction of ethyl trifluoroacetate to give trifluoromethyl ketones.
FIGURE 1–17 Nucleophilic trifluoromethylation of esters using CF3TMS reagent.
FIGURE 1–18 Trifluoromethylation of Weinreb amides for the preparation of trifluoromethyl ketones.
used in these transformations were formed, in situ, from the corresponding aryl halides and
a 1:1 mixture of isopropylmagnesium bromide and LiCl.56
Trifluoromethylation of esters using trifluoromethyltrimethylsilane (CF3TMS) affords the
corresponding trifluoromethyl ketones in good yields. However, the scope of this reaction is
limited mostly to esters of aromatic carboxylic acids.16 These trifluoromethylations using
CF3TMS proceed under relatively mild conditions when carried out in the presence of the
relatively weak Lewis acid catalyst, MgCl2 (Fig. 117).57
Trifluoromethylation of Weinreb amides of aliphatic and aromatic carboxylic acids,
using CF3TMS and CsF in catalytic amounts, gives the corresponding trifluoromethyl
ketones under mild reaction conditions. The intermediate hemiaminal silyl ether is
stable under these conditions, and its fluoride anioninduced desilylation, during workup
of the reaction, gives the corresponding ketones (Fig. 118).58 Thus, the use of Weinreb
18
Organofluorine Chemistry
FIGURE 1–19 Nucleophilic trifluoromethylation of N-alkylimines using CF3TIMS and in situgenerated
hydrofluoric acid.
amides as substrates in these reactions ensures monotrifluoromethylation, as the intermediate hemiaminal silyl ether decomposes to give the corresponding trifluoromethyl ketone,
only after the addition of TBAF.
1.6.2.3 Trifluoromethylation of imines
Nucleophilic trifluoromethylation of imines requires the presence of electron-withdrawing
substituents on the nitrogen such as N-sulfonyl and N-sulfinyl moieties.5966 Dilman has
shown that unactivated N-alkylimines could be trifluoromethylated using CF3TMS and stoichiometric amounts of potassium hydrogen difluoride (KHF2) and trifluoroacetic acid
(CF3CO2H).67,68 Under these conditions, solvated HF is generated, which activates the imines
toward nucleophilic trifluoromethylation, through N-protonation of the imines. The counter2
ion HF2
2 , in turn, activates the CF3TMS to generate the trifluoromethyl anion (CF3 ) in situ
(Fig. 119).
1.6.3 Fluoroacetone hydrates for the nucleophilic fluoroalkylations
Hexafluoroacetone (27) under basic conditions, at high temperatures, decomposes to give
the trifluoroacetate and trifluoromethyl anion, which reacts with aromatic aldehydes, such
as p-anisaldehyde, to give the corresponding α-trifluoromethyl alcohols. The high temperatures required for these reactions are a limiting factor for their applications in the synthesis
of fluorinated compounds. However, Colby and coworkers synthesized the amidinate salt
30 (now commercially available) through the reaction of hexafluoroacetone (27) and DBU,
as a crystalline, air-stable salt. Compound 27, upon reaction with various aromatic aldehydes and ketones at 2 30 C, gives the corresponding α-trifluoromethyl alcohols in high
yields.69
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
O
HO
MeO
HO OH
F3 C
NaOH, 100 °C
O O
F3 C
CF3
27
19
CF3
H
CF3
CF3
O
28
OMe
F3 C
O
29
N
O
N
F3 C
HO O
(DBU)
HO OH
F3 C
CF3
R
N
CF3
CF3
R
R′
31
78–96%
30
89%
HO
KOt-Bu/DMF; –30 °C
N
H
Et2 O
R′
R, R′ = aryl, H
O
KOtBu
HO OH
H
O O
H
CF3
32
R
CF3
CF3
HO
H
R
45–96%
33
34
R = aryl, alkyl
O
H
CF3
O
O
O HO OH
R
CF3
O
LiBr, Et3 N, THF
RT
O
H
F
R
F
F F
35
R′
36
OH
R
R′
F F
37
FIGURE 1–20 Trifluoromethylation using hexafluoroacetone as the source of the trifluoromethyl anion, and related
fluoroalkylations.
Trifluoroacetaldehyde hydrate (32) similarly reacts with aliphatic and aromatic aldehydes
in the presence of potassium tert-butoxide (KOtBu) in DMF to give the corresponding
α-trifluoromethyl alcohols in good yields.70 Difluoroenolates (36), generated, in situ, from
35, through the base-mediated expulsion of trifluoroacetate anion, undergo aldol reactions
with carbonyl compounds, to give the corresponding gem-difluoro compounds, α,α-difluoroβ-hydroxy carbonyl compounds (37) (Fig. 120).71
1.6.4 Trifuoromethylations using fluoroform (CHF3)
Prakash and coworkers developed a convenient, direct trifluoromethylation of carbonyl compounds using fluoroform as the source of CF2
3 , generated through potassium
20
Organofluorine Chemistry
(A)
(B)
FIGURE 1–21 Trifluoromethylation of aromatic aldehydes and ketones (A), and preparation of CF3TMS (B), using
fluoroform as the source of the nucleophilic CF2
3.
hexamethyldisilazide [potassium bis(trimethylsilyl)amide; KHMDS]mediated deprotonation of
the fluoroform (HFC-23; trifluoromethane) (Fig. 121).72 Fluoroform is a greenhouse gas,
formed as an abundant byproduct in the industrial-scale synthesis of polyvinylidene chloride
and poly(tetrafluoroethylene) from chlorodifluoromethane (CHF2Cl). Fluoroform is also a relatively nontoxic compound, and therefore there is a great interest in its use as a trifluoromethylating agent.7382 Interestingly, the stability of the CF2
3 anion is dependent on the counter
cations, and the trifluoromethylations proceed under mild conditions using KHMDS [K1
2
N(SiMe3)2] as the base for the deprotonation of the fluoroform.72 The trifluoromethylations of
carbonyl compounds, using the reagent combination of fluoroform and NaHMDS (sodium hexamethyldisilazide; sodium bis(trimethylsilyl)amide), or lithium hexamethyldisilazide (LiHMDS),
were not successful.83 Furthermore, the Ruppert-Prakash reagent, CF3SiMe3, can be synthesized
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
21
in high yields through the reaction of fluoroform with chlorotrimethylsilane, in the presence of
potassium hexamethyldisilazide (KHMDS) (Fig. 121B).
Whereas the earlier reported trifluoromethylations, using fluoroform as the source
2
of the CF2
3 anion, required the use of DMF to stabilize the CF3 anion (as the
7678,81,84,85
2
hemiaminolate salts),
the CF3 anion, generated using KHMDS or tBuOK, was
found to be stable and reactive in ether solvents, even in the absence of DMF. Using this
technique, a variety of aromatic carbonyl compounds could be trifluoromethylated to give
the corresponding α-trifluoromethyl alcohols in good yields.72 In subsequent work,
Prakash and coworkers have demonstrated the intermediacy of the in situformed CF2
3
anion in nucleophilic trifluoromethylations, through NMR spectroscopy and single-crystal
X-ray crystallography at low temperatures.83 Thus the reaction of tris(isopropyl)silyltrifluoromethane [(iPr)3SiCF3; TIPSCF3)] with potassium tert-butoxide in anhydrous tetrahydrofuran (THF) solution, in the presence of 18-crown-6, at 278 C, formed the
19
[K(18-crown-6)]1 CF2
F NMR spectrum of this trifluoromethanide anion shows a
3 . The
19
singlet at δ F 218.71, showing substantial negative charge for the anionic carbon of trifluoromethyl carbanion. The 13C NMR spectrum of the CF2
3 anion showed a quartet with a
1:3:3:1 signal intensity ratio at δ13C 175.0, showing that the three fluorines are equivalent.
The 13C NMR spectrum showed an unusually large one-bond CF coupling constant, 1J
(CF), of 432.5 Hz, as compared to a one-bond CF coupling constant of 293.3 Hz for the
fluoroform (CHF3). As expected, thus-obtained trifluoromethanide anion gave the
α-trifluoromethyl alcohols upon reaction with various carbonyl compounds such as benzaldehyde (Fig. 122).83
Grushin and coworkers have subsequently prepared the CF2
3 anion by performing the
above reaction of TIPSCF3 with KOtBu in the presence of 2.2.2-cryptand, in anhydrous THF,
at 278 C. The latter cryptand is even more effective in coordinating with the K1 ion than is
the 18-crown-6 and therefore is expected to give the relatively free trifluoromethyl anion.
Reaction of TIPSCF3 with potassium tert-butoxide-2,2,2-cryptand ([cryptand K2.2.2]1 tBuO2)
gave the trifluoromethanide anion, which showed a 19F NMR chemical shift (δ19F) of
217.2 ppm, somewhat deshielded as compared to that of [K(18-crown-6)]1CF2
3 . Reaction of
thus-generated trifluoromethyl anion with carbonyl compounds, such as benzaldehyde, also
gave the expected α-trifluoromethyl alcohols.8688
The trifluoromethyl anion is prone to the loss of the fluoride anion to give the difluoromethyl carbene, because of the thermodynamic force to overcome the repulsion of the nonbonding electron pair on the fluorine with the nonbonding electron pair on the carbon. The
CF2
anion, generated from the reaction of fluoroform and dimsyl potassium
3
1
(CH3 SOCH2
2 K ) in DMF, is stabilized as the hemiaminolate salt (38), which reacts with carbonyl compounds to give the corresponding trifluoromethylated alcohols 39.7678,81,84,85 The
intermediate 38 also reacts with dialkyl or diaryl disulfides to give the corresponding trifluoromethyl sulfides (RSCF3; 40) (Fig. 123).89 The latter trifluoromethyl thioethers are useful in
drug discovery and medicinal chemistry.90
Shibata and coworkers reported the catalytic effect of the monoglyme, triglyme, or tetraglyme in the direct trifluoromethylation of the carbonyl compounds using the reagent
–78 °C
–78 °C
FIGURE 1–22 Direct observation of the trifluoromethyl anion by NMR, through complexation of the K1 by the 18crown-6 and by the cryptand-2.2.2.
FIGURE 1–23 Trifluoromethylation of carbonyl compounds using fluoroform, a strong base, and DMF. DMF,
Dimethylformamide.
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
O
R
R′
CHF3 (excess)
t-BuOK or KHMDS (2.0 equiv)
Monoglyme
RT, 6 h (or –40 °C, 12 h)
23
F3 C OH
R
R′
Selected examples:
F3 C OH
F3 C OH
F3 C OH
F3 C OH
H
86%
66%
61%
80%
FIGURE 1–24 Trifluoromethylation of carbonyl compounds in glyme solvents, using fluoroform as the source of the
trifluoromethyl anion.
combination of fluoroform and potassium tert-butoxide or KHMDS.74 The glyme solvents,
as in the case of 18-crown-6, coordinate with the K1 ions, thus making the CF2
3 anion
more nucleophilic. The use of stoichiometric amounts of 18-crown-6 is impracticable in
the industrial scale synthesis, and therefore, the use of glyme solvents provides an alternative synthetic strategy. Various aryl aldehydes and ketones are trifluoromethylated, in
glyme solvents, to give the corresponding α-trifluoromethyl alcohols in good yields
(Fig. 124).
A phosphazene superbase (P4-tBu) mediates trifluoromethylation of carbonyl compounds, using fluoroform as the only reagent.91 In this reaction, because of the extended
delocalization of the conjugate acid, P4-tBu phosphonium cation, P4-tBu, acts as a strong
base to deprotonate the trifluoromethane, and the resulting CF2
3 anion reacts with carbonyl
compounds to give the corresponding α-trifluoromethyl alcohols. Due to the steric crowding
afforded by the P4-tBu base, the CF2
3 anion is stabilized, even in the absence of the added
DMF as a solvent or as a catalyst, and reacts readily with carbonyl compounds to give the
corresponding α-trifluoromethyl alcohols (Fig. 125).
The CF2
3 anion formed through the superbase P4-tBu- or KHMDS-mediated deprotonation of trifluoromethane reacts with chiral sulfinimines (41) of aromatic and aliphatic aldehydes to give the corresponding trifluoromethylated N-sulfinylamines (42) with high
diastereoselectivity.62 Acidification of the resulting sulfinimines in 4M HCl then gives the corresponding α-trifluoromethylammonium salts 43 (Fig. 126). Similarly, high diastereoselectivities were obtained in the trifluoromethylation of chiral sulfinimines using KHMDS and
fluoroform.
1.6.5 Borazine-mediated trifluoromethylation and difluoroalkylation
The abundantly available hexamethylborazine forms a stable adduct with trifluoromethyl
anion and serves as a nucleophilic trifluoromethylating agent toward carbonyl compounds.
Geri and Szymczak pioneered the nucleophilic trifluoromethylation reactions using the
24
Organofluorine Chemistry
FIGURE 1–25 Trifluoromethylation of carbonyl compounds using the phosphazene superbase P4-tBu and fluoroform.
FIGURE 1–26 Diastereoselective trifluoromethylation of N-sulfinylimines.
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
K
N
B
B
N
N
CHF3
KH (or NaH)/DMSO
B
B
O
CF3
N
B
N
N
25
Ph
Ph
HO CF3
Ph
B
N
+
B
Ph
B
N
N
B
72%
(Recyclable reagent)
CF3 SO2 – Na+
SO 2
Me 3 SiCl
Me 3 SiCF3
Langlois reagent
96%
Cl
66%
I O
F3 C
CF3 CO2– K+
I O
CO 2
Togni’s reagent
78%
FIGURE 1–27 Borazine-mediated trifluoromethylation of carbonyl compounds and synthesis of Langlois reagent,
Togni’s reagent, and CF3TMS.
hexamethylborazinetrifluoromethyl anion adduct as a cost-effective, atom-economical
reagent.92 The hexamethylborazinetrifluoromethyl anion adduct could be generated, in
situ, from the reaction of hexamethylborazine with the trifluoromethyl anion, which, in
turn, is generated through the reaction of fluoroform and a strong base (e.g., NaH). Thus
reaction of carbonyl compounds, such as benzophenone, in the presence of borazine,
fluoroform, and NaH, gives the α-trifluoromethyl alcohols in high yields, under mild reaction conditions (room temperature, 30 min). The borazine starting material is regenerated
during the reaction and is recyclable; hence, borazine-mediated trifluoromethylation is an
efficient and cost-effective means of trifluoromethylation of carbonyl compounds. The
borazine-mediated trifluoromethylation could also be used in the synthesis of the nucleophilic trifluoromethylating agents, such as CF3TMS (through reaction with trimethylsilyl
chloride); free-radical trifluoromethylating agents, such as Langlois reagent (through reaction with sulfur dioxide); and electrophilic trifluoromethylating reagents, such as Togni’s
reagent (through reaction with the corresponding iodonium chloride) in high yields
(Fig. 127).92
Szymczak and coworkers extended their synthetic method for the difluoromethylation
of carbonyl compounds. Thus the reaction of hexamethylborazine with (difluoromethyl)
benzene, in the presence of a strong base, such as potassium diisopropylamide KN(iPr)2,
gives the borazine-gem-difluorobenzyl adduct, which reacts with carbonyl compounds to
give the corresponding gem-(difluoro)benzyl-substituted alcohols in moderate yields.
This reagent can also be used in the Pd(0)-catalyzed difluoroalkylation of aryl halides
(Fig. 128).93
26
Organofluorine Chemistry
Re
FIGURE 1–28 Borazine-mediated gem-difluroalkylation of carbonyl compounds and aryl halides.
1.6.6 N-Trifluoromethylation of amines
Schoenebeck and coworkers have demonstrated that secondary amines, but not the primary amines, react with (Me4N)SCF3 to give the corresponding thiocarbamoyl fluorides
(44).94 This reaction is nearly quantitative in 10 min, and at the end of the reaction, the
initially clear, colorless reaction mixture turns into a cloudy solution. Desulfurative fluorination of the latter thiocarbamoyl fluorides (44) with AgF results in the formation of the
N-trifluoromethyl derivatives (45). These two reactions were combined in a one-pot
two-step method, in effect, to transform secondary amines to the corresponding
N-trifluoromethyl amines. The reaction sequence tolerates a variety of functional groups,
including nitro, nitrile, amide, sulfonyl, methoxy, and heterocyclic aromatics, and thus
serves as an efficient synthetic method for N-trifluoromethyl compounds. Secondary
amines consisting of electron-withdrawing as well as electron-donating groups react efficiently under the reaction conditions to give the corresponding N-CF3 compounds.
Protected versions of amino acids, such as proline and glycine, could be N-trifluoromethylated in high yields. Synthesis of N-trifluoromethyl analogs of the widely used pharmaceuticals, such as tetracaine (51; an anesthetic), antifungal agent terbinafine (52), drugs for
treating neurological disorders, such as amitriptyline (53) and naftifine (54), were synthesized in high yields. This late-stage N-trifluoromethylation of pharmaceutically interesting
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
S
R
N
(Me (Me 4N)SCF 3
H
R
DCM or MeCN, RT, 10 min
R′
N
AgF, < 4 h
F
44
R
Me 4N F
S
F
F
45
88%–99% overall
yield for two
steps
Mechanistic outline:
Me 4N
N
R′
R′
R/R′ = alkyl, aryl
F
F
R
27
F
N
H
R′
F
F
F
S
46
HF
Selected examples:
O
N
CF 3 O
N
Ot Bu
CF3
49
48
47
92%
N
CF3
91%
O 2N
50
N
CF3
95%
93%
CF3
N
O
O
Me
OEt
N
N
CF 3
97%
51 ; Tetracaine (anesthetic)
analog
95%
52 ; Terbinafine (Lamisil; antifungal)
analog
CF3
N
N CF 3
Me
98%
53; Amitriptyline (Elavil; for
mental illness) analog
88%
54 ; Naftifine (Naftin; for mental illness)
analog
FIGURE 1–29 N-Trifluoromethylation of secondary amines and synthesis of N-CF3 analogs of pharmaceuticals.
compounds may be useful in the synthesis of 18F-labeled compounds for PET studies,
although the pharmacological effectiveness of the latter N-trifluoromethylated compounds
are yet to be evaluated (Fig. 129).
28
Organofluorine Chemistry
In these reactions, the trifluoromethylthiolate anion (CF3S2), in equilibrium, forms the
thiocarbonyl fluoride (46) by the fluoride anion elimination. Nucleophilic addition of the secondary amines to 46 then gives the corresponding thiocarbamoyl fluorides (44), the substrates for
the desulfurative difluorination (using AgF). The in situgenerated thiocarbonyl fluoride (46),
formed through the reaction of the CF3SiMe3 with elemental sulfur and KF, also gives high yields
of the thiocarbamoyl fluorides (44) of the secondary amines.95 On the other hand, primary
amines, under these reaction conditions, give the corresponding isothiocyanates (RNCS).
1.6.7 Tetrakis(dimethylamino)ethylene-mediated fluoroalkylations
Pawelke first reported the reductive trifluoromethylation of various silicon and boron halides
using tetrakis(dimethylamino)ethylene (TDAE) as the reducing agent.96 Trifluoromethyl iodide
(and other perfluoroalkyl halides) forms a strong charge-transfer complex with TDAE and thus
serves as a source of the in situformed nucleophilic trifluoromethyl anion. This reaction was
later expanded for the synthesis and synthetic applications of various perfluoroalky-trialkylsilanes
by Petrov and more extensively by Dolbier and coworkers (Fig. 130).60,97104 The TDAEmediated nucleophilic fluoroalkylation method provides a convenient alternative strategy for the
trifluoromethylation and perfluoroalkylation of carbonyl compounds to that using the
FIGURE 1–30 TDAE-mediated trifluoromethylation and perfluoroalkylation of aldehydes, ketones, and imines.
TDAE, Tetrakis(dimethylamino)ethylene.
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
29
RuppertPrakash reagent (TMSCF3),16,48,59,66 as the fluoroalkylation reactions can be carried out
in a single step without the necessity of isolating the TMSCF3 reagent. As in the case of the
TMSCF3, the TDAE-mediated trifluoromethylation of a broad range of aliphatic and aromatic
aldehydes, ketones, and N-tosylimines gives the corresponding α-trifluoromethyl alcohols and
amines (Fig. 130).60,101,104
1.6.7.1 Trifluoromethylation of acyl chlorides
The TDAE-mediated trifluoromethylation of acid chlorides, using excess CF3I, gives the corresponding trifluoromethyl ketones as the initially formed products via nucleophilic substitution
reaction. The latter aryl trifluoromethyl ketones (56) rapidly react with the trifluoromethyl anion,
generated, in situ, to give the tertiary alkoxides, which undergo esterification with unreacted
aroyl chloride (55) to give the tertiary 1,1-bis(trifluoromethyl) benzoate (57) in nearly quantitative yields. Hydrolysis of 57 under mild conditions gives the corresponding 1-aryl-1,1-bis(trifluoromethyl)methanol (58).102 This synthetic strategy, using TDAE as the reductant, provides a
better alternative for the preparation of the 1,1-bis(trifluoromethyl)alcohols (58) as compared to
the related reactions using CF3TMS, in which case mixtures of the trifluoromethyl ketones and
the tertiary alcohols are usually formed (Fig. 131).
FIGURE 1–31 TDAE-mediated trifluoromethylation of benzoyl chloride to give the tertiary 1-aryl-1,1-bis
(trifluoromethyl)methanols. TDAE, Tetrakis(dimethylamino)ethylene.
30
Organofluorine Chemistry
Br
N
O
F
F
TDAE (1 mol equiv)
N
RSCN, anhyd. DMF
–20 °C to RT, 1–5 h
O
F
SR
N
N
F
N
N
TDAE
TDAE
N
F
O
F
R
-[TDAE]2+ Br– (CN – )
S
CN
[TDAE]2+Br –
Ph
Examples:
SPh
N
O
F
F
O
F
S
S
R
F
F
43%
CF3I (4.2–5.0 mol equiv)
TDAE ( 2.2 mol equiv)
S
N
O
F
62%
60%
R
NMe2
S
N
N
RSCF3
R = phenyl, butyl, ethyl, 4-pyridyl
~200% yield based on the
disulfide reactant
FIGURE 1–32 TDAE-mediated synthesis of gem-difluoro thioethers, as potential anti-HIV-1 agents. TDAE, Tetrakis
(dimethylamino)ethylene.
1.6.7.2 Synthesis of gem-(difluoromethyl)thioethers
TDAE-mediated sulfanylation of 2-(bromodifluoromethyl)benzoxazole using heteroarylthiocyanates as electrophilic reagents affords the corresponding heteroaryl-CF2SAr compounds, some of which were found to be anti-HIV-1 agents (Fig. 132). This sulfanylation
reaction can also be rationalized as proceeding through radical nucleophilic substitution
(SRN1).97,105 Reductive trifluoromethylation of dialkyl or diaryl disulfides using excess trifluoromethyl iodide in the presence of TDAE affords the corresponding trifluoromethyl
thioethers.101,102
Trifluoromethylation diaryldisulfides, using 18F-labeled CHF218F, in the presence of potassium tert-butoxide in DMF solvent, gives the corresponding 18F-labeled trifluoromethylthiolated aromatics. The 18F-labeled CHF218F is generated, in situ, from the reaction of the [18F]
fluoride anion with (difluoromethyl)(mesityl)(phenyl)sulfonium salt. Using this synthetic
approach, 18F-labeled trifluoromethylthiolation of aromatics was achieved in high radiochemical yields (Fig. 133; please see Chapter 6: Synthesis and applications of 18F-labeled
compounds).106
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
CHF2
S
[ 18F]F
ArSSAr
CHF218 F
31
ArSCF 218 F
KOtBu/DMF
Selected examples:
SCF218 F
73% RCY
NC
MeO
F
68% RCY
FIGURE 1–33 Synthesis of
diaryldisulfides.
SCF218 F
SCF218 F
SCF218 F
74% RCY
67% RCY
SCF218 F
N
45% RCY
18
F-labeled (trifluoromethyl)thio arenes through nucleophilic trifluoromethylation of
1.7 Nucleophilic trifluoromethylthiolation
Nucleophilic ring-opening of the cyclic sulfamidates (59), using tetramethylammonium
trifluoromethanethiolate (Me4NSCF3), gives the corresponding trifluoromethylthio (SCF3)
derivatives (60). Using this synthetic method, S-trifluoromethylated cysteine derivative 62
could be synthesized under mild conditions and further transformed into the corresponding S-trifluoromethyl dipeptides and tripeptides, Gly-Cys (64) and Ser-Phe-Cys (63)
(Fig. 134).107
Nucleophilic substitution reactions of thiocyanates and sulfenyl chlorides can be achieved
in moderate yields using CF3SiMe3 (Fig. 135). Thus reaction of alkyl thiocyanates, generated, in situ, through the reaction of the alkyl halides with sodium thiocyanate (NaSCN),
react with CF3SiMe3 to give the corresponding trifluoromethylthio ethers (an SN2-type of
reaction, with cyanide anion as the leaving group).108 Aryl thiocyanates, formed, in situ,
through the reaction of aryl diazonium salts with CuSCN, give the corresponding trifluoromethylthioarenes in moderate yields.109 Aryl(alkyl)sulfenyl chlorides, upon reaction with
CF3TMS, in the presence of TASF, give the corresponding trifluoromethylthioarenes.110
However, the high toxicity of the latter sulfenyl chlorides limits the applications of these
reagents for the trifluoromethylthiolations.
1.8 Trifluoromethoxylations
Trifluoromethoxy substituent, because of its metabolic stability and enhanced lipophilicity,
as compared to its methoxy analog, has found applications in the design of pharmaceuticals
and agrochemicals. Hansch lipophilicity values (πx) for OCF3, CF3, CH3, OCH3 substituents
are 1.04, 0.88, 0.52, 20.02, respectively, showing substantial lipophilicity enhancements
afforded by the OCF3 moiety as compared with trifluoromethyl and related nonfluorinated
32
Organofluorine Chemistry
FIGURE 1–34 Nucleophilic trifluoromethylthiolation of cyclic sulfamidates to give the S-trifluoromethyl derivatives
of cysteine and cysteine-containing peptides. Boc, tert-Butoxycarbonyl; DCM, dichloromethane.
RSCN/ TBAF
RSCF3
R = alkyl
RSCl/ TASF
RSCF3
R = alkyl/aryl
CF3 TMS
N N
SCF3
R′
R′
CuSCN, Cs2 CO3 , MeCN
R′ = for example OMe, CN, Br, I
FIGURE 1–35 Nucleophilic trifluoromethylthiolations of alkylthiocyanates, diazonium salts, and sulfenyl chlorides.
TASF, Tris (dimethylamino)sulfonium difluorotrimethylsilicate; TBAF, tetrabutylammonium fluoride.
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
33
FIGURE 1–36 Selected pharmaceuticals and agrochemicals containing OCF3 moiety.
substituents. The higher lipophilicity of a compound reflects in its enhanced cell permeability and bioavailability.
Trifluoromethoxyaryl-containing pharmaceuticals include rifluzole, a drug used to
treat amyotrophic lateral sclerosis, and sonidegib, an antineoplastic pharmaceutical.
Many agrochemicals, including the insecticides indoxacarb and flurprimidol, flucarbazone, a herbicide, and triflumuron, a plant growth regulator, are trifluoromethoxyarenes
(Fig. 136).
1.8.1 Trifluoromethyl benzenesulfonatemediated vicinal (bromo)
trifluoromethoxylation
Trifluoromethyl benzenesulfonate (TFMS), in the presence of AgF, reversibly forms Ag(OCF3)
and thereby brings about vicinal (bromo)trifluoromethoxylation of alkenes in the presence of
an electrophilic “Br1” source such as 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).
Reaction of TFMS with alkenes, in the presence of AgF and DBDMH, gives the corresponding
vicinal (bromo)trifluoromethoxylation products in high yields (Fig. 137).111 In the presence
of a chiral catalyst, such as (DHQD)2PHAL (dihydroquinidinephthalazine adduct), this
reaction affords the corresponding 1-bromo-2-trifluoromethoxy compounds in moderate to
high yields and enantioselectivity.
34
Organofluorine Chemistry
FIGURE 1–37 Vicinal bromo-trifluoromethoxylation of alkenes using trifluoromethyl benzenesulfonate (TFMS).
DBDMH, 1,3-dibromo-5,5-dimethylhydantoin.
1.8.2 Trifluoromethyl benzoatemediated trifluoromethoxylation
Hu and coworkers have developed trifluoromethyl benzoate (65) as a convenient, shelfstable, nucleophilic trifluoromethoxylation reagent. This reagent, as in the case of the
trifluoromethyl benzenesulfonate (TFMS), forms AgOCF3, in reversible equilibrium, in the
presence of AgF, and can be used in the enantioselective α-bromo-trifluoromethoxylation of
styrene derivatives 66 and nucleophilic trifluoromethoxylation of alkyl halides (e.g., 68 and
70).112 Trifluoromethyl benzoate (65) reacts with the aryne intermediates, in the presence of
an electrophilic “Br1” source (e.g., phenylethynyl bromide 73), to give the ortho-bromo(trifluoromethoxy)arenes (74).112 The latter aryne intermediates were generated, in situ, through
Chapter 1 • Nucleophilic reactions in the synthesis of organofluorine compounds
35
cis
FIGURE 1–38 Trifluoromethoxylation of aromatics, alkenes, and alkyl halides, using trifluoromethyl benzoate as
the source of the nucleophilic trifluoromethoxide anion.
the reaction of ortho-(trimethylsilyl)aryl triflates (72) with KF, complexed to a crown ether
such as cis-dicyclohexano-18-crown-6. Use of the crown ethers facilitates the stabilization of
the in situformed KOCF3 toward its decomposition and enhances its nucleophilicity
(Fig. 138).112
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38
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74. Saito, T.; Wang, J.; Tokunaga, E.; Tsuzuki, S.; Shibata, N. Direct Nucleophilic Trifluoromethylation of
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84. Russell, J.; Roques, N. Effective Nucleophilic Trifluoromethylation with Fluoroform and Common Base.
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2
Electrophilic reactions in the
synthesis of organofluorine
compounds
Chapter Outline
2.1 Introduction ................................................................................................................................... 43
2.2 Reagents for electrophilic fluorination ....................................................................................... 44
2.2.1 Fluorinated bioisosteres of phosphate esters ................................................................... 46
2.3 Enantioselective electrophilic fluorination ................................................................................. 48
2.3.1 Enantioselective α-fluorination of aldehydes ................................................................... 48
2.3.2 Enantioselective α-fluorination of amides ........................................................................ 50
2.3.3 Enantioselective fluorination of allylsilanes and enolsilyl ethers ................................... 50
2.3.4 Enantioselective α-fluorination of ketones and 1,3-dicarbonyl compounds ................. 51
2.4 Electrophilic fluorination in the synthesis of α-fluorinated amino acids................................ 53
2.5 Electrophilic fluoroalkylation ....................................................................................................... 54
2.5.1 Reagents for electrophilic trifluoromethylation............................................................... 55
2.5.2 NHC-catalyzed electrophilic trifluoromethylation............................................................ 57
2.5.3 Electrophilic difluoromethylation ...................................................................................... 57
2.6 Electrophilic trifluoromethylthiolation and trifluoromethoxylation ....................................... 61
2.6.1 Synthetic methods for O-trifluoromethylation................................................................. 61
2.7 Synthetic methods for trifluoromethylthiolation ...................................................................... 63
2.7.1 Reagents for electrophilic trifluoromethylthiolation....................................................... 63
2.7.2 Billard’s reagents ................................................................................................................. 65
2.7.3 Diethylaminosulfur trifluoridemediated trifluoromethylthiolation of
silylenol ethers and β-naphthols ........................................................................................ 66
2.8 Difluoromethylthiolation.............................................................................................................. 68
References............................................................................................................................................. 70
2.1 Introduction
Electrophilic fluorination, fluoroalkylation, fluoroalkoxylation, and fluoroalkylthiolation
reactions play an important role in the synthesis of pharmaceuticals, agrochemicals, fine
chemicals, and functional materials. Electrophilic fluorinations of organic compounds can be
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00002-X
© 2020 Elsevier Inc. All rights reserved.
43
44
Organofluorine Chemistry
achieved under relatively mild conditions, using the commercially available electrophilic
fluorinating reagents, such as Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]
octane bis(tetrafluoroborate), NFSI (N-fluorobenzenesulfonimide), and N-fluoropyridinium
salts (NFPy OTf, NFPy BF4). These reagents are milder alternatives to the use of highly corrosive elemental fluorine or moisture-sensitive xenon difluoride (XeF2).1 However, using
microfluidic-based continuous flow reactor techniques, elemental fluorine can be used in
the electrophilic fluorination reactions under relatively mild and safe conditions.2,3
Selectfluor-mediated electrophilic fluorination is used in the synthesis of pharmaceuticals,
such as fluticasone, a corticosteroid-based drug.
Difluoromethylation and trifluoromethylation reactions can be achieved, under mild reaction conditions, using the commercially available Umemoto’s and Togni’s reagents. These
reagents can be used, for example, in the trifluoromethylation of enolates, aromatics,
alkynes, thiols (S-trifluoromethylation), phosphines (P-trifluoromethylation), and alcohols
(O-trifluoromethylation).4,5 Electrophilic trifluoromethylthiolation and difluoromethylthiolation reactions can be achieved using N-fluoroalkyl sulfenamide and N-fluoroalkyl phthalimide reagents.69 The relatively greater lipophilicity-enhancing effect of SCF3 moiety, as
compared to that of OCF3 and CF3 substituents, is exploited in the design of pharmaceuticals, such as tiflorex (anorectic) and toltrazuril (antiprotozoal agent). SCF3-containing compounds are also used for veterinary drugs, such as monepantel and toltrazuril.
2.2 Reagents for electrophilic fluorination
Some of the commercially available electrophilic fluorinating agents include 1-chloromethyl4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1; Selectfluor), 1-fluoro4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)
(2;
Accufluor),
N-fluoropyridinium triflate (3), N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
(4), NFSI (5; NFSI). Selectfluor gives better yields and higher selectivity for the
α-fluorination, as compared to the other electrophilic fluorinating agents, such as
N-fluoropyridinium tetrafluoroborate (NFPy) and NFSI. NFPy reagent is, however, costeffective, although it is less reactive than the Selectfluor. Relative reactivities of some of
the electrophilic fluorinating reagents toward enol fluorination, as determined by
UVvis kinetic studies, are in the following order: 1 . 3c5 . 4.10 The relative reactivity
orders, based on the yields of enolate fluorination of β-ketoesters, are as follows: 1 . 2c5.11
Selectfluor has similar to, but slightly higher reactivity than, the Accufluor. The latter study
also revealed that the N-fluoropyridinium tetrafluoroborate reacts about 100 times slower
than the Selectfluor (Fig. 21).
Selectfluor and NFSI are among the most widely used fluorinating agents in electrophilic
fluorinations as well as in photoredox catalyzed CH fluorination reactions.1215 These
reagents are also useful in the preparation of 18F-labeled positron emission tomography
(PET) imaging agents (see Chapter 6: Synthesis and applications of 18F-labeled compounds).
18
F-labeled Selectfluor bis(triflate) was used for the synthesis of 18F-labeled PET tracers,
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
OH
N
N
2BF4
F
F
O
O
N
S O
O S
Me
Cl
N
N
1
N
2BF4
F
F
2
Selectfluor
CF3 SO3
(or BF4–)
Me
N
F
Accufluor
NFPy OTf
k rel
(enol fluorinations)
Me
BF4
4
3
45
5
NFTMP BF4
NFSI
or (NFPy BF4 )
1
–
0.2
10 –6
10 –4
1.84
–
–
0.04
k rel
(enolate fluorination
of β-ketoesters)
2.72
FIGURE 2–1 Structures of some of the commercially available electrophilic fluorinating reagents (krel is the relative
rate constants for enol fluorinations).
OSiMe3
Me
O
Me
18
MeCN, 5–15 min, 80 °C
Cl
F
~50% RCY
N
SnMe3
N
18
F
2 OTf
18
F
R
AgOTf (2 equiv)
acetone, RT 20 min
R
RCY = 14%–18%
18
FIGURE 2–2 Radiofluorination of enolsilanes and arylstannes using [ F]Selectfluor.
through the fluorination of enolsilanes or fluoro-destannylation of arylstannes (Fig. 22).16
This fluoro-destannylation is a convenient alternative to the destannylative radiofluorination
using [18F]F2.17
A mechanistic study of the Selectfluor-mediated fluorination of enol acetates (6) shows
that the reaction proceeds through the formation of an oxygen-stabilized carbocation (7)
(Fig. 23).18
Selectfluor is used as an electrophilic fluorinating agent in the synthesis of corticosteroids, such as fluticasone. Several fluorinated corticosteroids, including fluticasone,
46
Organofluorine Chemistry
Cl
N
N
O
F
2BF4
O
O
O
O
O
R
Selectfluor
6
F
R
F
R
H2 O
7
O
F
R
+ CH3 CO2 H
8
FIGURE 2–3 Mechanistic outline for the Selectfluor-mediated fluorination of the enol acetates.
are approved by the FDA as glucocorticosterone drugs, the topical antiinflammatory
agents. Various ester derivatives of fluticasone, such as fluticasone furoate and fluticasone
propionate, are used as nasal spray to treat nasal allergic rhinitis.19 Fluticasone furoate,
when used as a combination therapy, is also effective in the management of chronic
obstructive pulmonary disorders.20,21 Fluorinated corticosteroids, in most cases, have a
6-fluoro substituent, which can be introduced through electrophilic fluorination of the
corresponding dienolates.
The synthesis of fluticasone propionate or fluticasone furoate involves Selectfluormediated fluorination of the dienol acetate 9 and the ring-opening fluorination of the epoxide as the key steps.22 Thus fluorination of steroidal 3,5-dienol acetate 9 with Selectfluor
gave 6-fluoro enone 10 with high stereoselectivity (Fig. 24). The ring-opening hydrofluorination of the epoxide 10, using aqueous hydrogen fluoride (HF) (70% solution), gave compound 11 that could be transformed into the fluticasone furoate or other ester derivatives in
a series of steps. The aqueous HF used in the later step also hydrolyzed the acetate ester to
the alcohol 11.
2.2.1 Fluorinated bioisosteres of phosphate esters
Selectfluor-mediated electrophilic fluorination of the enolate derived from various dibenzylβ-ketophosphonates (12) gives the corresponding α,α-difluoro-β-ketophosphonates (13).
The gem-difluoromethylene (CF2) is isoelectronic and, to some extent, isosteric with respect
to oxygen (Charton’s steric parameters for OH and CF2H are 0.32 and 0.60, respectively23),
and thus these α,α-difluoro-β-ketophosphonates (13) serve as bioisosteric mimetics of the
corresponding phosphate esters (15). The α,α-difluoromethylated phosphonate esters are,
therefore, useful in the design of the pharmaceutically interesting, hydrolytically
stable phosphate esters. Due to the high electrophilicity of the carbonyl group adjacent to
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
F
F
O
Me
HO
Me
F
OH
Me
H
S O
O
H
F
F
Fluticasone propionate
Fluticasone furoate
O
O
Me
O
O
O
H
Me
Selectfluor
H
O
Me
O
OH
H
O
O
OH
HF/H 2 O
H
MeCN, RT
AcO
H
O
F
Synthesis:
Me
H
F
H
S O
O
Me
Me
O
Fluticasone
O
Me
HO
O
Me
6
F
Me
O
Me
HO
H
F
O
S
47
–15 °C to –10 °C
5h
F
10
9
O
Me
HO
H
Me
F
OH
OH
Fluticasone furoate
H
O
F
11
FIGURE 2–4 Electrophilic fluorination of enol acetates by Selectfluor.
the gem-difluoromethylene moiety, these β-keto phosphonate esters are in rapid equilibrium
with the corresponding hydrate form 14 and thereby can act as the transition state analog
inhibitors of proteases.
The α-fluorophosphonate esters also serve as hydrolytically stable analogues of
the corresponding phosphate esters. For example, the α-monofluorinated D-glucose-1phosphate analogues 20 and 21 serve as transition state analog inhibitors of
β-phosphoglucomutase (Fig. 25).24 The monofluorinated, α-fluorophosphonate esters,
21, could be synthesized through sequential electrophilic fluorination of the corresponding α-sulfonyl phosphonates (17), followed by reductive deprotection of the sulfonyl
group using tributyltin hydride (Bu3SnH) in the presence of 2,20 -azo-bis(isobutyronitrile)
as the free-radical initiator.15,25
gem-Difluoromethylene phosphonate 22, a bioisosteric analogue of N-palmitoylsphingosine-1-phosphate (sphingomyelin), is a hydrolytically sable, noncompetitive inhibitor of
sphingomyelinases (Fig. 25).26
48
Organofluorine Chemistry
FIGURE 2–5 Synthesis of α,α-difluoro- and α-fluorophosphonate esters as mimetics of the phosphate esters.
2.3 Enantioselective electrophilic fluorination
2.3.1 Enantioselective α-fluorination of aldehydes
Asymmetric synthesis of α-fluoro aldehydes can be carried out using Selectfluor or NFSI as
the electrophilic reagent, and chiral organocatalysts, such as L-proline or the imidazolidinone
catalyst 23.27,28 Although enantioselective fluorination of the α-unbranched aldehydes with
chiral proline-derived catalysts gives high yields and enantioselectivities for the
α-fluorination, α-fluorination of the α,α-dialkyl (or aryl) aldehydes, under similar conditions,
proceeds with poor enantioselectivities. Thus L-proline-catalyzed electrophilic α-fluorination
of α-alkyl linear aldehydes, using Selectfluor, as well as NFSI, as the electrophilic fluorinating
agent, gives relatively low enantioselectivity [4%25% enantiomeric excess (ee)]. However,
NFSI-mediated electrophilic fluorination of aldehydes, in the presence of the chiral imidazolidinone catalyst 23, gives low to moderate enantioselectivities (28%66% ee) for the
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
49
O
O
NFSI
R1
R1
H
N
R 1 = e.g., iPr, alkyl, benzyl
R 2 = e.g., H, Me, alkyl
Me
Me
Ph
N
H
H
R2 F
Me
O
R2
40%–97% yields
28%–66% ee for R2 = Me, alkyl
88%–96% ee for R2 = H
Organocatalyst (23)
FIGURE 2–6 Asymmetric electrophilic α-fluorination of aldehydes.
t-Bu
Ar
NFSI/25 (10 mol%)
Ar
O
R
R
3,5-(NO 2) 2C6 H3CO2 H
(10 mol%)
Toluene; 0 °C
24
t-Bu
Ar
O
F
OH
R
NH2
CO2 Et
F
t-Bu
27
26
t-Bu
Examples:
Chiral catalyst 25
F
Ph
Br
OH
F
76%; 90% ee
97%; 92% ee
28
F
OH
F
OH
F
98%; 92% ee
30
29
Ph
Ph
O
CrO 3 /H 2SO 4
OH
F
Acetone, RT 4 h
OH
F
F
F
69%
31
Analog of flurbiprofen
32
FIGURE 2–7 Enantioselective fluorination of α-branched aldehydes and synthesis of a flurbiprofen analog.
α-branched aldehydes and high enantioselectivities of 88%96% for the α-unsubstituted linear aldehydes (Fig. 26).27
The enantioselectivity of the α-fluorination of the α-branched aldehydes is drastically
improved when catalyzed by a highly crowded chiral binaphthyl-based primary amine
catalyst 25. The intermediate α-fluoro aldehydes 26 were reduced, in situ, to give the corresponding primary alcohols 27. CrO3 oxidation of the compound 31 gives the α-fluorinated
version of flurbiprofen, a nonsteroidal antiinflammatory drug (Fig. 27).29
50
Organofluorine Chemistry
O
O
F
F
O
F
O
N
O
N
O
O
LDA, NFSI
THF, –78 °C
O
O
34
92%
O
33
Me
F
OH
O
F
O
O
35
(GRP5 agonist; lowers blood glucose levels)
FIGURE 2–8 α-Fluorination of amides by NFSI in the synthesis of a G Protein-coupled receptor (GPCR) agonist. NFSI,
N-Fluorobenzenesulfonimide.
2.3.2 Enantioselective α-fluorination of amides
NFSI can be used in the α-fluorination of amide enolates. Thus reaction of the Evans’ chiral
N-acyl oxazolidinone 33 with lithium diisopropylamide (LDA), followed by reaction with Nfluorobenzenesulfonimide (NFSI), gives the corresponding α-fluorinated compound 34,
which was enantioselectively methylated and hydrolyzed to give the compound 35
(Fig. 28). Compound 35 was found to be a superagonist for the G-protein-coupled receptor, GPR4, which mediates fatty acidinduced glucose-stimulated insulin secretion from the
pancreatic beta cells, thereby lowering the blood glucose levels. It was demonstrated that the
compound 35 is highly efficacious in lowering the blood glucose levels, has superior in vitro
metabolic stability, and forms a stable acylglucuronide metabolite, as compared to its analog
that lacks the α-fluorine and methyl groups.30
2.3.3 Enantioselective fluorination of allylsilanes and enolsilyl ethers
Shibata and coworkers developed enantioselective fluorination of silylenol ethers and allylsilanes, using NFSI and bis-cinchona alkaloids, such as (DHQ)2PYR [a (2,5-diphenyl)pyrimidine-linked version of dimeric dihydroquinine] or (DHQ)2PHAL (a phthalazine-linked
version of dimeric dihydroquinine, used as AD-mix-alpha in the Sharpless asymmetric dihydroxylation) as a chiral catalyst.31 In some cases, high yields and enantioselectivities are
obtained using these catalysts (Fig. 29). In these reactions, NFSI reversibly transfers the
“F1” to the cinchona alkaloids to form the corresponding N-fluoroammonium salt, which,
upon anion metathesis with K2CO3, followed by desilylative fluorination gives the fluorinated
compounds, regenerating the cinchona catalysts. The fluorination reactions are relatively
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
51
O
Me3Si
O
NFSI (1.2 equiv)
(DHQ)2 PYR (10 mol%)
R
F
N
H
O H
NN
N
R
K2 CO3 /MeCN
N
O
N
R = PhCH2 ; 75% yield (94% ee)
(DHQ)2PHAL
Me3Si
O
O
O
R
NFSI (1.2 equiv)
(DHQ)2 PHAL (10 mol%)
F
N
O
R
K2 CO3 /MeCN
H
N
R = PhCH2 ; 90% yield (71% ee)
R = e.g., PhCH2 , p-Cl, p-Me, or p-OMe-benzyl
O
N
H
N
N
O
N
(DHQ)2PYR
Mechanistic outline:
F N(SO2Ph)2
X
Me3 SiOK
H
N
F
+
CO2
H
F N
R
N(SO2Ph)2
K2 CO3
Me3Si
H
F N
X
R
K+ –N(SO2Ph)2
KCO3
X = O, CH2
FIGURE 2–9 Enantioselective fluorination of allylsilanes and enolsilyl ethers.
slower in the absence of the K2CO3, suggesting that the weakly basic sulfonamide anion is
ineffective in the desilylation reactions.
2.3.4 Enantioselective α-fluorination of ketones and 1,3-dicarbonyl
compounds
Use of the cinchona alkaloids as chiral catalysts gives moderate yields and enantioselectivities in the α-fluorination of tetralones (Fig. 210).32 The 2-aryltetralones are potentially useful as pharmaceuticals, such as aromatase inhibitors and hepatitis C virus inhibitors, based
on the effectiveness of their isoflavanone analogs.
Selectfluor-mediated diastereoselective fluorination of enolates with preexisting chiral
centers in the molecule proceeds with high diastereoselectivities. For example, the enolate
52
Organofluorine Chemistry
O
O
1. 1:1 Cinchonine/Selectfluor (2 equiv;
NaH (2.0 equiv)/THF
R
R
F
2. MeCN, 29 h, 0°C
Examples:
O
O
O
F
F
F
O
F
Me
16% ee
74% ee
O
Me
59% ee
FIGURE 2–10 Enantioselective fluorination of tetralones.
O
O
O
N
H
O
OTBS
O
KHMDS/Selectfluor
O
12
THF, –78°C
O
N
H
O
OTBS
F
12
93%; dr = >20:1
36
37
O
TFA/DCM
O
O
N
H
O
F
OH
12
38
FIGURE 2–11 Stereoselective electrophilic fluorination of the β-diketone 1 using Selectfluor. DCM,
Dichloromethane; KHMDS, potassium hexamethyldisilazide (KN(SiMe3)2); TBS, tert-butyl(dimethyl)silyl; TFA,
trifluoroacetic acid.
derived from the 1,3-dicarbonyl compound 36 gives the α-fluorinated compound 37 in high
yields and diastereoselectivity (diastereomeric ratio . 20:1) (Fig. 211).33
Enantioselective fluorination of β-carbonyl esters, using chiral ((S)-BINAP)Pd(II)-based
catalysts, gives access to the chiral α-fluoro carbonyl compounds. The β-amidoester 39 upon
electrophilic fluorination, using NFSI, in the presence of the (S)-BINAP-Pd(OTf)2, gave 44%
ee of the fluorinated compound 40 (Fig. 212). Chiral enrichment of this compound through
chiral HPLC gives 99% ee. The α-fluorinated compound 41 is an intermediate for the synthesis of a selective spleen tyrosine kinase (SYK) inhibitor 43. SYK proteins are nonreceptor
kinases, which mediate diverse cellular functions, including cell proliferation, differentiation,
and phagocytosis. The SYK inhibitors, therefore, are of pharmaceutical interest for a number
of pathologies, including rheumatoid arthritis, B-cell lymphoma, asthma, and nasal rhinitis.34
Through further improvements in the synthetic design, multikilogram scale synthesis
of compound 41 could be achieved with high enantiomeric purity. Thus fluorination of
(1)-menthol ester 42, (synthesized, in situ, from the ethyl ester 39) in the presence of
(S)-BINAP-Pd(OTf)2 (serves as a matched stereochemical combination), gave up to 100%
diastereoselectivity for the desired α-fluorinated ester, which was then reduced to the
primary alcohol 41 using borane-dimethyl sulfide (BH3-SMe2).34
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
O
1. ((S)-BINAP)Pd(OTf) 2
2,6-lutidine
NFSI, EtOH, 0 °C, 18 h
O
EtO
NH
O
F
O
F
BH 3 -SMe 2
NH
EtO
53
O
NH
HO
2. Chiral HPLC
41
40
39
59% (44% ee; 99% ee after HPLC)
O
1. (S)-BINAP-Pd(OTf) 2
2,6-lutidine
NFSI, EtOH
O
F
O
HO
NH
Multiple steps
NH
O
2. BH 3-SMe 2
41
42
68%; up to 100% ee for the first step
F
HN
NH
N
N
N
N
43
(SYK inhibitor)
FIGURE 2–12 Enantiomeric fluorination of β-amido esters toward the synthesis of a fluorinated SYK inhibitor. SYK,
Spleen tyrosine kinase.
2.4 Electrophilic fluorination in the synthesis of α-fluorinated
amino acids
Fluorinated, noncanonical amino acids, when incorporated into the peptides and proteins,
alter their physicochemical and biochemical properties, including pharmacokinetics, metabolic stability, and enhance thermal stabilities. Most of the fluorinated amino acids that have
been used in protein engineering and material design are those containing fluoroalkyl(aryl)
side chains, such as β-fluoroalanine [(fluoromethyl)glycine; 44], β,β-difluoroalanine [(difluoromethyl)glycine; 45], β,β,β-trifluoroalanine (trifluoromethylglycine; 46), 5,5,5,50 ,50 ,50 -hexafluoroleucine (47), (2-fluorophenyl)alanine (48), and (4-trifluoromethyl)phenylalanine (49)
(Fig. 213).3537
Synthesis of α-fluoro amino acids, however, is challenging, as these compounds are too
unstable to isolate, because the strong electron-releasing adjacent amino group brings about
rapid defluorination and thereby formation of the imines, which are hydrolyzed to the
α-keto carboxylic acids. It was, however, possible to synthesize the N-phthalimido-protected
α-fluoroglycine and its derivatives.38 The decreased basicity of the amino group in
these amino acid derivatives disfavors the elimination of the fluoride anion. Thus bromofluorination of the N-phthalimido-protected dehydroalanine (50), using Olah’s reagent
[pyridinium polyhydrogen fluoride (PPHF)] and 1,3-dibromo-5,5-dimethylhydantoin, gave
54
Organofluorine Chemistry
O
F2 HC
O
O
HF2C
OH
NH2
44
OH
F3C
OH
NH2
NH2
45
46
F
O
F 3C
O
OH
OH
NH2
CF3 NH2
47
48
O
OH
NH2
F3 C
49
FIGURE 2–13 Structures of selected fluorinated, noncanonical amino acids.
O
O
O
N
O
DBH, PPHF (9:1 HF-Py)
O
Me
N
DCM, RT, 23 h
O
50
O
O
Me
F
Br
51
FIGURE 2–14 Synthesis of N-protected α-fluoro-β-bromo glycine ester.
the β-bromo-α-fluoro alanine derivative (51) (Fig. 214). Deprotection of the phthalimido
group, however, results in degradation of the product.
An improved strategy for the preparation of the α-fluorinated amino acid derivatives was
developed by Molander and coworkers, using the photoredox catalysis and N,N-di(Boc)-protected dehydroalanine esters.14 Photoredox-catalyzed fluoroalkylation of dehydroalanine, using
Selectfluor and alkyltrifluoroborates (precursors for the alkyl radicals), in the presence of the
mesitylacridinium (MesAcr) organo-photocatalyst, gives α-fluoroninated amino acids in high
yields. Various alkyl, alkoxyalkyl, and aminoalkyl α-fluoroalanines could be synthesized using
the corresponding alkyltrifluoroborates as the source of the nonstabilized, reactive alkyl radicals (Fig. 215). A possible mechanism of the reaction involves the formation of alkyl radicals
from the corresponding alkyltrifluoroborates, catalyzed by the highly oxidizing photo-excited
mesitylacridinium salt (Mes Acr1; Ered 5 12.06 V vs SCE). Addition of these alkyl radicals
to the dehydroalanine gives the α-amino-radical species (52), which abstracts fluorine atom
from the Selectfluor to give the α-fluoro-α-amino acids. The MesAcr1 photocatalyst is regenerated through its redox reaction with the Selectfluor-derived radical cation 53.
2.5 Electrophilic fluoroalkylation
Trifluoromethyl moiety is one of the most frequently used structural motifs in the drug
design. Incorporation of the CF3 moiety into pharmaceutical compounds enhances metabolic stability, bioavailability, and in some cases shows improved enzymesubstrate
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
55
Me
R
RBF3K (2 equiv)
CH2
Boc
N
Boc
Selectfluor (4 equiv)
OCH 2 Ph
MesAcr (5 mol%)
DMF (0.1 M), blue LEDs, RT
Dehydroalanine
(N,O-protected)
OCH 2 Ph
Me
Me
Boc O
α-fluoro- α-amino acid
(N,O-protected)
+
Boc O
F
N
N
Me BF
4
R = primary or secondary alkyl,
α -alkoxymethyl, α-aminomethyl
Selected examples:
Mes–Acr +
Br
Ph
O
S
O
NH
O
Boc
F
N
OCH 2 Ph
Boc
Boc O
F
N
OCH 2 Ph
F
Boc
N
OCH 2 Ph
Boc O
Boc O
Boc
F
N
OCH 2 Ph
Boc
Boc O
F
N
OCH2 Ph
Boc O
62%
81%
32%
82%
72%
Mechanistic outline:
N
Cl
BF4
R
N
Mes–Acr +
Boc
54
Blue LEDs
F
N
OCH2 Ph
Boc O
α-fluoro- α-amino acid
Cl
N
N
Mes–Acr +*
Mes–Acr
53
Cl
N
N
F
2BF 4
Selectfluor
R
RBF3– K+
2BF 4
R
CH2
Boc
N
OCH 2Ph
Boc O
Boc
N
Boc O
Dehydroalanine
OCH 2Ph
52
FIGURE 2–15 Selectfluor-mediated synthesis of α-fluoro-α-amino acid derivatives through photoredox catalysis.
interactions. Some of the widely prescribed drugs, such as efavirenz, an anti-HIV drug, are
trifluoromethylated compounds (Fig. 216).
2.5.1 Reagents for electrophilic trifluoromethylation
Umemoto’s and Togni’s reagents are widely used in the trifluoromethylation (or perfluoroalkylation) of a variety of strong as well as weak nucleophiles (Fig. 217).4,5 Due to the
56
Organofluorine Chemistry
O
F 3C
F3C
Cl
O
N
H
Fluoxetine
(antidepressant)
N
O
N
H
CF 3
N
H
O
Cotoran
(herbicide)
Efavirenz
(anti-HIV)
FIGURE 2–16 Structure of selected trifluoromethylated pharmaceuticals and a herbicide.
F
S
CF3
F
F
F
S
CF3
BF4–
(or –OSO2 CF3 )
Umemoto's reagents
–
OSO2 CF3
F
F
S
–
CF3 OSO2 CF3
Umemoto's second-generation reagents
O
O
I
CF 3
O
I
CF 3
Togni's reagents
FIGURE 2–17 Structures of Umemoto’s and Togni’s reagents.
broad range of reactions achievable using these reagents, only a cursory coverage of these
reagents is provided in this chapter.
Umemoto’s second-generation reagents, consisting of 2,8-difluoro- and 2,3,7,8-tetrafluoro-dibenzothiophenium salts, are recyclable reagents and could be synthesized in a onepot process.4 These reagents are also thermally more stable than the first-generation
Umemoto’s reagents. As in the case of the Umemoto’s first-generation reagents, these
improved-version reagents can be used in the electrophilic trifluoromethylation of a variety
of nucleophiles. Trifluoromethylation of 1,3-dicarbonyl enolates, alkynes, thiols, and
FriedelCrafts reactions of aromatics, such as indoles, gives the corresponding trifluoromethylated compounds in good yields. Phosphines and arylsulfonyl anions are also trifluoromethylated using Umemoto’s reagents, under mild conditions (Fig. 218).4
Similarly, Togni’s reagents achieve FriedelCrafts trifluoromethylation of aromatics
and are effective reagents for the trifluoromethylation of 1,3-dicarbonyl compounds,
silylenol ethers, thiols, phosphines, amines, and alcohols (Fig. 219). Togni’s reagents
are used in the synthesis of the pharmaceutically interesting compounds, such as S-trifluoromethylated coenzyme A, S-trifluoromethylated nucleoside analogs, and anti-HIV
agents.5
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
PhSO2 Na
57
PhSO 2CF3
DMF, RT
70%
O
H
O
Me
F 3C
O
F
F
Me
NaH, DMF
–50 °C to RT
F
F
S
–
CF3 OSO2 CF3
O
88%
N
H
CF3
N
H
69%
DMF, RT
Umemoto's second generation
reagent
H
CF3
TsO
TsO
CuCl,s-collidine
DMAC, 30 °C
65%
SH
Br
Et 3 N, DMF, RT
SCF3
Br
67%
FIGURE 2–18 Electrophilic trifluoromethylations using Umemoto’s reagent.
2.5.2 NHC-catalyzed electrophilic trifluoromethylation
N-Heterocyclic carbenes (NHC)-catalyzed electrophilic trifluoromethylations of α-chloro
aldehydes, using Togni’s reagent, gives the corresponding α-trifluoromethyl esters.39 A wide
range of substituents, including terminal alkyne, olefin, chloro, cyano, azido, ester, and ether
substituents, are tolerated in this reaction. Using a chiral NHC, moderate to good enantioselectivities were obtained. The NHC catalysis is rationalized as follows. The aldehyde, in
reversible equilibrium with the NHC, forms the enol 58. 1,5-diazabicyclo[4.3.0]non-5-ene
(DBN)-mediated dehydrohalogenation of 58 forms the enolate 59, which abstracts the electrophilic “CF31” from the Togni’s reagent to give 60. Methanolysis of 60 then gives the
α-trifluoromethyl ester (57), regenerating the NHC catalyst (Fig. 220).39
2.5.3 Electrophilic difluoromethylation
The gem-difluoromethylene moiety (CF2) is isopolar and isosteric with carbonyl (CQO)
and hydroxymethyl (CH2OH) moieties. The CF2 moiety provides enhanced lipophilicity
and metabolic stability to the pharmaceutical candidates, and relatively high thermal
and mechanical stability to the materials. Therefore, it is a key structural element in the
design of pharmaceuticals, as well as functional materials. Prakash and coworkers have
designed an S-(difluoromethyl)diarylsulfonium tetrafluoroborate for the electrophilic
58
Organofluorine Chemistry
N
H
R
CF3
O
N
H
R
O
O
OR
O
OR
CF3
RSH
RSCF3
CoA-SH
CoA-SCF3
O
O
O or
I
CF3
O
NH
I
CF3
O
N
O
HO
NH
Togni’s
reagents
O
N
OH
SH
O
HO
O
OH
PH2
SCF3
R
P
CF3
DBU
ROH
Zn(NTf 2) 2
N
H
N
R = H (1 equiv of Togni's reagent)
R = CF3 (2 equiv of Togni's reagent)
ROCF3
N
CF3
N
Cl
O
R
OH
S
N
N
O
Anti-HIV agent
FIGURE 2–19 Electrophilic trifluoromethylations using Togni’s reagents.
difluoromethylation of tertiary amines, phosphines, and sulfonate anions to give their
corresponding N-, P-, and O-difluoromethylated products (Fig. 221).40 A related
S-(fluoromethyl)diarylsulfonium tetrafluoroborate is effective in the monofluoromethylation of C, S, O, N, and P nucleophiles.41
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
O
O
R
Cl
55
56
R
N N
O
O
I
CF3
+
H
NHC (20 mol%)
R
DBN (2 equiv)
MeOH/DCM (1:2), 0 °C, 2 h
OMe
N
CF3
57
Selected examples:
MeO 2 C
O
O
59
NHC
CF3
OMe
OMe
CF3
MeO
CF3
N
Boc
75%
45%
51%
Mechanistic outline:
O
R
O
R
N N
OMe
CF3
R
H
Cl
N
57
NHC
MeOH
OH
O
R
N
R
R
N
CF3
R
N
N
Cl
N
N
58
60
O
DBN
O
OH
R
N
R
I
N
O
56
O
I
CF3
DBN.HCl
N
59
FIGURE 2–20 NHC-catalyzed electrophilic trifluoromethylation of α-halo aldehydes.
Shen and coworkers have achieved O-trifluoromethylation of alcohols using difluoromethyl-(4-nitrophenyl)-bis(carbomethoxy) methylide sulfonium ylide (Fig. 222). This
sulfonium ylide, as an electrophilic difluoromethylating reagent, was synthesized through
the Rh-catalyzed reaction of dimethyl diazomalonate with 4-nitrophenyl(difluoromethyl)
thio ether.42 Biologically interesting compounds such as nerol, vitamin-D3, and stigmasterol could be transformed into their difluoromethoxy derivatives in moderate to good
yields.
60
Organofluorine Chemistry
R1
R2 N
R3
CF2H
S
BF4
R1
R 2 N CF2H
R3
BF4
R1
R2 P
R3
R
O
S
O
R1
R 2 P CF2H
R3
BF4
M+
O
R
O
S
O
O
CF2 H
FIGURE 2–21 Electrophilic difluoromethylation of tertiary amines, phosphines, and sulfonate anions.
CO2 Me
MeO 2C
S
CF2 H
ROH
S
N2
O2 N
CO2 Me
MeO 2C
CF2 H
[Rh]
ROCF2 H
O2 N
R = alkyl
Selected examples:
HF2 CO
HO
82%
Nerol
OH
OCF2H
62%
Vitamin-D3
Me
Me
Me
H
Me
Me
Me
H
H
H
H
HO
HF2 CO
51%
Stigmasterol
FIGURE 2–22 Electrophilic O-difluoromethylation of alcohols.
H
H
H
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
61
2.6 Electrophilic trifluoromethylthiolation and
trifluoromethoxylation
Trifluoromethylthio group (SCF3) is comparable to OCF3 or CF3 groups in terms of enhancing lipophilicity of compounds. Hansch lipophilicity parameters (π) for SCF3 (1.44),
OCF3 (1.04), and CF3 (0.88) substituents indicate that SCF3 moiety has relatively greater
lipophilicity-enhancing effect as compared to the OCF3 and CF3 substituents.43,44
The Hansch lipophilicity parameter of the SCF3 moiety is comparable to SeCF3 moiety
(1.29), a less commonly used substituent in medicinal chemistry.45 The relatively lower
electron-withdrawing effect of SCF3 (EN 5 2.44) moiety, as compared to OCF3 (EN 5 3.50)
moiety,46 combined with its relatively higher steric crowding, can be used in fine-tuning
the stereoelectronic effects of the compounds in drug discovery. Compounds with OCF3
and SCF3 substituents have found applications as pharmaceuticals and agrochemicals
(pharmaceuticals: riluzole, sonidegib, tiflorex, toltrazuril; agrochemicals: indoxacarb,
flurprimidol, triflumuron, and flucarbazone; veterinary drugs: monepantel and toltrazuril
(Figs. 223 and 224).7,43
2.6.1 Synthetic methods for O-trifluoromethylation
O-Trifluoromethylation of phenols can be achieved using Umemoto’s reagent 61 or Togni’s
reagent.43 Alternatively, the oxidative decarboxylative fluorination of aryloxy(difluoromethyl)
carboxylic acids, using xenon difluoride (XeF2), gives the corresponding O-trifluoromethyl
phenolic derivatives in moderate yields (Fig. 225).47
F3 CS
N
H 3C
N
O
Monepantel (Zolvix)
(used for the veterinary treatment of
gastrointestinal nematodes)
N
N
H
H
N
O
F3 CS
S
NH2
N
N
H
CH3
CH3
Tiflorex (anorectic)
SCF3
O
Toltrazuril (used for veterinary treatment
of coccidiosis)
SCF3
H 3C
O
O
O H 3 C CN
O
N
H
F
F
F
H 3C
N
O
N
SCF3
O
CH3
SCF3 analog of riluzole
Toltrazuril (antiprotozoal agent)
FIGURE 2–23 Selected examples of SCF3-containing pharmaceuticals and veterinary medicines.
62
Organofluorine Chemistry
CH 3
H 3C
HO
O
F3 CO
F 3CO
S
N
CH 3 O
NH2
N
N
F3CO
S
O
N
H
O
N
O
N
O
O
Cl
N
H
N N
Cl
CH3
N
CH3
Flucarbazone
(herbicide)
OCF3
OCH3
OCF3
O
N
H
N
Flurprimidol
(plant growth regulator)
Sonidegib
(antineoplastic agent)
O
OCF3
O O
CH3
N
N
H
Riluzole
(for the treatment of amyotrophic
lateral sclerosis)
CH3
O
Triflumuron
(insecticide)
N
OCH 3
O
Indoxacarb
(insecticide)
FIGURE 2–24 Selected examples of OCF3-containing pharmaceuticals and agrochemicals.
BF 4
OH
O
CF3
OCF3
61
(iPr) 2 NEt
62
75%
O
Ar
O
F F
OH
XeF2 (1 equiv)
CDCl3
Ar
O
F
F F
42%–77%
FIGURE 2–25 Electrophilic O-trifluoromethylation of phenols and aryloxy(difluoromethyl)carboxylic acids.
The trifluoromethoxy compounds, however, can be more conveniently synthesized
through nucleophilic substitutions of alkyl halides, using the in situgenerated silver
trifluoromethoxide (CF3OAg) (Fig. 226) (see Chapter 1: Nucleophilic reactions in the
synthesis of organofluorine compounds).48 Thus the glycosyl bromide 63, upon reaction with
trifluoromethyl benzoate, in the presence of AgF, gives the trifluoromethoxy glycoside 64,
with inversion of configuration.
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
63
O
OH
OH
OCF3
O
HO
HO
OH
O
HO
HO
AgF, MeCN, RT
Br
OCF3
OH
84%
63
64
FIGURE 2–26 Trifluoromethoxylation of glycosyl halides through the in situ formed AgOCF3 reagent.
O
O
I
N
N SCF3
N SCF3
O
SCF3
O
O
O
S
N SCF3
SCF3
O
O
67
66
65
(Haas’ reagent)
(Munavalli’s reagent)
SO2 CF3
(Shibata’s reagent)
(Billard and Langlois’
reagent)
69
(Lu and Shen’s
reagent)
(Shen’s reagent)
SCF3
I
O
OSCF3
Ar
S
IPh
70
68
I
O
N
SCF3
O
71
72
(Buchwald’s reagent)
(Billard’s reagent)
73
(Lu and Shen’s reagent)
FIGURE 2–27 Selected commercially available trifluoromethylthiolating reagents.
2.7 Synthetic methods for trifluoromethylthiolation
2.7.1 Reagents for electrophilic trifluoromethylthiolation
A number of electrophilic trifluoromethylthiolation reagents, such as compounds 6573,
are commercially available (Fig. 227).8 Because of the pharmaceutical and agrochemical
importance of the trifluoromethylthio compounds and the possibility of achieving late-stage
trifluoromethylthiolations, there is a resurgence of interest in developing efficient synthetic
methods for the trifluoromethylthiolations. Many of the commercially available trifluoromethylthiolating agents, such as Haas's reagent (65),49 Munavalli’s reagent (66),50 Billard
and Langlois' reagent (67),51 Shen’s reagent (69),52,53 and Billard’s reagent (72),54 are based
on the trifluoromethylsulfenamide moiety. Shibata has developed the hypervalent iodonium
ylide reagent 70,55 and Lu and Shen have developed the reagents 68 and 73.52,53 Buchwald
and coworkers56 developed the reagent 71, the reagent containing the OSCF3 moiety.
Among these reagents, Munavalli's- and Billard's reagents have found relatively wide
applications.
64
Organofluorine Chemistry
O
O
N
O
Li +
O
N
SCF3
O
O
O
N Cl
CF3 SCu
N SCF3
RNH2
RNHSCF3
or CF3SAg
O
O
O
Munavalli's reagent
O
R
H
Cl
R
H
Cl
O
N
O
K+
CF3 SCl
H
SCF3
B(OH)2
O
R
H
CuI
R
SCF3
CuI (10 mol%)
SCF3
FIGURE 2–28 Electrophilic trifluoromethylthiolation of carbonyl compounds, amines, alkynes, and arylboronic acids.
2.7.1.1 Munavalli’s reagent
The synthesis of the Munavalli’s reagent [N-(trifluoromethylthio)phthalimide] can be
achieved by the reaction of potassium phthalimide with trifluoromethylsulfenyl chloride
(highly toxic), or through reaction of the N-chlorophthalimide with CF3SCu or CF3SAg
(relatively nontoxic), in large quantities. This reagent is moisture- and air-stable and thus
is convenient to handle. Munavalli’s reagent serves as a convenient reagent for the electrophilic N-trifluoromethylthiolation of amines, α-trifluoromethylthiolation of carbonyl
compounds,7,50,57 and trifluoromethylthiolation of arylboronic acids and terminal
alkynes.7 Munavalli’s reagent serves as a source of the electrophilic “CF3S1” in reactions
with nucleophilic reagents, such as amines, alkynes, and α-carbanions, derived from the
carbonyl compounds. N-(trifluoromethylthio)succinimide can also be used for these trifluoromethylthiolations (Fig. 228).58
2.7.1.2 Asymmetric trifluoromethylthiolation
N-Acyl derivatives of the Evan’s chiral oxazolidinones (74) can be diastereoselectively trifluoromethylthiolated at the α-carbon using Munavalli’s reagent as the electrophilic trifluoromethylating reagent at low temperatures (Fig. 229). This reaction proceeds in two steps,
involving lithium hexamethyldisilazide (LiHMDS)mediated deprotonation of the acidic
α-hydrogen, followed by electrophilic trifluoromethylthiolation by the (N-SCF3)-phthalimide
(Munavalli’s reagent) to give 75. These reactions proceed with 87%100% diastereomeric
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
O
O
O
O
R
N
1. LiHMDS (1.2 equiv)
R
N
R
O
N SCF3
SCF3
2. Munavalli's reagent
O
(Munavalli's reagent)
THF, –78°C, 7 h
74
OH
[H]
O
SCF3
O
65
75
76
R = e.g., Me, benzyl, isopropyl, n-pentyl
dr 87:13–100:0
Yields: 60%–85%
FIGURE 2–29 Electrophilic α-trifluoromethylthiolation of chiral N-acyl oxazolidinones.
selectivity. Reductive cleavage of the oxazolidinone moiety gives the corresponding 2-(trifluoromethylthio)-primary alcohols (76) in high enantiomeric purity (up to 100% ee).
Hydrolysis of the oxazolidinone 75 to the corresponding carboxylic acids, on the other hand,
resulted in partial racemization at the α-carbon.59
2.7.2 Billard’s reagents
The trifluoromethanesulfenamides 77, 78, and 79 (Billard’s reagents) can be used for the trifluoromethylthiolation of amines, thiols, terminal alkynes, Grignard reagents, and
α-trifluoromethylthiolation of carbonyl compounds (Fig. 230).9,54,6063 The sulfonamide
reagent 79 is more reactive than the first-generation reagents 77 and 78 in these reactions.62
Billard’s reagent 78 was used for the synthesis of N-trifluoromethylthiolated analog of imipramine, an antidepressant.64
2.7.2.1 Synthesis of the Billard’s reagents
The synthesis of the Billard’s reagents is achieved through the reaction of primary amines
with the reagent combination of CF3TMS and diethylaminosulfur trifluoride (DAST) in the
presence of a tertiary amine, such as triethylamine or N,N-(diisopropyl)ethylamine (Hunig’s
base, DIEA). Using this convenient synthetic method, a variety of aromatic and aliphatic
amines give the corresponding N-trifluoromethylthiolated products 81 (R 5 alkyl/aryl) in
good yields.65 A probable mechanism for this reaction sequence involves reaction of the tertiary amine with DAST to give the intermediate ammonium salt 82, which is in equilibrium
with compound 83 (not isolated). The latter compound 83 then reacts with the CF32 (generated through the fluoride ioninitiated reaction of CF3TMS) to give the intermediate compound 84. Subsequent steps, involving nucleophilic substitution of the fluoride ion in (84) by
the primary amine, followed by the fluoride-induced elimination of N-ethylethanimine (80)
gives the N-trifluoromethylthiolated amine 81 (Fig. 231).
2.7.2.2 Trifluoromethylthiolation of alkynes and Grignard reagents
The reaction of the terminal alkynes with the Billard’s reagent [PhN(Me)SCF3], in the presence of catalytic quantities of LiHMDS, gives the corresponding trifluoromethylthiolated
alkynes in high yields. The latter compounds serve as precursors for the Cu(I)-catalyzed
66
Organofluorine Chemistry
H
N
Me
N
SCF3
SCF3
O
O
S
SCF3
Me
Me
77
N
78
79
O
H
R
O
77 , 78 ,
or 79
SCF3
cat. LiHMDS
R
N
H
cat. TMSCl
H
N
R
SCF3
R′
RMgCl
SCF3
R
N
R′
SCF3
RSCF3
N
H
N
N SCF3
Me
SCF3 -Imipramine
(antidepressant)
FIGURE 2–30 Billard’s reagents for the trifluoromethylthiolations.
alkyneazide cycloaddition reactions (click reactions) for the synthesis of 1,2,3-triazoles
(Fig. 230).61 Only a catalytic amount of LiHMDS is required for these reactions, as the conjugate base formed in the catalytic cycle serves as a base for the deprotonation of the alkyne
in the subsequent steps.
The trifluoromethylthiolation of the Grignard reagents gives the corresponding trifluoromethylthiolated products in moderate yields and the yields are dependent on the choice of
the sulfenamide or sulfonamide reagents. The use of the sulfonamide reagent improves
yields of these reactions (Fig. 232).
2.7.3 Diethylaminosulfur trifluoridemediated
trifluoromethylthiolation of silylenol ethers and β-naphthols
β-Naphthols (e.g., 89) and enolsilyl ethers of ketones (e.g., 93) are trifluoromethylthiolated
upon reaction with CF3TMS and DAST, using a procedure similar to that of N-trifluoromethylthiolation of primary amines,65 to give their corresponding α-trifluoromethylthiolated
β-naphthols (e.g., 90), and α-trifluoromethylthiolated ketones (e.g., 94), respectively
Chapter 2 • Electrophilic reactions in the synthesis of organofluorine compounds
+
CF3SiMe 3
Et
N
Et
1. Et3N or DIEA (1 equiv)
SF3
R
2. RNH2
(DAST)
SCF3
81
H
N
Et
80
Some examples:
H
N
H
N
67
H
N
SCF3
H 3C
H
N
SCF3
Cl
H
N
SCF3
F
90%
80%
H
N
SCF3
SCF3
CH 3
75%
75%
75%
+F
Me
F
Me
F C Si
Me
F
Mechanistic outline:
Et
Et
Et
N
S
F
F
R3 N
Et
F
S
F
NR3
82
(DAST)
H
Et
N
F
N
H
F
NH2 R
S
RNH2
Et
F
CF3
Et
N
F
Et
F
S
F
F3 C
Et
N
S
F
84
F
F
Me
F
Me
F C Si
Me
F F
83
R 3N
R3 NH+ F
H
Et
N
H
F
NHR
R
S
F
CF3
H
N
SCF3
81
H
+ HF
Et
N
80
FIGURE 2–31 Synthesis of Billard’s reagents [N-(alkyl)trifluoromethanesulfenamides] and a mechanistic outline.
(Fig. 233).66 The proposed mechanism for these trifluoromethylthiolations involves the formation of the reactive intermediate 95 in equilibrium with DAST. The reaction of 95 with the
trifluoromethyl anion, derived from the fluoride anion activation of CF3TMS, gives diethylamino(trifluoromethyl)sulfur difluoride 96. Electrophilic trifluoromethylthiolation of enolates
derived from enolsilyl ethers and β-naphthols with the intermediate 96 then gives the
observed products, such as 90 and 92, in a series of steps, analogous to that of N-trifluoromethylthiolation of amines, as shown in Figure 231.65
68
Organofluorine Chemistry
H
SCF3
LiHMDS (10 mol%)
MeO
CH3
N
Ph
SCF3
THF, 0 °C
85
DMF,60 °C, 4 h
MeO
86
SCF3
MeO
87
75%
54%
LiHMDS
(or 4)
N N
NH
NaN 3 (1.5 equiv)
Li
MeO
CH3
N
Ph
SCF3
Ph
CH3
N
Li
88
MgCl
CH3
N
Ph
SCF3
THF, 0 °C
SCF3
86%
CH3
N
Ph
SCF3
THF, 0 °C
MgCl
SCF3
10%
O
O
S
MgCl
Me
N
SCF3
Me
SCF3
THF, 0 °C
63%
FIGURE 2–32 Trifluoromethylthiolation of terminal alkynes and Grignard reagents.
2.8 Difluoromethylthiolation
Similar to the trifluoromethylthiolated compounds, difluoromethythiolated organic compounds have found applications as pharmaceuticals or agrochemicals. Flomoxef is a
cephalomycin-based antibiotic, used in postoperative prophylaxis. It is active against
methicillin-resistant and susceptible Staphylococcus aureus and is active against other bacteria, including Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.67 Pyriprole is
used as a veterinary medicine for treating tick infections in dogs (Fig. 234).68
Lu, Shen, and coworkers have developed synthetic methods for the difluoromethylthiolation of amines, thiols, alkynes, and enolates of carbonyl compounds and for the difluoromethylthiolation of aromatic compounds.6 They synthesized the CF2 analog of the
Munavalli’s reagent, 98, through the reaction of the N-(chlorothio)phthalimide (97) with
the N-heterocyclic carbene(SIPr)stabilized difluoromethyl-silver(I) [SIPrAg(CF2H)].
SCF3
OH
DAST/CF3TMS
OH
DIPEA,DCM
–60°C–RT, 18 h
89
90
O
OSiMe3
SCF3
DAST/CF3TMS
DIPEA,DCM
–60°C–RT, 18 h
91
H 3C
92
H 3C
CH3
H 3C
H 3C
H 3C
H 3C
H 3C
H
H
CH3
DAST/CF3TMS
H
H 3C
F3 CS
H
H
DIPEA,DCM
Me 3 SiO
H
O
–60°C, 4 h
93
(silylenol ether of
4-cholesten-3-one)
94
55% (dr: 9:1)
Mechanistic outline:
Et
Et
N
S
F
DAST
F
Et
F
Et
N
–Me 3 SiF
F
F
S
Et
F C SiMe3
F
F
Et
N
F
S
F
F3 C
F
96
95
OSiMe3
O
91
SCF3
+
Multiple
steps
Et
92
HF
+
N
FIGURE 2–33 Electrophilic trifluoromethylthiolation of enolsilyl ethers and a mechanistic outline.
OH
O
N N
N
N
S
N
OO
N
OH
O
H
N
OH
Me
Flomoxef
(a cephalomycin antibiotic)
H
F
S
F
N
F
F3 C
F
S
HN
Cl
N
N
Cl
Pyriprole
(veterinary medicine for
tick infections)
FIGURE 2–34 Difluoromethylthiolated compounds used in pharmaceutical and veterinary applications.
70
Organofluorine Chemistry
O
N SCl
97
O
B(OH) 2
SCF2 H
i-Pr i-Pr
N
Cat. CuI and bpy
i-Pr
Li2 CO3 , diglyme
60°C, 15 h
99
N
i-Pr
Ag(CF2 H)
SIPrAg(CF 2H)
O
O
CO2 R
O
SCF2H
CO2R
100
N SCF2 H
K2CO3 , DCM
RT, 24 h
98
H
N
R
R'
Toluene, 80°C
14–24 h
SCF2H
R
O
R
N
R'
103
H
R
SCF2H
Cat. CuTc and bpy
Li2 CO3 , diglyme, 60°C, 15 h
SCF2 H
TMSCl
N
H
101
N
H
104
RSH
RSSCF2H
ClCH2CH 2Cl
80–120°C, 16 h
ClCH2CH 2Cl
80°C, 16–24 h
102
FIGURE 2–35 Difluoromethylthiolation reactions using the N-(difluoromethyl)phthalimide. bpy, Bipyridine; CuTc,
copper(I)-thiophen-2-carboxylate; DCM, dichloromethane; TMSCl, trimethylsilyl chloride.
This reagent is shelf-stable, has similar reactivity as for the Munavalli’s reagent, and is a powerful electrophilic difluoromethylthiolation reagent. A wide range of aryl and vinylboronic
acids, alkynes, amines, thiols, β-ketoesters, oxindoles, electron-rich aromatics, such as
indole, pyrrole, isoxazole, and pyrazole, could be difluoromethylthiolated with this reagent
under relatively mild conditions (Fig. 235). Electron-rich aromatics, such as indoles and
pyrroles, undergo electrophilic aromatic substitution with this reagent in the presence of catalytic amounts of the mild Lewis acid, trimethylsilyl chloride (TMSCl). Aryl- and vinylboronic
acids and terminal alkynes undergo Cu(I)-catalyzed trifluoromethylthiolation with 98 in high
yields. Relatively more nucleophilic compounds, such as amines, thiols, β-ketoesters, and
oxindoles, react with 98, even in the absence of any organometallic catalyst.
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17. Fuchtner, F.; Steinbach, J. Efficient Synthesis of the 18F-Labeled 3-O-Methyl-6-[18F]Fluoro-L-DOPA. Appl.
Radiat. Isot. 2003, 58, 575578.
18. Wood, S. H.; Etridge, S.; Kennedy, A. R.; Percy, J. M.; Nelson, D. J. The Electrophilic Fluorination
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55745585.
19. Kaiser, H. B.; Naclerio, R. M.; Given, J.; Toler, T. N.; Ellsworth, A.; Philpot, E. E. Fluticasone Furoate
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Immunol. 2007, 119, 14301437.
20. Parri, G.; Nieri, D.; Roggi, M. A.; Vagaggini, B.; Celi, A.; Paggiaro, P. Fluticasone Furoate, Umeclidinium
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21. Malerba, M.; Nardin, M.; Santini, G.; Mores, N.; Radaeli, A.; Montuschi, P. Single-Inhaler Triple Therapy
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72
Organofluorine Chemistry
22. Cherniak, S.; Cyjon, R.; Ozer, I.; Nudelman, I. Process for the Preparation of 17-Desoxy-Corticosteroids
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23. Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF2H, a Hydrogen Bond
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24. Jin, Y.; Bhattasali, D.; Pellegrini, E.; Forget, S. M.; Baxter, N. J.; Cliff, M. J.; Bowler, M. W.; Jakeman, D. L.;
Blackburn, G. M.; Waltho, J. P. α-Fluorophosphonates Reveal How a Phosphomutase Conserves
Transition State Conformation Over Hexose Recognition in Its Two-Step Reaction. Proc. Natl. Acad. Sci.
U.S.A. 2014, 111, 1238412389.
25. Wnuk, S. F.; Bergolla, L. A.; Garcia, P. I., Jr. Studies Toward the Synthesis of α-Fluorinated Phosphonates
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Cyclization of the α-Phosphonyl Radicals. J. Org. Chem. 2002, 67, 30653071.
26. Yokomatsu, T.; Murano, T.; Akiyama, T.; Koizumi, J.; Shibuya, S.; Tsuji, Y.; Soeda, S.; Shimeno, H.
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27. Steiner, D. D.; Mase, N.; Barbas, C. F., III Direct Asymmetric α-Fluorination of Aldehydes. Angew. Chem.,
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29. Shibatomi, K.; Kitahara, K.; Okimi, T.; Abe, Y.; Iwasa, S. Enantioselective Fluorination of α-Branched
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30. Huang, H.; Meegalla, S. K.; Lanter, J. C.; Winters, M. P.; Zhao, S.; Littrell, J.; Qi, J.; Rady, B.; Lee, P. S.; Liu,
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31. Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Cinchona Alkaloid
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Int. Ed. 2008, 47, 41574161.
32. Souza, L. G.; de O. Domingos, J. L.; de A. Fernandes, T.; Renno, M. N.; Sansano, J. M.; Najera, C.; Costa,
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33. Sun, Y.; Zhou, R.; Xu, H.; Wang, D.; Su, X.; Wang, C.; Ding, Y.; Wang, L.; Chen, Y. Syntheses and
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34. Curtis, N. R.; Davies, S. H.; Gray, M.; Leach, S. G.; McKie, R. A.; Vernon, L. E.; Walkington, A. J.
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35. Huhmann, S.; Koksch, B. Fine-Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids.
Eur. J. Org. Chem. 2018, 2018, 36673679.
36. Marsh, E. N. G. Fluorinated Proteins: From Design and Synthesis to Structure and Stability. Acc. Chem.
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37. Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Synthetic Strategies to α-Trifluoromethyl and
α-Difluoromethyl Substituted α-Amino Acids. Chem. Soc. Rev. 2008, 37, 17271739.
38. Ulbrich, D.; Daniliuc, C. G.; Haufe, G. Halofluorination of N-Protected α,β-Dehydro-α-Amino Acid Esters
a Convenient Synthesis of α-Fluoro-α-Amino Acid Derivatives. J. Fluorine Chem. 2016, 188, 6575.
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39. Gelat, F.; Patra, A.; Pannecoucke, X.; Biju, A. T.; Poisson, T.; Besset, T. N-Heterocyclic Carbene-Catalyzed
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40. Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. New Electrophilic Difluoromethylating Reagent. Org.
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41. Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Olah, G. A. Direct Electrophilic Monofluoromethylation. Org.
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42. Zhu, J.; Liu, Y.; Shen, Q. Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated
Sulfonium Ylide. Angew. Chem., Int. Ed. 2016, 55, 90509054.
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Trifluoromethoxyarenes. Org. Lett. 2016, 18, 45704573.
48. Zhou, M.; Ni, C.; Zeng, Y.; Hu, J. Trifluoromethyl Benzoate: A Versatile Trifluoromethoxylation Reagent.
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49. Haas, A.; Moeller, G. Preparation and Reactivity of Tris(trifluoromethylselanyl)carbenium [(CF3Se)3C1]
and Trifluoromethylsulfanylacetic Acid Derivatives [(CF3S)3-nCXn(O)OR]. Chem. Ber 1996, 129,
13831388.
50. Munavalli, S.; Rohrbaugh, D. K.; Rossman, D. I.; Berg, F. J.; Wagner, G. W.; Durst, H. D.
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56. Vinogradova, E. V.; Mueller, P.; Buchwald, S. L. Structural Reevaluation of the Electrophilic Hypervalent
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59. Chachignon, H.; Kondrashov, E. V.; Cahard, D. Diastereoselective Electrophilic Trifluoromethylthiolation
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3
Free-radical reactions in the
synthesis of organofluorine
compounds
Chapter Outline
3.1 Introduction ................................................................................................................................... 75
3.2 Reagents for the free-radical trifluoromethylation ................................................................... 77
3.3 Decarboxylative fluoroalkylation ................................................................................................ 78
3.3.1 Decarboxylative trifluoromethylation ............................................................................... 78
3.3.2 Decarboxylate difluoromethylation................................................................................... 78
3.4 β-Amino-fluoroalkylation of alkenes .......................................................................................... 80
3.4.1 Cu(I)-catalyzed amino-fluoroalkylation ............................................................................. 80
3.4.2 Fe(II)-catalyzed azido- and amino-trifluoromethylation.................................................. 81
3.4.3 Ru(II)-catalyzed amino-fluoroalkylation ............................................................................ 81
3.5 Fluoroalkylation using sodium triflinate (Langlois reagent) .................................................... 82
3.5.1 Aromatic trifluoromethylation........................................................................................... 84
3.5.2 Hydro-trifluoromethylation of alkenes ............................................................................. 86
3.5.3 Trifluoromethylation of arylboronic acids ........................................................................ 86
3.5.4 Azido-fluoroalkylation of alkenes ..................................................................................... 88
3.5.5 Electrochemical oxy- and amino-trifluoromethylation .................................................... 91
3.5.6 Selective trifluoromethylation of proteins........................................................................ 93
3.6 Photoredox-catalyzed S-fluoroalkylation and arylation ........................................................... 94
3.7 Radical fluoroalkylation of enolates ........................................................................................... 96
References............................................................................................................................................. 98
3.1 Introduction
Fluoroalkylation, in particular, trifluoromethylation and difluoromethylation, plays a key
role in the design of pharmaceuticals. In some cases, trifluoromethyl moiety significantly
enhances metabolic stability and bioavailability of the drug candidates. Sitagliptin, an antidiabetic drug, for example, has an oral bioavailability of 76%, whereas its analog, with CF3
replaced by ethyl moiety (the lead candidate), has negligible oral bioavailability (2%)
(Fig. 31).1 The corresponding derivative with a CF2 moiety in place of the CF3 has 39%
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00003-1
© 2020 Elsevier Inc. All rights reserved.
75
76
Organofluorine Chemistry
F
F
NH2 O
F3 C
N
N
O
H
N
N
N
F
Cl
N
N
Me
CF3
N
Me
F
O
R
NH 2
CNP520
BACE-1 inhibitor; in AD prevention clinical trials
at Novartis
R = CF3; Sitagliptin (antidiabetic)
Oral bioavailability: 76% (R = CF3 );
39% (R = CF2H); 2% (R = Et)
Log D (pH 6.8) = 3.5
pKa = 7.2
F F
N
CF3
N
F3 C
Cl
O
O
O
N
H
CF3
HO
O
H
N
O
H3 C
H3 C
O
CH3
NH
N
CH3 O
Mefloquine
(antimalarial drug)
Efavirenz
(anti-HIV drug)
N
NH
O
O
O
HN S
F O CH3
F
F
Cl
N
F
O
H
N
Cl
Voxilaprevir
(antihepatitis drug)
O
O
Roflumilast
(NSAID for the treatment of COPD)
FIGURE 3–1 Selected pharmaceuticals containing CF3 or CF2H substituents.
bioavailability, substantially higher than that of the lead compound with the ethyl moiety.
Sitagliptin acts as an antidiabetic drug through its inhibition of dipeptidyl peptidase-4
(DPP-4), thereby increasing insulin secretion from the pancreatic beta cells. The DPP-4
inhibitory effect of the sitagliptin and its CF2H analog is also significantly higher than that
of the parent lead compound (i.e., with an ethyl group instead of CF3). The
trifluoromethyl-substituted aryl rings also may be involved in donor-acceptor ππ stacking
interactions with the side-chain aryl moieties at the enzyme active sites, thereby enhancing
their binding affinity. The fluoroalkyl moieties adjacent to the amino groups substantially
reduce the basicity of the amines, thereby enhancing the lipophilicity and cell permeability
of the compounds. Novartis’ CNP520, a drug candidate in clinical trials for the prevention
of Alzheimer’s disease, is a β-secretase-I (BACE-1) inhibitor. The effect of the two trifluoromethyl moieties in this drug candidate is to lower the basicity of the compound and
thereby to improve the lipophilicity.2,3 Many other pharmaceuticals or drug candidates in
clinical trials are trifluoromethyl- or, in some cases, difluoromethyl-containing compounds
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
77
(e.g., voxilaprevir, an antihepatitis drug; glecaprevir, an antiviral drug) (Fig. 31) (see
Chapter 5: Pharmaceutical applications of organofluorine compounds). Roflumilast, a nonsteroidal antiinflammatory agent, for treating chronic obstructive pulmonary disease, has a
difluoromethoxy moiety. Thus in addition to the fluoroalkyl-containing compounds, fluoroalkoxy (RFO)- and also fluoroalkylthio (RFS)-containing compounds, show pharmacological activities. Novel and increasingly more eco-friendly synthetic methods for the
fluoroalkylation are continually developed, and it is hoped that the drug discovery would
be accelerated through these improved synthetic methods. Fluoroalkyl moieties also impart
favorable properties to functional materials, and therefore fluoroalkylation and perfluoroalkylation are increasingly applied in the design of materials, including liquid crystals,
biomaterials, high energy materials, and surface-active agents (see Chapter 7: Materials
applications of organofluorine compounds).
A variety of commercially available electrophilic trifluoromethylating reagents, such
as Togni’s reagent and Umemoto’s reagent can be used in the free-radical fluoroalkylation
reactions, under photoredox conditions, or using transition metal catalysis. Organometallic
catalysis, for example, Ir(III) or Cu(I) catalysis, is used in the decarboxylative trifluoromethylations and difluoromethylations; these reactions proceed through the formation of the fluoroalkyl radicals as the reactive intermediates. Togni’s and Umemoto’s reagents can be used as
the sources of trifluoromethyl radicals, under the free-radical conditions (vide infra).
Langlois reagent has emerged as the convenient trifluoromethylating reagent for aromatic trifluoromethylations, oxidative- and azido-trifluoromethylation of alkenes, and dehalogenative
trifluoromethylation of aryl iodides. These reactions, when carried out under organometallic
or photoredox conditions, involve trifluoromethyl radical as the reactive intermediate.
Langlois reagent, thus, provides a cost-effective alternative for the trifluoromethylations over
the other conventionally used trifluoromethylating agents (vide infra). Langlois reagent also
is used for the selective trifluoromethylation of proteins under free-radical conditions. The
trifluoromethyl radical, generated from the Langlois reagent, selectively achieves trifluoromethylation of the electron-rich tryptophan residues, as compared to the histidine, tyrosine,
and phenylalanine residues (vide infra).
3.2 Reagents for the free-radical trifluoromethylation
Some of the widely used reagents for the electrophilic trifluoromethylation, for example,
Togni’s and Umemoto’s reagents (Fig. 32), can also generate trifluoromethyl radicals under
O
O
I
CF3
Togni's reagent I
O
I
CF3
Togni's reagent II
FIGURE 3–2 Structures of Togni’s and Umemoto’s reagents.
S
CF3
BF 4
Umemoto's reagent
78
Organofluorine Chemistry
the photoredox conditions or in the presence of organometallic catalysts. Thus in the freeradical trifluoromethylation reactions, reactive CF3 radicals could be generated through
single-electron transfer (SET) redox reactions of CF3I,46 Togni’s reagent,7,8 Umemoto
reagent,9 CF3SiMe3 (RuppertPrakash reagent), trifluoroacetic anhydride,10 and sodium triflinate (Langlois reagent).11,12 gem-Difluoromethylation and polyfluoroalkylation can similarly be achieved using the corresponding fluoroalkyl analogs of these reagents.47
3.3 Decarboxylative fluoroalkylation
3.3.1 Decarboxylative trifluoromethylation
Under free-radical conditions, through a combination of photoredox and copper/iridium
dual catalysis, carboxylic acids undergo decarboxylative trifluoromethylation by the Togni’s
reagent, used as a source of the trifluoromethyl free radical, to give their corresponding trifluoromethylated compounds.13 Togni’s reagent I was found to be superior to Togni’s
reagent II and Umemoto reagents in the decarboxylative trifluoromethylation of aliphatic
carboxylic acids. This synthetic method is of broad scope, tolerating a variety of functional
groups, such as olefins, alcohols, carbonyls, alcohols, heterocycles, and strained rings,
and therefore provides a means of late-stage functionalization of pharmaceuticals.
Pharmaceutically interesting compounds, such as fenbufen, ionazolac, and isoxepac, are decarboxylative trifluoromethylated through this Ir(III)/Cu(II) dual catalysis, in high yields. In
this dual catalysis mechanism, the Cu(II)OCOR is oxidized to Cu(III)OCOR by the photoexcited Ir(III) catalyst. Decarboxylation of the Cu(III)-carboxylate, followed by SET to the corresponding intermittent alkyl radical forms the [Cu(III)]R. The latter Cu(III) species, through
a series of steps involving Ir(II)-catalyzed reduction to Cu(II) species, followed by reaction
with the Togni's reagent, and reductive elimination, forms the RCF3 (Fig. 33). This onestep synthetic method thus gives access to trifluoromethyl analogs of the pharmaceuticals
through their late-stage modification.
A silver-catalyzed decarboxylative trifluoromethylation, with AgNO3 as the catalyst and
K2S2O8 as the oxidant, also involves formation of the transient alkyl radicals, from the carboxylic acids.14
3.3.2 Decarboxylate difluoromethylation
Cu(I)-catalyzed gem-difluoromethylation of redox-active carboxylic acid phthalimido esters
was accomplished under mild conditions, using the in situ generated Cu(I)(CF2H) reagent
[formed through transmetalation of [Zn(II)](CF2H) with Cu(I)Cl].15 The phthalimido esters of
the carboxylic acids can also be prepared in situ by the peptide coupling methods. This decarboxylative difluoromethylation reaction tolerates a variety of functional groups, including
halogens, aldehydes, esters, nitrogen- and oxygen-containing heterocycles, phenolic hydroxyls, and terminal alkynes (Fig. 34). The electron-withdrawing phthalimido moiety in the
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
F3 C
Ir[dF(CF3 )ppy](4,4' -dCF 3 bpy)PF 6 (1 ); 1 mol%
CuCN (20 mol%), bathophen (30 mol%)
O
R
OH
O
+
I
CF3
F3C
BTMG (0.5 Eq), EtOAc, H2 O
blue LEDs, 6 h
+
PF6
F
N
N
RCF3
79
F
F
Ir
N N
F3C
F
F3C
Togni’s reagent I
1
F 3C
Selected examples:
O
CF3
CF3
CF3
Ph N
O
N
F
O
Cl
(From fenbufen)
(From ionazolac)
(From isoxepac)
Mechanistic outline of Ir(III)/Cu(II) dual catalysis:
CO2
Ir(III) *
Ir(III)
[Cu(II)]OCOR
[Cu(II)] R
[Cu(III)]OCOR
SET
Ir(II)
[Cu(III)]R
[Cu(II)]R
O
[Cu(III)]R
OH
F
O
[Cu(II)]OCOR
[Cu(II)]
I
O
R = 4-fluoroethyl
I
CF3
OH
I
[Cu(III)]R(CF3)
CF3
O
I
F
FIGURE 3–3 Decarboxylative trifluoromethylation of carboxylic acids under photoredox and copper/iridium
catalysis. bathophen, 4,7-Diphenyl-1,10-phenanthroline; BTMG, 2-tert-butyl-1,1,3,3-tetramethylguanidine.
redox-active ester 2 lowers the redox potential of the carboxy moiety. The Cu(I)(CF2)H,
through a SET to the redox-active ester 2, gives the transient carboxy radical (R0 CO2•), spontaneous decarboxylation of which forms the corresponding alkyl radical (R0 •). The Cu(II) species 5, through a subsequent single-electron redox reaction with the alkyl radical (R0 •), forms
the high-valent Cu(III) intermediate (6), which undergoes reductive elimination to give the
difluoromethylated product 3, regenerating the Cu(I) catalyst for further propagation of the
catalytic cycle.15
80
Organofluorine Chemistry
Cl
Cl
O
Cl
O
O
O
OH
N
bipyridine (20 mol%)
Cl
O
DIC, DMAP
(DMPU) 2Zn(CF 2 H)2
CuCl (20 mol%)
DMSO, 60 °C, 8 h
R
R
2
Prepared in situ
or isolated
CF2H
R
3
Selected examples:
Br
CF2H
CF2H
N
F
O
F
O
O
CF2 H
CF2H
H
O
85%
88%
80%
94%
Mechanistic outline:
[Zn]-CF2 H
L-Cu(I)-X
[Zn]X
L-Cu(I)-CF 2H
4
R′CF2 H
Redox-active
ester 2
3
SET
O
CO2 + N
O
L-Cu(III)(CF 2 H)(R′)(X)
6
L-Cu(II)(X)(CF 2 H)
.
R′
5
Cl
Cl
Cl
Cl
CH 2
R' =
R
FIGURE 3–4 Cu(I)-catalyzed decarboxylative gem-difluoromethylation of carboxylic acids. DIC, N,N'diisopropylcarbodiimide; DMAP, 4-(N,N-dimethylamino)pyridine; DMPU, N,N'-dimethylpropyleneurea.
3.4 β-Amino-fluoroalkylation of alkenes
3.4.1 Cu(I)-catalyzed amino-fluoroalkylation
Cu(I)-catalyzed β-amino-trifluoromethylation of γ-ureido-alkenes (7), using the Togni’s
reagent as the source of the trifluoromethyl radical, and a chiral phosphoric acid as a
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
81
O
O
R1
R2
N
H
N
H
R'
O
I
CF3
(Togni's reagent)
CuCl
R1
R2
HN R'
N
O
Chiral phosphoric acid
catalyst
R
R
CF3
7
8
R1
O
R1
R2
N
H
R
7
N
H
R'
n-C 4F9 SO2 Cl
R2
HN R'
N
O
CuBr (10 mol%)
Ag 2CO3 (0.6 equiv)
Chiral phosophoric acid
R
n-C 4 F9
9
FIGURE 3–5 Cu(I)-catalyzed asymmetric amino-trifluoromethylation reactions using Togni’s reagent, and
aminoperfluoroalkylation reactions using perfluoroalkylsulfonyl chloride as the source of the fluoroalkyl radicals.
catalytic system, gives the corresponding trifluoromethylated aza-heterocycles 8 with high
enantiomeric purity (Fig. 35).16 This synthetic method was also extended to aminoperfluoroalkylation of γ-ureido-alkenes to give the perfluoroalkyl-substituted pyrrolidines 9,
using perfluoroalkylsulfonyl chlorides, as the source of the perfluoroalkyl radicals, and catalytic
amounts of CuBr and a chiral phosphoric acid catalyst.17 In this synthetic approach for the
β-(polyfluoroalkyl)amines, Ag2CO3 was added as a mild base to neutralize the HCl byproduct.
3.4.2 Fe(II)-catalyzed azido- and amino-trifluoromethylation
Xu et al. have developed Fe(II)-catalyzed azido-trifluoromethylation of alkenes, using Togni’s
reagent as a source of trifluoromethyl free-radical intermediate and trimethylsilyl azide
(TMSN3) as the azide anion precursor.18 Reduction of the azide moiety to the corresponding
amino group could be effected using catalytic hydrogenation in high yields. The mechanism
for this azido-trifluoromethylation was shown to involve the Fe(II)-catalyzed generation of the
trifluoromethyl radical, which adds to the terminal carbon of the olefins to give the secondary
free radical 13. Oxidation of the free radical to the carbocation species by the [Fe(III)], followed
by azide anion capture gives the β-(azido)trifluoromethyl compounds, 10 (Fig. 36).
3.4.3 Ru(II)-catalyzed amino-fluoroalkylation
Umemoto’s reagent (15), under photoredox conditions, acts as a source of trifluoromethyl
radical and thus is useful for the β-azido- or β-amino-trifluoromethylation of alkenes, in
the presence of a nucleophilic source, such as trimethylsilyl azide (TMSN3) or an amine.
Using Ru(II) as a photocatalyst, and azide anion as the nucleophile, various substituted
82
Organofluorine Chemistry
Togni's reagent
Fe(OAc) 2 (10 mol%)
R
R = alky/aryl
Ligand 12 (10 mol%)
TMSN3 (1.5 equiv)
DCM/MeCN, RT
1. H2 , Pd/C
R
CF3
2. TsOH
N3
CF3
NH3 + – OTs
N
N
12
Ligand
O
11
10
87%
86% (R = Ph)
O
I
CF3
Togni's reagent
Proposed mechanism:
O
TMSN3
Ln Fe(II)(OAc) 2
O
R
Ln Fe(II)(N 3) 2
O
I
CF3
R
CF3
R
CF3
13
Ln Fe(III)(N3 )2 (O2CAr)
LnFe(III)(N 3 )2 (O 2CAr)
Ln Fe(II)(N3)(O2CAr)
CF3
R
10
N3
FIGURE 3–6 Fe(II)-catalyzed vicinal azido-trifluoromethylation of alkenes using Togni’s reagent as a source of
trifluoromethyl radicals.
styrenes, as well as activated and nonactivated (i.e., with electron-donating as well as
electron-withdrawing substituents) alkenes, could be transformed into their corresponding β-(azido)trifluoromethyl derivatives (16) in good yields (Fig. 37).19 Similarly, reactions of alkenes with the Umemoto’s reagent (15) and primary amines (or amides such as
p-toluenesulfonamide), under these free-radical conditions, give the corresponding
β-aminotrifluoromethylated derivatives (17).
A likely mechanism for these reactions involves the photo-generated Ru(II) catalyst,
which acts as a free-radical initiator, forming trifluoromethyl radical from the Umemoto’s
reagent (15). A sequence of reactions involving the trifluoromethyl radical addition to the
olefins, followed by Ru(III)-mediated oxidation would give the carbocation intermediate 19,
which is trapped by the nucleophilic azide anion or amines to give the corresponding products 16 and 17, respectively. The azide moiety could also be reduced to the corresponding
primary amino group, and thus this synthetic strategy is useful for the convenient preparation of a broad range of β-amino-trifluoromethyl compounds.
3.5 Fluoroalkylation using sodium triflinate (Langlois reagent)
Langlois reagent (sodium trifluoromethanesulfinate; sodium triflinate; CF3SO2Na) provides a
cost-effective means of trifluoromethylation for the synthesis of a wide variety of organic
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
83
N3
R'
Ru(bpy) 3 (PF6 )2 (5 mol%)
R
TMSN 3 (3 equiv)
blue LEDs
DCM, RT
62%–80% yields
R = e.g., p-OMe, p-tBu, p-Cl, o-Br
R' = e.g., H, Me
R
R
CF3
16
+
S
CF3 BF4
14
15
NHR'
Ru(bpy) 3 (PF6 )2 (5 mol%)
R'
R
R'NH2
(3 equiv)
blue LEDs
CF3
17
39%–66% yields
R' = e.g., aryl, benzyloxycarbonyl (cbz),
p-toluenesulfonyl (Ts)
Mechanistic outline:
Ru(II)
R
hν
R
Ru(II)*
Ru(III)
R
(14)
CF3
S
CF3
R
BF4
CF3
18
15
Ru(III)
N3
R'
R
N 3-
Ru(II)
CF3
R
16
R
CF3
19
NHR'
R'
R
RNH2
CF3
17
FIGURE 3–7 β-(Azido)trifluoromethylation and β-amino-trifluoromethylation of alkenes under photoredox
conditions.
compounds, under free-radical conditions. Free-radical trifluoromethylation of aromatic
compounds using this reagent was first demonstrated by Langlois et al. in the early 1990s.20
Baran and coworkers and others have more recently demonstrated the wide applicability of
84
Organofluorine Chemistry
R
CF3
R
O
CF3
R
R
R
RCF3
RBF3 K
R
RB(OH)2
N3
CF3
R
R
R
R
R
R
OR'
RCF3
CF3SO2 Na
R
R
I
R
CF3
CF3
R
R
CF3
R
R
R
FIGURE 3–8 Various functional group transformations using the Langlois reagent.
the Langlois reagent and related fluoroalkyl sulfinates in various functional groups transformations.21 These fluoroalkyl sulfinates (also marketed as diversinates) proved to be of fundamental and practical interest in the modern drug discovery.2227
Langlois reagent has been used extensively for the trifluoromethylation of aromatics,28,29
oxidative-trifluoromethylation of alkenes,3034 hydro-trifluoromethylation of alkenes,30,35
azido-trifluoromethylation of alkenes,36,37 dehalogenative trifluoromethylation of aryl
iodides,38 and for the transformation of alkyl- and arylboronic acids39 and organotrifluoroborates40 to the corresponding trifluoromethyl compounds (Fig. 38; vide infra). The area of
fluoroalkylation reactions mediated by Langlois reagent continues to expand at a rapid
rate.37,4143
3.5.1 Aromatic trifluoromethylation
Li et al. have demonstrated photoredox-catalyzed trifluoromethylation of aromatics, using
acetone or diacetyl (2,3-butanedione) as the photocatalysts, and Langlois reagent as the
source of the trifluoromethyl radical.28 Whereas acetone as a photocatalyst requires irradiation in the UV range, below 330 nm, diacetyl-photo-catalyzed reactions could be performed
in the visible range, .400 nm. These photoredox-catalyzed reactions of aromatics, in both
cases, tolerate a broad range of substituents on the aromatic ring. Trifluoromethyl derivatives
of uridine and deoxyuridine (trifluridine) could be synthesized from the corresponding
nucleosides (or deoxynucleosides) in relatively low yields of 38% and 44%, respectively, using
acetone as the photosensitizer. Free-radical trifluoromethylation of aromatics using diacetyl
(2,3-butanedione) as the photocatalyst, under visible light irradiation, affords the trifluoromethylated products in moderate to high yields. Trifluoromethylated purine derivatives
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
85
O
Het
R
CF3
NaSO 2CF3
Arenes
or heteroarenes
Me
Me
Het
R
O
>400 nm, air
EtOAc:diacetyl (4:1)
Diacetyl
(photocatalyst)
42%–93% yields
Selected examles:
OH
O
Me
Me
CF3
N
H
CF3
O
20
21
65% (20 h)
75% (40 h)
Me
Me
N
N
23
82% (20 h)
O
F3 C
Me
25
N
O
OH
27
Uridine-CF3
38% (40 h acetone/UV)
O*
hν
F3 C
O
S
+
O Na
Me
Me
O
F3 C
O
O Na
28
H
O
S
O
HO
OH OH
26
75% (40 h)
NH
O
O
Mechanistic outline:
Me
F3 C
HO
N
H
93% (10 h)
O
NH
N
CF3
24
Me
65% (20 h)
O
CF3
O
N
N
22
O
O
CF3
CF3
N
N
Me
Me
Me
H
N
N
Trifluridine
44% (40 h acetone/UV)
R
CF3
O
+
SO 2
O
H
CF3
CF3
R
R
-H +
CF3
R
30
29
Me
+
O Na
H
Me
O
31
FIGURE 3–9 Photoredox-catalyzed trifluoromethylation of aromatics.
22 and 23, trifluoromethylated derivative of the aromatics, including phenolic antioxidant
(4-trifluoromethyl-2,6-di-tert-butylphenol), 20, and heterocyclic aromatics, such as trifluoromethylated indoles (e.g., 21 and 25), were synthesized under visible light photoredox catalysis using diacetyl as the photocatalyst (Fig. 39).
86
Organofluorine Chemistry
A proposed mechanism of this photoredox-catalyzed trifluoromethylation is as follows.
Photoexcited diacetyl oxidizes the sodium triflinate to give the trifluoromethylsulfonyl radical, which spontaneously fragments to give the trifluoromethyl (CF3•) radial. The reaction of
thus generated trifluoromethyl radical (CF3•) with aromatics gives the corresponding trifluoromethylaryl radical 29, which undergoes redox reaction with the photo-generated diacetyl
radical anion 28 to give the arenium cation 30. Spontaneous deprotonation of the latter arenium cation (Wheland intermediate) gives the trifluoromethylated aromatics (Fig. 39).
As an alternative approach, using CF3SiMe3 as the source of the trifluoromethyl radical,
under oxidative conditions, Surya Prakash and coworkers have developed the direct C(sp2)
H trifluoromethylation of enamides, such as naturally occurring isoindolinones, isoquinolinones, and 2-pyrinones.44
3.5.2 Hydro-trifluoromethylation of alkenes
Nicewicz and coworkers have achieved hydro-trifluoromethylation of alkenes using the
Langlois reagent under photoredox conditions.45 Through this free-radical, anti-Markovnikov
reaction, hydro-trifluoromethylation of aliphatic alkenes (terminal and internal) as well as
variously substituted styrenes, using the Langlois reagent, in the presence of trifluoroethanol
(TFE) and methyl thiosalicylate as hydrogen atom donors, gave moderate yields of the corresponding trifluoromethyl compounds. 9-Mesitylacridinium salt was used as the organophotocatalyst in these reactions (Fig. 310). This hydro-trifluoromethylation is of broad scope,
and a range of mono-, di-, and trisubstituted aliphatic and styrenyl alkenes gave the corresponding trifluoromethylated hydrocarbons with high anti-Markovnikov regioselectivity.
According to a proposed mechanism, trifluoromethyl radical, generated from the Langlois
reagent, undergoes free radical addition to the alkene, forming the relatively more
stable secondary alky radical (e.g., an internal free radical from the terminal alkenes). The
latter free radical then abstracts the hydrogen atom from the thiol (methyl thiosalicylate) or
TFE to give the anti-Markovnikov products of hydro-trifluoromethylation Fig. 310.45
Iridium photoredox catalysis was also used for the hydro-trifluoromethylation of terminal
alkenes, using Langlois reagent in methanol solvent.35 Various synthetically useful functional
groups, such as ester, aldehyde, ether, sulfone, and aryl boronates, are tolerated and remain
unchanged under the reaction conditions.
3.5.3 Trifluoromethylation of arylboronic acids
Sanford and coworkers and Beller and coworkers have developed trifluoromethylation of
arylboronic acids under photoredox conditions.4,39,46 Copper-mediated trifluoromethylation
of arylboronic acids under free-radical conditions, using tert-butylhydroperoxide (tBuOOH)
as the oxidant and Langlois reagent as a source of the trifluoromethyl radical, gives the corresponding trifluoromethylaromatics under mild conditions (Fig. 311).39 The trifluoromethylation of arylboronic acids could be performed in the presence of ambient air and moisture
without adversely affecting the yields. A related photoredox-catalyzed trifluoromethylation of
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
CF3
CF3 SO2 Na (1.5 – 3.0 equiv)
R
R'
R = alkyl, aryl
R ' = H, alkyl
87
SH
R
9-Mes-Acr (5 mol%)
methyl thiosalicylate (20 mol%)
450 nm LEDS
CHCl3 /TFE (9:1), RT
R'
OMe
H
N
Me
O
9-Mes-Acr
Methyl thiosalicylate
Selected examples:
HO
HO
CF3
50%
Ph
CF3
OH
Ph
OH
51%
Mechanistic outline:
9-Mes-Acr
9-Mes-Acr*
CF3
9-Mes-Acr
RSTFE
R
R
CF3 SO2 Na
hν
RS
.
+ SO2
.
RSH
R
CF3
CF3
(Hydrogen atom transfer
from ArSHl/TFE)
FIGURE 3–10 Anti-Markovnikov hydro-trifluoromethylation of alkenes under photoredox conditions. TFE,
Trifluoroethanol.
arylboronic acids using CF3I as the source of the trifluoromethyl radicals, and [Ru(bpy)3]21
as the photocatalyst, also gives the trifluoromethylarenes in high yields.4
A proposed mechanism46 for the trifluoromethylation of arylboronic acids involves Cu(I)catalyzed formation of the trifluoromethyl radical from the reaction of tert-butylhydroperoxide with the Langlois reagent. The trifluoromethyl radical, upon reaction with Cu(II), forms
the Cu(III)CF3 intermediate (32). The later intermediate may undergo transmetalation with
arylboronic acid to give the CF3Cu(III)Ar (33), which then undergoes spontaneous reductive
elimination to give the trifluoromethylarenes, regenerating the Cu(I) species for the continuation of the catalytic cycle. Alternatively, transmetalation of the Cu(II) species with arylboronic acids gives ArCu(II) (34), which upon SET to the trifluoromethyl radical may form the
CF3Cu(III)Ar (33) (Fig. 311).
88
Organofluorine Chemistry
B(OH)2
NaSO2 CF3 (3 equiv)
CF3
CuCl (1 equiv), TBHP (5 equiv)
R
R
DCM or MeOH
Selected examples:
CF3
CF3
CF3
CF3
MeO
Ph
N
H
MeO
85%
94%
O
74%
CF3
O
80%
67%
Mechanistic outline:
F3C
t-BuO
O
S
O
t-BuO
+ SO2
Ln Cu(II)
+ OH
F3 C
t-BuOOH
Ln Cu(I)
O
S
O
ArB(OH) 2
CF3
Ln Cu(III)CF3
32
B(OH) 2X
ArB(OH) 2
ArCu(II)L n
34
B(OH) 2X
ArCF3
CF3
Ln CF3 Cu(III)Ar
33
FIGURE 3–11 Trifluoromethylation of arylboronic acids using Langlois reagent.
The Cu(I)-catalyzed reaction of aryl- or vinyltrifluoroborate salts with Langlois reagent, in
the presence of tert-butyl hydroperoxide, also affords the corresponding trifluoromethylsubstituted compounds in high yields. In these reactions, CuCl was found to be the optimal
catalyst, as compared to other copper salts (Fig. 312).47 The aryl- and vinyltrifluoroborate
salts are, in turn, synthesized from the corresponding boronic acids and KHF2.
3.5.4 Azido-fluoroalkylation of alkenes
β-(Azido)trifluoromethyl compounds are versatile intermediate for the synthesis of the corresponding β-(trifluoromethyl)amines and also as substrates in the Cu(I)-catalyzed
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
R
KHF2 /MeOH/H2 O
B(OH) 2
R
BF3 K
NaSO 2CF3 /TBHP/CuCl
CF3
R'
DCM/H2 O/MeOH
RT 6–15 h
R'
R'
R
89
74%–94%
FIGURE 3–12 Cu(I)-catalyzed trifluoromethylation of vinyl (or aryl) trifluoroborates.
O
Me
N
O
O
F
N
OH
Me
H 2N
Me
O
Br
CF3
F3 C
NH 2
34
35
AAK1 kinase inhibitor
Antimicrobial agent
FIGURE 3–13 Structures of some biologically important β-(trifluoromethyl)amines.
azidealkyne cycloaddition reactions (click chemistry) for further functionalization. The trifluoromethyl group attenuates the basicity of the β-trifluoromethyl amines and increases the
lipophilicity of the compounds. Through appropriate choice of the fluoroalkyl groups, the
lipophilicity and solubility characteristics can be fine-tuned for optimal biological activity.
The β-(amino)trifluoromethyl moiety is a component of some biologically and pharmaceutically interesting compounds, such as compound 34, an adaptor-associated kinase 1 (AAK1)
inhibitor, and compound 35, an antimicrobial agent (Fig. 313).18,48,49
Langlois reagent is a cost-effective reagent for the transformation of alkenes to the corresponding β-(azido)trifluoromethyl compounds. Furthermore, various sodium fluoroalkyl sulfinates could be used as the source of the fluoroalkyl free radicals (monofluoroalkyl,
difluoroalkyl, trifluoromethyl, and polyfluoroalkyl radicals) in the free-radical fluoroalkylation
reactions. Zhang and coworkers have developed synthetic methodology for the azidofluoroalkylation of alkenes, using the Langlois reagent and its analogs, in the presence of trimethylsilyl azide, Cu(I) catalyst, and tert-butyl peroxybenzoate (TBPB) as the free-radical
initiator.50 Their observations showed that other peroxide radical initiators were not as successful as TBPB in these reactions.
The proposed mechanism involves the Cu(I)-catalyzed formation of the fluoroalkyl freeradicals (•CF3 and •CHF2) that add to the olefins to give the internal radicals, 42. Oxidative
addition of the Cu(II)N3 (formed in the first step) to the radical 42, followed by reductive
elimination of the Cu(III) complex 43, then gives the β-(azido)fluoroalkyl compounds (37),
regenerating the Cu(I) catalyst in the process (Fig. 314).50 The β-(azido)trifluoromethyl
compounds formed in these reactions, for example, compounds 38 and 39, could be further
transformed into the corresponding triazoles 40 and 41, respectively, using the Sharpless
azide-alkyne click chemistry.
Interestingly, use of sodium alkylsulfinates (nonfluorinated compounds) in these reactions results in the β-(azido)sulfonylation to give 44, and not the expected β-(azido)
90
Organofluorine Chemistry
O
R FSO 2Na (1.5 equiv)/TMS N 3
R'
CuCl/TBPB (1.5 equiv)/MeCN/H 2 O
16 h, 30 °C –60 °C
R
N3
R'
R
RF
O
37
O
TBPB
36
R, R ' = aryl, alkyl
Some examples:
Ph
Ph
N3
N3
EtO
CF3
EtO
CF2 H
H 3C
MeO
MeO
N
N
N
N
N
N
CF3
CF2H
Ph
38
39
5
40
41
68%
70%
50%
40%
Mechanistic outline:
O
Cu(I)
O
O
Me 3SiN 3
Na + O
NaSO 2R F
O
RF
O
TBPB
OSiMe 3 + Cu(II)N 3
R'
R
N3
R'
R
RF
37
–Cu(I)
R'
N3 (III)Cu
R
R'
Cu(II)N 3
RF
43
36
R
RF
42
FIGURE 3–14 β-(Azido)fluoroalkylation of alkenes, and a mechanistic outline.
alkylation, as the reaction of the alkylsulfinates proceeds through the formation of the corresponding alkylsulfonyl radicals (RSO2•), which do not extrude sulfur dioxide to form the alkyl
radicals. In other words the nonfluorinated alkylsulfonyl radicals, unlike the fluoroalkylsulfonyl radicals, do not form the corresponding alkyl radicals, in accordance with the relatively
lower stability of the alkyl radicals as compared to the fluoroalkyl radicals (Fig. 315).
A Mn(III)-catalyzed version of the β-(azido)trifluoromethylation of terminal alkenes has
been demonstrated using the Langlois reagent as the source of the trifluoromethyl radical.37
The β-(azido)trifluoromethyl compounds (46) could be further transformed into the
β-aminotrifluoromethyl compounds (47), or used as the starting materials for the Cu(I)-catalyzed azidealkyne cycloaddition reactions (CuAAC; click reactions), to give the corresponding 1,2,3-triazoles (48) (Fig. 316).37
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
N3
R"SO2Na (1.5 equiv)
R'
R
TMSN3
CuCl/TBPB (1.5 equiv)
MeCN/H 2O
16 h, 30 ºC–60 ºC
R
-e –
R"SO2 Na
R"
91
R'
O S R"
O
44
R" = alkyl
O
S O
R"
O
S O
R
.
FIGURE 3–15 Formation of the β-(azido)sulfones from the reactions of alkenes with sodium alkylsulfinates.
CF3 SO2 Na (2 equiv)
TMSN3 (3 equiv)
Mn(OAc) 2 (20 mol%),TBHP (3 equiv)
MeO
CF3
MeO
MeCN, air, 45 °C
45
N3
46
Ph3 P
THF/H2 O
CuSO4
Sodium ascorbate
H2 O/tBuOH, 70 °C
CF3
NH2
MeO
CF3
N
MeO
47
N
N
48
Ph
FIGURE 3–16 β-(Azido)trifluoromethylation of terminal alkenes and the transformation of the azido-moiety into
the amines or triazoles.
3.5.5 Electrochemical oxy- and amino-trifluoromethylation
Electrochemical oxy-trifluoromethylation and amino-trifluoromethylation of alkenes were
achieved using Langlois reagent (sodium trifluoromethanesulfinate; CF3SO2Na), using a carbon anode and a Pt cathode. A variety of β-alkoxy and β-acyloxy trifluoromethyl compounds
could be synthesized from the reaction of styrenes with alcohols, carboxylic acids, and
amines through this electrochemical synthesis in an undivided cell under constant current
conditions (Fig. 317).51
A free-radical mechanism was proposed for these electrochemical trifluoromethylation
reactions based on the electron spin resonance (ESR) spectroscopic studies and mechanistic
92
Organofluorine Chemistry
Oxy-trifluoromethylations:
CF3
RO
Carbon anode and Pt cathode, 15 mA
+
CF3 SO2 Na
n-Bu 4BF4 , ROH/Y(OTf) 3, RT, 3 h
R = e.g., Me,85%;
Et, 60%;
Selected examples:
Cl
CF3
O
O
O
O
CF3
CF3
CF3
CF3
60%
53%
H
CH3
O
O
53%
59%
Amino-trifluoromethylations:
CF3
R 2 NH
+
CF3 SO2 Na
R 2N
Carbon anode and Pt cathode, 15 mA
n-Bu 4BF4
Y(OTf)3, CH3CN/CH2Cl2, RT, 3 h
R
R
Selected examples:
N
N
CF3
Cl
N
N
CF3
N
N
Br
CF3
R
40%
43%
39%
Mechanistic outline:
CF3
-e –
CF3 SO2 –
.
CF3 + SO2
CF3
(anodic oxidation)
-e –
(anodic oxidation)
ROH or R 2NH
+
CF3
-H
+
X
CF3
X = OR or NR2
FIGURE 3–17 Electrochemical oxy-trifluoromethylation and amino-trifluoromethylation of styrenes.
studies, using a radical trapping agent DMPO (5,5-dimethyl-1-pyrroline N-oxide). No ESR
signal could be detected from the reaction mixtures under the standard reaction conditions.
However, the reaction mixture, in the absence of the alkenes (e.g., styrene), showed a strong
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
93
ESR signal attributable to the DMPO adduct of the trifluoromethyl radical.51 Thus the trifluoromethyl radicals, formed through a single-electron electrochemical oxidation of the
Langlois reagent, react with the styrene and aryl-substituted styrenes to form their corresponding more stable β-trifluoromethyl radicals. The latter β-trifluoromethyl radicals upon
further electrochemical oxidation to the corresponding carbocations, followed by nucleophilic capture, give the β-alkoxy- or β-amino-trifluoromethyl compounds. The use of yttrium
triflate [Y(OTf)3] as a Lewis acid catalyst gave relatively higher yields (B80%) than without
the Lewis acid (B65%), implying prior coordination of the Lewis acid with the nucleophile
that is captured by the carbocation intermediate. The Lewis acidnucleophile adduct may
also complex to the alkene, thereby activating it for the electrophilic addition of the trifluoromethyl radical.
3.5.6 Selective trifluoromethylation of proteins
The radical trifluoromethylation of proteins, using the Langlois reagent as the source of trifluoromethyl radical, affords the trifluoromethyl-modified proteins, under physiological conditions.52 The high selectivity of the trifluoromethyl radical is shown by the selective
trifluoromethylation of the relatively electron-rich tryptophan residues as compared to histidine, tyrosine, and phenylalanine residues. A 19F NMR competition assay for the equimolar
mixture of various amino acids, at ,40% conversion, showed that the predominant product
arises from the regioselective C2-aryl trifluoromethylation of tryptophan, with minor products
arising from the trifluoromethylation of cysteine, phenylalanine, and tyrosine (Fig. 318).
FIGURE 3–18 Limited-conversion competition 19F NMR assay of natural amino acids (0.03 mmol), revealing chemoand regioselectivity toward Trp with minor products (Cys and lower levels of Phe, His, Tyr isomers). Adapted from
Imiolek, M.; Karunanithy, G.; Ng, W. -L.; Baldwin, A. J.; Gouverneur, V.; Davis, B. G. Selective Radical
Trifluoromethylation of Native Residues in Proteins. J. Am. Chem. Soc. 2018, 140, 15681571.
94
Organofluorine Chemistry
NH
CF3 SO2 Na (200 equiv)
TBHP (12.5 equiv)
100 mM NH 4OAc, pH 6–8
NH
F 3C
FIGURE 3–19 Selective radical trifluoromethylation of tryptophan residues in proteins, using Langlois reagent.
The radical trifluoromethylation of proteins, using this protocol, affords greater than 50%
conversions to the C2-aryl tryptophan residues at a moderate pH of about 6 (Fig. 319).52 At
pH 6.0, histidine residues are protonated and thereby become less reactive with the electrophilic trifluoromethyl radical, thus increasing selectivity toward tryptophan trifluoromethylation by 30-fold. Under optimal conditions, this chemoselective radical trifluoromethylation of
tryptophan residues proceeds in 10 min, although it does not show absolute selectivity over
other aromatic amino acid residues. This method allows direct access to 19F NMR experiments and in vitro protein modifications.
3.6 Photoredox-catalyzed S-fluoroalkylation and arylation
S-Trifluoromethylation and S-perfluoroalkylation of thiol moieties can be effected through
visible light photoredox catalysis, using a Ru(II) photocatalyst. N-Boc-cysteine methyl ester
(49), under these conditions, in batch- and continuous flow reactors, gave the corresponding
S-fluoroalkyl derivatives (50) in moderate yields and at relatively short reaction times (2 h in
batch and 4 min in flow reactors). The proposed mechanism for this fluoroalkylation involves
reductive formation of the fluoroalkyl radicals by the Ru(I) catalyst, which is generated in the
presence of tetramethylethylenediamine under photoredox catalysis. The cysteine thiolate
51, reversibly formed under the basic conditions, undergoes oxidative addition to the fluoroalkyl radical (RF•), forming the sulfur radical anion 52. The radical anion 52, upon SET to
the fluoroalkyl iodide (RFI) then gives the product 50 and the fluoroalkyl radical (RF•), which,
in turn, propagates the catalytic cycle through its reaction with the thiolate anion 51
(Fig. 320).53
Selective functionalization of the cysteine thiol moiety in a pentapeptide derivative (53)
could be achieved under metal-free photoredox conditions (and also under physiological
conditions, in a phosphate buffer medium), using Eosin Y as the photocatalyst, to give the
corresponding 4-fluoroaryl- or 4-(trifluoromethoxy)aryl derivative 54 (Fig. 321). The diazonium cation required in these reactions is generated, in situ, in a microflow reactor from the
corresponding anilines using tert-butyl nitrite.54 The reaction is tolerant to unprotected serine and lysine residues and involves the photoredox-catalyzed formation of intermediate aryl
free radicals from the diazonium ions.
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
O
O
RFI
MeO
MeO
SH
OtBu
HN
Ru(II), TMEDA, MeCN
SR F
OtBu
HN
Blue LED irradiation
O
O
50
49
RF = e.g., –CF 3, –CF2 CF2 CF3, –CF2 CO2Et
60%–84% yields
O
Mechanistic outline:
MeO
S
OtBu
HN
51
RFI
Ru(I)
O
TMEDA
Ru(II)*
RF
O
MeO
Ru(II)
RFI
MeO
S
OtBu
HN
O
O
hν
RF
MeO
SR F
OtBu
HN
O
Chain propagation
O
O
52
51
SR F
OtBu
HN
50
FIGURE 3–20 Free-radical S-fluoroalkylation under photoredox conditions.
O
HN
NH 2
X
O
HS
NH
O
H
N
HO
O
H
N
N
H
O
O
N
H
OH
(X = F, OCF3)
N N
NH 2
Eosyn Y, phosphate buffer, RT
White CFL irradiation, 30 min
O
53
N-acyl-cys-gly-ser-ser-lys-NH2
O
HN
NH 2
O
S
X
NH
H
N
HO
O
N
H
O
H
N
O
O
N
H
OH
54
(X = F, OCF3)
FIGURE 3–21 Selective functionalization of cysteine thiol moiety in a pentapeptide derivative.
NH 2
O
95
96
Organofluorine Chemistry
3.7 Radical fluoroalkylation of enolates
Radical trifluoromethylation of lithium- or titanium-enolates, or diethylzinc (Et2Zn) complexed silyl enol ethers can be accomplished using iodotrifluoromethane (CF3I) and the
free-radical initiator triethylborane (Et3B), in the presence of oxygen. These reactions,
however, have limited substrate scope and give low yields in some cases, due to the competing defluorination of the α-CF3 ketones by the enolate anions or other bases
(Fig. 322).5558 Free-radical trifluoromethylation of chiral N-acyl-oxazolidinones, however, gives the corresponding α-trifluoromethylated carbonyl compounds in moderate to
good yields and with high diastereoselectivities. The presence of the bulky substituents on
the oxazolidinone moiety in these reactions disfavors the accompanying defluorination
reactions.59
Chiral N-acyl oxazolidinones could be fluoroalkylated using trifluoromethyl iodide or perfluoroalkyl iodides and a binary mixture of transition metal reagents, ZrCl4 and [Ph3P]3Ru(II)
Cl2, with high diastereoselectivities. The α-fluoroalkylated N-acyl-oxazolidinones can be
hydrolyzed (using LiOH and aqueous H2O2) or reduced (using LiAlH4 in THF) to the corresponding carboxylic acids (9) and primary alcohols (10), respectively, in high yields and with
high enantiomeric purity (enantiomeric ratios .97:3).60
The proposed mechanism for these trifluoromethylation and perfluoroalkylation reactions
involves SET redox reactions, mediated by Ru(II) (Fig. 323).60 Thus the enolate ion formed
from the N-acyl-oxazolidinone is complexed to the ZrCl4 to give the Zr(IV) enoalate 61. Ru
(II)-catalyzed SET reduction of trifluoromethyl iodide gives the trifluoromethyl radical, which
undergoes free-radical addition to the enolate complex 61 to give the radical anion 62.
Subsequent Ru(III)-catalyzed oxidation of the radical anion 62 then gives the
α-trifluoromethylated N-acyl-oxazolidinone.
R1
OSiMe3
R2
H
O
1. Et 2Zn/THF
2. CF3I/Et3 B/O2
R2
R1
CF3
R1
R2
R1
H
O
OM
R2
CF3
M = e.g., Li
FIGURE 3–22 Radical trifluoromethylation of enolates.
OLi
CF3I/Et3 B/O2
R2
R1
F
F
Chapter 3 • Free-radical reactions in the synthesis of organofluorine compounds
O
O
O
N
R FI
ZrCl 4 (1.5 equiv); Et3N
Ph
[Ph 3P] 3RuCl2 (7 mol%)
DCM, 45 °C, 16 h
O
N
O
CF3
O
O
RF
Ph
N
O
Ph
74%; dr 9:1
O
O
O
N
O
N
F
F
F
C 4 F9
C 3 F7
57
N
O
56
O
O
O
O
55
Selected examples:
O
97
F
Ph
F
Ph
Ph
58
59
60
74%; dr 24:1
71%; dr 24:1
73%; dr 98:2
F
F
O
Mechanistic outline:
O
O
O
+ ZrCl4
N
O
O
Ph
Et3 N
ZrCl 4
LiOH/H 2 O2
63
O
CF3
N
CF3
55
HO
Ph
56
LiAlH 4 /THF
HO
CF3
64
Cl4
Zr
O
O
O
L nRu(II)
N
CF3
Ph
61
CF3 I
L nRu(III)
Cl4
Zr
O
O
O
N
CF3
Ph
62
FIGURE 3–23 Trifluoromethylation and perfluroalkylation of the chiral enolates, mediated by Ru(II)-catalyzed redox
reactions.
98
Organofluorine Chemistry
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4
Organotransition metal catalysis in
the synthesis of organofluorine
compounds
Chapter Outline
4.1 Introduction ............................................................................................................................... 104
4.2 Pd-catalyzed fluorination of aryl halides and triflates.......................................................... 105
4.3 Transition metalcatalyzed CH fluorination ....................................................................... 106
4.3.1 Aryl fluorination .............................................................................................................. 106
4.3.2 Benzylic fluorination ....................................................................................................... 108
4.3.3 Fluoroalkylation of hydrazones ..................................................................................... 111
4.4 Au(I)-catalyzed hydrofluorination of alkenes and alkynes................................................... 114
4.5 Ni-catalyzed fluoroalkylation of aromatics ............................................................................ 116
4.5.1 Fluoroalkylation of arylsilanes ....................................................................................... 116
4.5.2 Aryl difluoromethylation ................................................................................................ 118
4.6 Ag(II)-catalyzed oxidative ring-opening fluorination of cyclic amines ................................ 121
4.7 Ag(I)-catalyzed decarboxylative fluorination......................................................................... 123
4.8 Cu(I)-mediated dediazoniative difluoromethylation ............................................................. 124
4.9 Fluoroalkylation of arylboronic acids and esters ................................................................... 125
4.9.1 Copper-mediated trifluoromethylation ........................................................................ 125
4.9.2 Cu(I)-catalyzed trifluoromethylation of arylboronate esters ...................................... 126
4.9.3 Pd(0)-catalyzed difluoroalkylation of arylboronic acids .............................................. 126
4.10 Cu(I)-catalyzed fluoroalkylation of aryl halides ..................................................................... 126
4.11 Ni-catalyzed trifluoromethylthiolation ................................................................................... 127
4.12 Pd(II)-catalyzed (amino)trifluoromethoxylation..................................................................... 129
References........................................................................................................................................... 131
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00004-3
© 2020 Elsevier Inc. All rights reserved.
103
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Organofluorine Chemistry
4.1 Introduction
Nearly one-third of the pharmaceuticals are fluorinated compounds, and a vast majority of
these compounds have either fluoroaryl moieties or fluoroalkyl moieties. A single fluorine on
the aromatic ring, at the metabolic degradation sites, often improves metabolic stability of the
drug candidates. The widely prescribed pharmaceuticalsatorvastatin and rosuvastatin (cholesterol-lowering drugs), safinamide (for treating Parkinson’s disease), ciprofloxacin (an antibacterial drug), flurbiprofen (a nonsteroidal antiinflammatory agent), and dacomitinib (an anticancer
drug for treating non-small-scale lung cancers)have a monofluorinated aryl ring (Fig. 41).
Many pharmaceuticals, including the widely prescribed antimalarial drug ciprofloxacin and
antidepressant drug fluoxetine, are trifluoromethylated compounds. Difluoromethylated pharmaceuticals include roflumilast (for treating chronic obstructive pulmonary disease), pantoprazole (for treating gastrointestinal diseases), tafluprost (for treating glaucoma), and maraviroc
(anti-HIV drug) (see Chapter 5: Pharmaceutical applications of organofluorine compounds).
FIGURE 4–1 Structures of selected pharmaceuticals containing a fluoroaryl moiety.
Chapter 4 • Organotransition metal catalysis in the synthesis
105
Fluorination of aryl rings can be achieved through the BalzSchiemann reaction [Cu
(I)-catalyzed dediazoniative fluorination of aryldiazonium salts],1 nucleophilic aromatic
substitution (SNAr) of aryl halides (a nontransition metalcatalyzed reaction, limited to
deactivated aromatics),2 Pd-catalyzed fluorination of aryl halides and triflates,3 or Pdcatalyzed CH activation using a directing group, such as pyridine moiety, in proximity
to the fluorination site.4 Transition metalmediated or transition metalcatalyzed fluorination and fluoroalkylation reactions are especially useful in the late-stage fluorination of
pharmaceuticals and in the synthesis of 18F-labeled positron emission tomography (PET)
tracers (see Chapter 6: Synthesis and applications of 18F-labeled compounds).5
Fluoroalkyl groups afford favorable pharmacokinetic properties to the drug candidates,
because of their effectiveness in improving lipophilicity, membrane permeability, and oxidative stability. The efficient synthetic methods for fluorinations and fluoroalkylations,
achievable by organometallic catalysis, expand the synthetic strategies for the fluorinated
drugs and also provide access to the late-stage synthesis of pharmaceuticals and 18Flabeled compounds for PET.
4.2 Pd-catalyzed fluorination of aryl halides and triflates
Buchwald and coworkers, in 2009, developed the Pd(0)-catalyzed ipso-fluorination of aryl
bromides or triflates, in the presence of a sterically crowded ligand, t-Bu-Brettphos (1).6
Although oxidative addition of aryl halides (triflates) to Pd(0) is relatively fast, the reductive
elimination to form the aryl fluorides is too slow and is not practicable for the synthetic
applications, using the conventional triarylphosphine ligands. However, Buchwald and
coworkers have demonstrated that the sterically crowded phosphine ligands accelerate this
reductive elimination and thus achieved the synthetically useful Pd(0)-catalyzed arylfluorination reactions. However, relatively high temperatures (80 C130 C) are still
required for these aryl fluorinations. This Pd(0)-catalyzed trifluoromethylation reaction was
improved using even more sterically crowded ligand adamantly-Brettphos (2).7 A variety of
pharmaceutically interesting phenolic compounds, such as estrone and vitamin E
(α-tocopherol), were deoxyfluorinated through Pd(0) catalysis in a two-step process,
involving the conversion of the phenols to the triflates, followed by Pd(0)-catalyzed ipsoarylfluorination (Fig. 41). Whether these deoxyfluorinated versions of the estrone or vitamin E have comparable pharmacological effects as that of the parent compounds is yet to
be established.
This aryl-fluorination reaction involves oxidative addition of the aryl triflate (or bromide)
to Pd(0) to give the Ar(X)Pd(II) intermediate (3), which upon transmetalation with CsF forms
the Ar(F)Pd(II) intermediate (4). Reductive elimination of the latter Pd(II) intermediate, facilitated by the sterically crowded ligands, such as t-Bu-BrettPhos or adamantly-BrettPhos,
gives the corresponding fluoroaromatic compounds, regenerating the Pd(0) catalyst that
reenters the catalytic cycle (Fig. 42).
106
Organofluorine Chemistry
FIGURE 4–2 Pd-catalyzed fluorination of aryl halides (or triflates).
4.3 Transition metalcatalyzed CH fluorination
4.3.1 Aryl fluorination
Aryl fluorination through CH activation serves as an atom economical synthetic method and
provides a convenient synthetic strategy for the late-stage fluorination of pharmaceuticals. Pd
(II)-catalyzed CH fluorination of aromatics, using the Pd(II) complex 5, proceeds under relatively mild conditions to give the fluorinated aromatics. Aromatic substrates, consisting of
electron-releasing groups (such as alkoxy groups), as well as mildly electron-withdrawing substituents (such as halogens), give the regio-isomeric mixture of fluoroaryl compounds in moderate to good yields (Fig. 43).8 For example, through this Pd catalysis, bromobenzene gives
isomeric mixture of o- and p-fluorobromobenzene. Similarly, procymidone (a pesticide) gives
Chapter 4 • Organotransition metal catalysis in the synthesis
FIGURE 4–3 Pd-catalyzed electrophilic aromatic CH fluorination.
107
108
Organofluorine Chemistry
fluorination at the ortho- and para-positions with respect to the amino moiety. This synthetic
method can be used in the late-stage fluorination of pharmaceuticals or agrochemicals, such as
fluorinated versions of the procymidone and butyl ciprofibrate, a lipid-lowering drug.
In these aryl fluorinations, unlike most other organometallic reactions involving CH
bond activation, arylorganometallic intermediates are not formed as the intermediates.
Instead, a reactive FPd(IV) intermediate, 6, is formed as the transient species through the
Selectfluor-mediated oxidation of the Pd(II) complex. A single electron transfer (SET) from
the high-valent Pd(IV) complex 6 to the arenes forms a fluoride-bridged aryl radical intermediate 7. This aryl radical intermediate, 7, through a fluoride-coupled intramolecular electron
transfer, that is, electron transfer from the aryl radical to the Pd(III), forms the fluoroarenium
cation 8, regenerating the Pd(II) catalyst. In effect, this two-step sequence is equivalent to
the transfer of “F1” from the high-valent Pd(IV) intermediate to the arenes to form the fluoroarenium cation (8). A subsequent deprotonation of the fluoroarenium cation by a base
(e.g., F2) then gives the fluoroaromatic compound. This mechanistic outline is substantiated
by density functional theory calculations.8
4.3.2 Benzylic fluorination
4.3.2.1 Mn(III)-catalyzed benzylic fluorination
Benzylic hydrogens in pharmaceuticals are prone to metabolic oxidation, and therefore
fluorination of benzylic hydrogens provides a means of enhancing the metabolic stability as
well as potency and bioavailability of the drug candidates. Benzylic fluorination can be
achieved using electrophilic fluorinating agents, such as Selectfluor and N-fluorobenzenesulfonimide, using organometallic catalysis.912 The organometallic catalysis also allows latestage benzylic fluorination of pharmaceutically interesting compounds.
Groves and coworkers developed regioselective benzylic fluorination using Mn(III)(salen)
Cl (1) as the catalyst and iodosobenzene as the oxidant in the presence of Et3N3HF. Using
this method, pharmaceutically interesting compounds, such as ibuprofen, celestolide,
δ-tocopherol, and homophenylalanine were selectively fluorinated at the benzylic site in
moderate yields (Fig. 44).11 The proposed mechanism involves oxidation of the Mn(III)
complex (9) to the Mn(V) complex (10) by iodosobenzene, followed by abstraction of the
benzylic hydrogen to form the benzylic radical. Fluoride ion exchange of Mn(IV)-OH (11) to
give Mn(IV)-F (12), followed by the recombination of fluorine to the benzylic radical then
gives the corresponding benzyl fluorides, regenerating the Mn(III) catalyst (9). This methodology was adapted for the synthesis of the pharmaceutically interesting 18F-labeled compounds, such as ibuprofen [a nonselective cyclooxygenase (COX) inhibitor], rasagiline
(monoamine oxidase-B inhibitor), dopamine (neurotransmitter), celecoxib (a COX-2 inhibitor), and enalaprilat (angiotensin-converting enzyme inhibitor), using the no-carrier-added
[18F]fluoride (see Chapter 6: Synthesis and applications of 18F-labeled compounds).13,14
4.3.2.2 Pd(II)-catalyzed benzylic fluorination
Pd(II)-catalyzed enantioselective benzylic CH fluorination 2-alkylbenzaldehydes (13) was
achieved, using N-fluoro(2,4,6-trimethyl)pyridinium tetrafluoroborate (14) as the source of
Chapter 4 • Organotransition metal catalysis in the synthesis
N
109
N
Mn
t-Bu
O
Cl
t-Bu
H
t-Bu
O
t-Bu
F
( 9) 20 mol%
R2
R2
PhIO, Et 3 N.3HF/AgF
MeCN, 50 °C, 6–9 h
R1
R1
Selected examples:
O
F
F
F
F
CO2 Me
NPhth
MeO 2 C
Ph
48%
58%
F-ibuprfen ester
55%
F-celestolide
67%
F-homophenylalanine
Mechanistic outline:
PhIO
N
N
Mn III
O
O
Cl
t-Bu
t-Bu
t-Bu
PhI
t-Bu
9
O
Mn V
R-F
Cl
10
R
R-H
F
Mn IV
R
OH
Cl
12
Mn IV
Cl
F–
11
FIGURE 4–4 Mn(III)-catalyzed benzylic fluorination.
electrophilic fluorine (F1) as well as the oxidizing agent, in the presence of the catalytic
amounts of a chiral α-amino acid diethylamide (15). The reaction gives moderate to low
yields of the fluorinated products (e.g., 1820) along with a minor by-product 17
(Fig. 45).15
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Organofluorine Chemistry
H2N
O
H
BF 4–
+
R1
15 O
20 mol%
O
Pd(OAc 2) (10 mol%)
H
14
H
+
OCOC 6F5
R1
Bu4 NPF6 (50 mol%)
R1
R2
C 6F5 CO2H (5.0 equiv)
13
O
F
N
F
R2
N
R2
16
Benzene (0.5 M)
17
70 °C, 24 h
Minor byproduct
Examples:
O
F3 C
H
F
61% (91% ee)
F
N
R2
R2
36% (86% ee)
19
18
20
+
Mechanistic outline:
t-Bu
Pd(OAc) 2
–AcOH
H
R1
14
t-Bu
NEt2
NF O
Pd IV
OAc
R2
"F+"
22
NEt2
N
t-Bu
O
Inner sphere
fluorination
H
21
R2
F3 C
58% (90% ee)
R2
H
H
H
F
R1
O
O
O2 N
C 6 F5CO2
O
N
OCOC 6 F5
SN 2
–Pd(II)
NEt2
–
H
R2
O
O
H
t-Bu
NEt 2
H
OCOC 6F 5
F
R1
N
R2
H
O
16
H
(Major product)
R1
13
R2
R2
23
F
O
R1
R2
17
(Minor byproduct)
FIGURE 4–5 Pd-catalyzed enantioselective benzylic fluorination via CH oxidative addition.
24
t-Bu
NEt2
H 2N
O
+
15
Chapter 4 • Organotransition metal catalysis in the synthesis
111
A mechanistic rationalization of the enantioselective benzylic fluorination is as follows.15
The N-fluoropyridinium salt (14) oxidizes Pd(II) to Pd(IV), which undergoes benzylic CH
insertion from the chiral imine 21, followed by elimination of acetic acid to give 22. The Pd
(IV) complex 22 undergoes reductive elimination, through inner sphere fluorine transfer, to
give the benzylic fluoride 23. Reversible equilibration of 23 with the starting 2alkylbenzaldehyde 13 forms the benzylic fluorination product 16. A minor byproduct, 17, is
formed from the competitive SN2 reaction of the Pd(IV) intermediate 22 with the weakly
nucleophilic (perfluoro)benzoate anion. Because of the relatively low nucleophilicity of the
perfluorobenzoate, the latter SN2 reaction is disfavored over the reductive elimination to give
23 (Fig. 45).15 The use of a sterically crowded (amino)amide transient directing group (15)
is critical for achieving high enantioselectivity in these reactions. That is, the CH insertion
of 21 to Pd(IV), as well as CF bond formation through reductive elimination, occurs from
the side opposite to the bulky tert-butyl substituent in the chiral auxiliary.
4.3.3 Fluoroalkylation of hydrazones
4.3.3.1 Difluoroalkylation of hydrazones
The sp2-CH difluoroalkylation, trifluoromethylation, and perfluoroalkylation of hydrazones
can be achieved using organometallic catalysis, in tandem, with photoredox catalysis. These
fluoroalkylation reactions, involving fluoroalkyl radical addition to the imino carbon, followed by SET from the resulting nitryl radical to the high-valent transition metal [e.g., Ir(IV)],
and then deprotonation of the nitrenium cation, constitute indirect CH activation (vide
infra; Fig. 46).
Difluoroalkylation of aldehyde hydrazones, such as morpholino hydrazones of aromatic
and aliphatic aldehydes, could be achieved under the photoredox conditions in the presence
of an Ir(III) photo-catalyst [fac-Ir(ppy)3] to give the corresponding difluoroalkyl hydrazones.16
In these reactions the imino CH bond is substituted by the difluoroalkyl moiety, in a multistep process. Ethyl bromodifluoroacetate reacts with aliphatic and aromatic aldehyde hydrazones under these photochemical conditions to afford the corresponding difluoroalkylation
products in high yields, and these reactions can also be carried out in a one-pot procedure
from the reaction mixture, consisting of the aldehydes, N-aminomorpholine, CF2BrCO2Et,
and the Ir(III) catalyst (Fig. 46).
This visible-light photocatalyzed reaction provides an indirect route to CH activation
leading to the difluoroalkylation. The mechanistic rationale for this photoredox reaction is as
follows.16 A SET from the photoexcited Ir(III) to the ethyl bromodifluoroacetate generates
the transient gem-difluoroalkyl radical species 28, which undergoes free-radical addition to
the hydrazones, forming the hydrazinyl radical intermediates 29. The later radical species is
oxidized by Ir(IV) formed in the first step (through a SET mechanism), to the corresponding
nitrenium cation 30, regenerating the Ir(III) photocatalyst. Finally, deprotonation of the
nitrenium cation 30 by a base (e.g., Br2) gives the corresponding fluoroalkyl-substituted
hydrazones 26.
112
Organofluorine Chemistry
FIGURE 4–6 [Ir(III)] photoredoxcatalyzed difluoroalkylation of hydrazones using ethyl bromodifluoroacetate.
ppy 5 2-phenylpyridine.
Chapter 4 • Organotransition metal catalysis in the synthesis
113
FIGURE 4–7 Au(I)-catalyzed fluoroalkylations of hydrazones. dppm 5 1,1-bis(diphenylphosphino)methane
Au(I)-catalyzed photoredox reactions can also be used for the sp2-CH difluoroalkylation and perfluoroalkylation of hydrazones, using the difluoroalkyl- and perfluoroalkyl bromides (e.g., 34), or diethyl bromo(difluoromethyl)phosphonate (37).17 Reduction of these
gem-difluoroalkyl-substituted hydrazones gives the β-hydrazino carboxylic acid esters (36)
and gem-difluoromethylated β-hydrazino phosphonic acid esters (39). These gem-difluoromethylated carboxylic acid and phosphonic acid derivatives have potential biological and
medicinal applications, such as in the design of peptide isosteres and enzyme inhibitors
(Fig. 47).
4.3.3.2 Trifluoromethylation of hydrazones
Aldehyde N, N-(dialkyl)hydrazones react with Togni’s reagent, in the presence of catalytic
amounts of CuCl to give the corresponding trifluoromethyl-substituted hydrazones
(Fig. 48). This trifluoromethylation reaction was suggested to involve a SET from Cu(I) to
the Togni’s reagent to generate the trifluoromethyl radical, which reacts with the imino carbon of the hydrazone, forming the hydrazinyl radical, as in the case of the gem-difluoromethylations, described earlier. Oxidation of this radical by Cu(II), followed by
deprotonation from the neighboring carbon would then give the α-trifluoromethyl hydrazones.18 The fluoroalkyl hydrazones, if transformed into their corresponding amines, would
give biologically and pharmaceutically interesting α-(fluoroalkyl)amines. The reduced basicity of the amines through incorporation of the fluoroalkyl moieties would enhance their lipophilicity and metabolic stability.
114
Organofluorine Chemistry
FIGURE 4–8 Cu(I)-catalyzed α-trifluoromethylation of hydrazones using Togni’s reagent.
FIGURE 4–9 Fluorinated peptide bioisosteres as transition state analog inhibitors of proteases.
4.4 Au(I)-catalyzed hydrofluorination of alkenes and alkynes
Fluroalkenes are biologically interesting compounds. For example, fluoroalkene peptide
bioisosteres, such as Cbz-Glyψ[(Z)-CF 5 CH]Leu (41) are inhibitors of endopeptidase thermolysin, a Zn-dependent metalloproteinase, produced by the Gram-positive bacteria
(Fig. 49).19 The synthesis of the peptide isosteres 41 usually involves a multistep process.
An attractive strategy for these compounds would be the hydrofluorination of the corresponding alkynes.
Sadighi and coworkers demonstrated the (NHC)Au(I)-catalyzed trans-hydrofluorination
of alkynes in the presence of triethylamine tris(hydrofluoride) [Et3N (HF)3] (Fig. 410).20
The π-complex of the alkynes with Au(I) species (44) was isolated and characterized by
single-crystal X-ray crystallography. Nucleophilic addition of fluoride anion to this cationic
Au(I)alkyne complex gives the trans-fluoroalkenyl-Au(I) species 45, which undergoes
stereoselective protolysis, in the presence of Et3N (HF)3 to give the corresponding fluoroalkenes. The formation of the trans-fluoroalkenyl-Au(I) intermediate 45 was confirmed by 1H
NMR spectroscopy. Due to the relatively weaker acidity of the Et3N (HF)3, strong acid catalysts, such as amine-triflic acid and KHSO4, are used as additives for enhancing the rates of
these reactions. In some cases, these reactions are not completely regioselective. However,
the major product contains fluorine vicinal to the more strongly electron-releasing aryl rings
Chapter 4 • Organotransition metal catalysis in the synthesis
Et3 N.(HF)3 /KHSO4
R1
R2
PhNMe 2 .HOTf (10 mol%)
Au(I) catalyst (2.5 mol%)
42
115
H
SIPr Au O
R1
R2
Au(I) catalyst
F
43
DCE, RT, 18–30 h
i-Pr i-Pr
74%–86%
R 1 = for example, Ph, 4-OMePh, n-C 5H 11
N
R 2 = for example, Ph, n-C 5 H 11
N
i-Pr
i-Pr
SIPr (NHC)
Proposed mechanistic outline:
L
R1
Au X
R2
X = e.g., F
L
AuL H F
AuL
Au X
R1
F
+
R2
44
F
F AuL
H
R1
R1
R2
F
45
R2
F
46
FIGURE 4–10 Au(I)-catalyzed hydrofluorination of alkynes and a proposed mechanism.
(Fig. 410). Hydrofluorination of alkynes with amineHF reagents, in the absence of the Au
(I) catalysis, on the other hand, results in the predominant formation of the dihydrofluorination products, that is, the gem-difluoro compounds, as the major products, because the intermediate fluoroalkenes are rapidly hydrofluorinated to give the corresponding gem-difluoro
compounds.21
Hammond and coworkers, using a phthalimido-Au(I) complex 47 as the organometallic
catalyst and HF/DMPU [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone] reagent,
achieved regioselective hydrofluorination of alkynes. The reaction scope and regioselectivity
of the hydrofluorination of the alkynes is dramatically improved when 65%:35% wt/wt HF/
DMPU (i.e., 12:1 mol ratio of HF:DMPU) is used in these reactions. A variety of aryl- and
alkyl-substituted terminal and internal alkynes give the corresponding hydrofluorination products in moderate to high yields (Fig. 411).22
In these Au(I)-catalyzed hydrofluorination reactions, the phthalimide ligand in the Au(I)
catalyst 47 serves as a good leaving group in the presence of the amineHF complex, forming the Au(I)1 as the active catalyst. The Au(I)1 forms a π-complex with the alkyne (42), to
give 44. The alkyneAu1 complex 14 then undergoes regio- and stereoselective trans-hydrofluorination to give fluoroalkenes, 46. The π-complexes 44 were isolated and characterized
through single-crystal X-ray crystallography.20
The fluoroalkenes 43 are unreactive under the abovementioned reaction conditions.
However, in the presence of Lewis acids, such as Ga(OTf)3, or Bronsted acids, such as
KHSO4, the fluoroalkenes react with DMPU/HF and Au(I) catalyst to give the corresponding
gem-difluoro compounds in high yields (Fig. 412).22
116
Organofluorine Chemistry
n
FIGURE 4–11 Au(I)-catalyzed hydrofluorination of alkynes using DMPU/HF amine complex.
4.5 Ni-catalyzed fluoroalkylation of aromatics
4.5.1 Fluoroalkylation of arylsilanes
Ni-catalyzed fluoroalkylation of arylsilanes or (heteroaryl)silanes, using monofluoroalkyl bromides (RCHFBr) or gem-difluoroalkyl bromides (RCF2Br), affords the corresponding
Chapter 4 • Organotransition metal catalysis in the synthesis
117
FIGURE 4–12 Au(I)-catalyzed dihydrofluorination of alkynes in the presence of a strong acid.
monofluoroalkyl- or gem-(difluoroalkyl)arenes in moderate to high yields. After careful optimization of the reaction conditions, it was found that the 4,40 -di-tert-butyl-2,20 -bipyridyl ligand
(dtbbpy) is critical for achieving high yields.23 This reaction has a wide substrate scope, including aryl and heteroaryl substrates, and is tolerant to various functional groups, such as ketone,
ester, halogen, and ether moieties. Both electron-withdrawing as well as electron-donating
groups on the aryl ring favored the fluoroalkylation reactions (Fig. 413). This reaction allows
late-stage fluoroalkylations and thus is useful for the synthesis of fluorine-containing pharmaceuticals and their derivatives. Thus ezetimibe, a cholesterol-lowering drug that lowers intestinal cholesterol absorption, could be fluoroalkylated through its triethoxysilane derivative.
The following proposed mechanism rationalizes the Ni(I)-catalyzed fluoroalkylation of
aromatics.23 The (Dtbbpy)Ni(I)Cl complex (51), formed from the Ni(II)(dme)Cl2, is the active
catalyst in these reactions. The fluoride anioninitiated formation of the aryl carbanions
from the arylsilanes [ArSi(OEt)3], followed by transmetalation with (dtbbpy)Ni(I)Cl (51) gives
(dtbbpy)Ni(I)-Ar intermediate (52). [Ni(I)]Ar intermediate (52) then undergoes oxidative
addition to the fluoroalkyl substrates to give the [Ni(III)] intermediate 54. The subsequent
reductive elimination of 54 gives the (fluoroalkyl)arenes, regenerating the Ni(I) catalyst.
Radical-trapping experiments suggested the involvement of a transient [Ni(II)] species, associated with the fluoroalkyl free radical (53), for these fluoroalkylations (Fig. 414).23
118
Organofluorine Chemistry
′
′
FIGURE 4–13 Ni-catalyzed fluoroalkylation of arylsilanes. dtbbpy 5 4,4’-di-tert-butyl-2,2’-bipyridyl.
4.5.2 Aryl difluoromethylation
Ni(0)-catalyzed cross-coupling of various substituted (hetero)aryl chlorides using chlorodifluoromethane (CHF2Cl), an inexpensive industrial chemical, gives the corresponding
difluoromethylated products in moderate to high yields. A variety of functional groups on
the aromatics, such as amines, esters, imines, and ketones, are tolerated in these Ni(0)-catalyzed difluoromethylations.24 Through this innovative synthetic methodology, Zhang and
coworkers have synthesized a large variety of difluoromethylated versions of the pharmaceuticals, starting from their corresponding aryl chlorides. Chlorine-containing pharmaceuticals, such as fenofibrate (cardiovascular drug), chlorodiphenhydramine (antihistamine
Chapter 4 • Organotransition metal catalysis in the synthesis
119
FIGURE 4–14 Mechanistic rationale for the Ni-catalyzed fluoroalkylation of aromatics. dtbbpy 5 4,4’-di-tert-butyl2,2’-bipyridyl.
and anticholinergic), buclizine (antihistamine), tolvaptan (hyponatremia agent), clofibrate
(cardiovascular disease drug), clomipramine (antidepressant), loratadine (antihistaminergic agent), empagliflozin (treatment of type II diabetes) were transformed into the corresponding difluoromethylated compounds (Fig. 415). These new fluorinated versions of
the pharmaceuticals are useful in the structure-activity studies toward developing more
effective pharmaceuticals, as well as in the synthesis of the 18F-labeled compounds for PET
applications. Preliminary mechanistic studies suggested that the reaction proceeds through
the oxidative addition of aryl chlorides to Ni(0), which is formed through reduction of
Ni(II) by Zn metal. The resulting Ar-Ni(II)-Cl species through a SET with the difluoromethyl
FIGURE 4–15 Ni(0)-catalyzed difluoromethylation of chloroarenes, and synthesis of difluoromethylated versions of
pharmaceuticals.
Chapter 4 • Organotransition metal catalysis in the synthesis
121
[Ni(0)]
Zn
ArCl
[Ni(I)]
[Ar-Ni(II)-Cl]
ArCF2 H
Zn
[Ar-Ni(III)-CF2 H(Cl)]
[Ar-Ni(I)]
[Ar-Ni(II)-Cl
CHF2H
ClCF2H
FIGURE 4–16 Proposed mechanism for the Ni(0)-catalyzed difluoromethylation of aryl chlorides.
radical intermediate (•CF2H), presumably generated through a single-electron reduction of
ClCF2H by the Ni(I) catalyst, forms the Ar-Ni(III)-CF2H species. The reductive elimination of
the latter Ar-Ni(III)-CF2H intermediate then gives the difluoromethylarenes (Ar-CF2H)
(Fig. 416).
4.6 Ag(II)-catalyzed oxidative ring-opening fluorination of
cyclic amines
Sarpong and coworkers used the so-called deconstructive approach in the fluorinative ringopening of the N-benzoylazacycloalkanes (or other N-acyl-protected cyclic amines), such as
piperidines, azetidines, and pyrroles, using the reagent combination of Selectfluor and silver
tetrafluroborate (AgBF4) to give the corresponding linear, terminal alkyl fluorides
(Fig. 417).25 While in most cases, the formyl group is attached at the amide nitrogen in the
product, in some cases, such as N-benoylazetidine and N-benzoyl-2-alkylazacyclohexanes,
the N-formyl group is lacking in the product. Although this reaction is applicable to fourmembered and other larger rings, unexpectedly, the five-membered ring N-acyl amines do
not give the ring-opened fluorination products.
This deconstructive ring-opening fluorination reaction was further developed toward
practical applications in the synthesis of fluorinated peptide derivatives.25,26 Thus using pipecolic acid amides as the N-terminal protecting group of the peptides (or amino acids), the
corresponding ring-opened fluoroalkyl-substituted unnatural peptides (e.g., 62) are formed
in good yields. The ring-opening fluorination synthetic strategy was also used for the
122
Organofluorine Chemistry
F
Selectfluor (4 equiv)
AgBF4 (4 equiv)
acetone:H 2O (1:9); 40 °C 1 h
N
Ph
N
O
N
Ph
N
F
O
O
Cl
2BF4 –
Selectfluor
56 81%
55
F
Above conditions
NH
H3 C
N
H3 C
Ph
Ph
O
O
57
58 81%
Above conditions
N
F
NH
Ph
Ph
O
O
59
60
40 %
F
H
N
N
O
Ph
O
O
HN
OCH 3
RT, 15 h
O
Ph
63
Acetone:h2O (1:1)
RT, 15 h
F
F
F
N
H3 C
O
OCH 3
62 50%
Selectfluor (4 equiv)
AgBF4 (0.25 equiv)
N
O
O
Ph
61
H3 C
H
N
Above conditions
Ph
64
OH
O
H3 C
N
Ph
O
O
65
FIGURE 4–17 Ring-opening fluorination of cyclic amines to give the linear fluoroalkyl (gem-difluoroalkyl) amides.
preparation of the terminal gem-difluoroalkyl amides (e.g., 65) from the corresponding Nacyl enamines, such as 63. Fluorohydrin 64 was proposed as the reaction intermediate in
this reaction (Fig. 417).
One of the two probable mechanisms for the deconstructive fluorination of the N-acyl
cyclic amines, suggested by Sarpong and coworkers, involves the Ag(II)-catalyzed SET oxidation of the N-acyl cyclic amine (55), forming the corresponding N-acylaminium radical
cation (66).25 The Ag(II), required for this transformation, is formed through Selectfluormediated oxidation of the Ag(I). Selectfluor radical cation abstracts the α-CH hydrogen
atom of the radical cation 66 to give the imine 67, hydration of which forms the hemiaminal
68. Complexation of Ag(II) ion with 68 gives the intermediate 69, which undergoes
Chapter 4 • Organotransition metal catalysis in the synthesis
123
FIGURE 4–18 Probable mechanism for the deconstructive ring-opening fluorination of N-acyl cyclic amines.
homolytic CC bond cleavage to form the terminal alkyl radical 70. The latter alkyl radical
70 then abstracts the fluorine atom from the Selectfluor to give the terminal alkyl fluoride,
regenerating the Selectfluor radical cation for further propagation of the catalytic cycle
(Fig. 418).
4.7 Ag(I)-catalyzed decarboxylative fluorination
Decarboxylative fluorination of carboxylic acids using Selectfluor and AgNO3 gives the corresponding alkyl fluorides. The decarboxylative fluorination of the (carboxymethyl)thio ester
71 gives fluticasone propionate in high yields, under mild reaction conditions (Fig. 419).27
The proposed mechanism involves Selectfluor-mediated oxidation of the Ag(I) to F-Ag(III),
which undergoes a SET redox reaction with the carboxylic acid 71 to form F-Ag(II) and the
alkyl radical 72. F-Ag(II) then transfers the fluorine atom to 72 to give the fluticasone propionate, regenerating the Ag(I) catalyst.
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Organofluorine Chemistry
FIGURE 4–19 Ag(I)-catalyzed decarboxylative fluorination in the synthesis of fluticasone propionate.
4.8 Cu(I)-mediated dediazoniative difluoromethylation
Goossen and coworkers have developed Sandmeyer-type of dediazoniationdifluoromethylation reaction of aromatic amines, using in situ generated Cu-CHF2 reagent. The Cu-CHF2
reagent was synthesized in situ from the reaction of copper thiocyanate and CHF2TMS in
dimethylformamide (DMF) in the presence of CsF. This reaction was demonstrated to involve
a free-radical pathway through mechanistic studies, using the difluoromethylation of 2-(allyloxy)diazonium tetrafluoroborate as the substrate. The formation of the cyclized product in
this reaction indicates that the reaction goes through a free-radical mechanism (Fig. 420).28
Chapter 4 • Organotransition metal catalysis in the synthesis
125
FIGURE 4–20 Sandmeyer-type of dediazoniative difluoromethylation of arylamines.
FIGURE 4–21 Cu-catalyzed trifluoromethylation of arylboronic acids.
4.9 Fluoroalkylation of arylboronic acids and esters
4.9.1 Copper-mediated trifluoromethylation
Cu(II)-catalyzed trifluoromethylation of arylboronic acids using TMSCF3 proceed under
mild conditions to afford the trifluoromethyl aromatics in moderate to good yields.29 The
reaction is useful for the trifluoromethylation of a variety of aromatic and heteroaromatic
compounds, such as quinoline, thiazole, and indole derivatives (Fig. 421). In the absence
of oxygen, when exposed only to air, the trifluoromethylated products are formed in much
lower yields.
126
Organofluorine Chemistry
FIGURE 4–22 Cu(I)-catalyzed trifluoromethylation of arylboronate esters.
4.9.2 Cu(I)-catalyzed trifluoromethylation of arylboronate esters
Hartwig and coworkers have developed the Cu(I)-catalyzed trifluoromethylation of arylboronate esters to give the corresponding trifluoromethylarenes, using the (phen)CuCF3
(phen 5 1,10-phenanthroline) reagent. The Cu(I)CF3 reagent could be synthesized from the
complexation of tBuOCu(I) with 1,10-phenanthroline, followed by reaction with CF3TMS, in
high yields.30,31 Perfluoroalkylcopper(I) reagents, under similar reaction conditions, give the
corresponding perfluoroalkylarenes (Fig. 422).
4.9.3 Pd(0)-catalyzed difluoroalkylation of arylboronic acids
Pdmediated difluoroalkylation using difluoroalkyl halides and arylboronic acids affords the
corresponding difluoroalkyl derivatives in high yields (Fig. 423).32,33 The Pd(0)-catalyzed
gem-difluoroallylation provides access to the late-stage synthesis of biologically active compounds, such as steroidal compound 78.33 The mechanism of these reactions is similar to
that of the Pd(0)-catalyzed Suzuki reactions and involves oxidative addition of the difluoroalkyl halides to the Pd(0), ligand exchange from the arylboronic acid, and finally reductive
elimination to give the difluoroalkyl aromatics.
4.10 Cu(I)-catalyzed fluoroalkylation of aryl halides
Cu(I)-catalyzed trifluoromethylation and pentafluoroethylation of aryl iodides can be
achieved under relatively mild conditions, whereas the corresponding reactions of aryl bromides or chlorides require more drastic conditions.34 Hartwig and coworkers have
Chapter 4 • Organotransition metal catalysis in the synthesis
127
FIGURE 4–23 Transition metalcatalyzed difluoroalkylation of arylboronic acid.
achieved trifluoromethylation and pentafluoroethylation of aryl bromides, including
heteroaryl bromides, using phen(RF)Cu(I) complexes (phen 5 1,10-phenanthroline)
(Fig. 424A).35
Grushin and coworkers have generated CuCF3 from fluoroform and used in the trifluoromethylation of aryl iodides and bromides, in the presence of Et3N3HF as a stabilizing
agent.36 This ligand-less CuCF3 could be used in the trifluoromethylation of a wide range of
iodoarenes, bromoarenes, such as pyridine, pyrimidine, pyrazine, and thiazole derivatives,
and bromoarenes bearing electron-withdrawing groups (Fig. 424B).
Hu and coworkers have generated pentafluoroethyl-Cu(I) reagent [(CF3CF2)Cu(I)], in situ,
by the reaction of CuCl with CF3TMS in the presence of KF and pyridine in DMF solvent, at
relatively high temperature. The formation of the CuCF2CF3 may involve the intermediate
formation of the difluoromethylene carbene (:CF2) from the initially formed CF3Cu(I), and its
insertion into the CuCF3 bond to give the CuCF2CF3.37 This in situ generated reagent reacts
with various aryl iodides to give their corresponding pentafluoroethyl derivatives in good
yields (Fig. 424C).
4.11 Ni-catalyzed trifluoromethylthiolation
Trifluoromethylthiolated compounds have found applications as pharmaceuticals, agrochemicals, and as veterinary medicines. Synthetic methods for the electrophilic trifluoromethylthiolations have been extensively investigated, and there are many commercially
available electrophilic trifluoromethylthiolating reagents (see Chapter 2: Electrophilic reactions in the synthesis of organofluorine compounds).
128
Organofluorine Chemistry
FIGURE 4–24 Cu(I)-catalyzed trifluoromethylation and pentafluoroethylation of aryl halides: (A) trifluoromethylatin
of ArI and ArBr, mediated by (phen)CuCF3 (Hartwig and coworkers); (B) trifloromethyhlation of ArI and ArBr, using
ligand-less CF3Cu (Grushin and coworkers); and (C) pentafluoroethylation of ArI using the in situ generated
CuCF2CF3 (Hu and coworkers). phen 5 1,10-phenanthroline
Schoenebeck and coworkers have developed Ni-catalyzed trifluoromethylthiolation of aryl
and vinyl triflates, using (Me4N)SCF3 as the trifluoromethylthiolating agent (Fig. 425). This
organometallic approach for the trifluoromethylthiolation is applicable for the synthesis of
biologically interesting compounds, such as flavanones and estrone derivatives and serves as
an alternative approach to the electrophilic trifluoromethylthiolations (see Chapter 2:
Electrophilic reactions in the synthesis of organofluorine compounds). These Ni(0)-catalyzed
trifluoromethylthiolations presumably proceeds through oxidative addition of the aryl triflates to Ni(0), transmetalation, and reductive elimination of the ArSCF3.
Chapter 4 • Organotransition metal catalysis in the synthesis
129
FIGURE 4–25 Ni-catalyzed trifluorothiomethylation of aryl triflates.
4.12 Pd(II)-catalyzed (amino)trifluoromethoxylation
Introduction of the trifluoromethoxy group into organic compounds is challenging as the
nucleophilic CF3O2 anion is prone to dissociate into fluoride anion and fluorophosgene
(COF2). Transition metaltrifluoromethoxide complexes also have a tendency to undergo
β-fluoride elimination to give COF2. AgOCF3, on the other hand, is stable to dissociation of
fluoride anion and is useful in the trifluoromethoxylation of alkenes.
The oxidative (amino)cyclization of N-tosyl-2,2-dialkyl-4-pentenamines (e.g., 79, 81, 83,
and 85), in the presence of AgOCF3, catalytic amounts of Pd(II) catalyst, and Selectfluor as
the oxidant, gives the corresponding trifluoromethoxy piperidines in moderate-to-high
yields. The unsubstituted compound 79 (when R and R0 5 H) failed to cyclize in these reactions, implying that the gem-dialkyl groups exert angle-suppression effect (ThropeIngold
effect) on the linear chain, favoring the cyclization (Fig. 426).38
A possible mechanism was suggested to involve a reversible (amino)palladation, followed
by oxidation of the resulting secondary alkylPd(II) intermediate (87) by Selectfluor to give
the high-valent (alkyl)(OCF3)Pd(IV) complex (88), which spontaneously undergoes reductive
elimination to give the 3-(trifluoromethoxy)piperidines (Fig. 426). Apparently, the reductive
elimination of the high-valent Pd(IV)(alkyl)(OCF3) (88) is relatively faster than the
130
Organofluorine Chemistry
FIGURE 4–26 Pd(II)-catalyzed (amino)trifluoromethoxylation of N-tosyl-4-pentenamines, in the presence of AgOCF3
and Selectfluor; Ts 5 4-methylbenzenesulfonyl.
β-elimination of the fluoride in these reactions, so that the major products are the trifluoromethoxylated compounds. Liu and coworkers confirmed the intermediacy of the Pd(IV)
(OCF3) intermediates in these reactions by the single-crystal X-ray analysis of the intermediate and by NMR studies.38
Chapter 4 • Organotransition metal catalysis in the synthesis
131
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5. Preshlock, S.; Tredwell, M.; Gouverneur, V. 18F-Labeling of Arenes and Heteroarenes for Applications in
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6. Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L.
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van Gastel, M.; Neese, F.; Ritter, T. Palladium-Catalysed Electrophilic Aromatic CH Fluorination.
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10. Koperniku, A.; Liu, H.; Hurley, P. B. Mono- and Difluorination of Benzylic Carbon Atoms. Eur. J. Org.
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11. Liu, W.; Groves, J. T. Manganese Catalyzed CH Halogenation. Acc. Chem. Res. 2015, 48, 17271735.
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14. Liu, W.; Huang, X.; Placzek, M. S.; Krska, S. W.; McQuade, P.; Hooker, J. M.; Groves, J. T. Site-Selective
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15. Park, H.; Verma, P.; Hong, K.; Yu, J.-Q. Controlling Pd(IV) Reductive Elimination Pathways Enables Pd
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16. Xu, P.; Wang, G.; Zhu, Y.; Li, W.; Cheng, Y.; Li, S.; Zhu, C. Visible-Light Photoredox-Catalyzed CH
Difluoroalkylation of Hydrazones Through an Aminyl Radical/Polar Mechanism. Angew. Chem., Int. Ed.
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Highly Selective Photoredox C(sp2)-H Difluoroalkylation and Perfluoroalkylation of Hydrazones. Angew.
Chem., Int. Ed. 2016, 55, 29342938.
18. Pair, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O. Copper-Catalyzed Trifluoromethylation of N,NDialkylhydrazones. Angew. Chem., Int. Ed. 2013, 52, 53465349.
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20. Akana, J. A.; Bhattacharyya, K. X.; Mueller, P.; Sadighi, J. P. Reversible CF Bond Formation and the AuCatalyzed Hydrofluorination of Alkynes. J. Am. Chem. Soc. 2007, 129, 77367737.
21. Olah, G. A.; Li, X. Y.; Wang, Q.; Prakash, G. K. S. Synthetic Methods and Reactions. 169. Poly-4Vinylpyridinium Poly(Hydrogen Fluoride): A Solid Hydrogen Fluoride Equivalent Reagent. Synthesis
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Regioselective Synthesis of Fluoroalkenes and gem-Difluoromethylene Compounds From Alkynes. J. Am.
Chem. Soc. 2014, 136, 1438114384.
23. Wu, Y.; Zhang, H.-R.; Cao, Y.-X.; Lan, Q.; Wang, X.-S. Nickel-Catalyzed Monofluoroalkylation of
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5
Pharmaceutical applications of
organofluorine compounds
Chapter Outline
5.1 Introduction ............................................................................................................................... 134
5.1.1 Bloodbrain permeability .............................................................................................. 136
5.1.2 Metabolic stability and bioavailability .......................................................................... 137
5.1.3 ππ Stacking interactions............................................................................................... 140
5.2 Antibacterial pharmaceuticals.................................................................................................. 141
5.2.1 Fluoroquinolones............................................................................................................. 142
5.2.2 Tetracyclines..................................................................................................................... 145
5.3 Antidiabetic pharmaceuticals................................................................................................... 146
5.3.1 Sitagliptin ......................................................................................................................... 146
5.3.2 Carmegliptin .................................................................................................................... 150
5.3.3 Canagliflozin .................................................................................................................... 151
5.4 Anti-Alzheimer pharmaceuticals.............................................................................................. 152
5.4.1 BACE-1 inhibitors ............................................................................................................. 153
5.4.2 γ-Secretase inhibitors and modulators .......................................................................... 159
5.5 Anti-HIV pharmaceuticals ......................................................................................................... 163
5.5.1 Bictegravir ........................................................................................................................ 163
5.5.2 Doravirine......................................................................................................................... 165
5.6 Antimalarial pharmaceuticals................................................................................................... 165
5.6.1 Tafenoquine..................................................................................................................... 165
5.6.2 Mefloquine....................................................................................................................... 166
5.7 Anticancer pharmaceuticals ..................................................................................................... 167
5.7.1 Dacomitinib.................................................................................................................... 167
5.7.2 Lorlatinib ........................................................................................................................ 169
5.7.3 Cobimetinib.................................................................................................................... 171
5.7.4 Abemaciclib.................................................................................................................... 172
5.7.5 PARP inhibitors: rucaparib (Rubraca) and olaparib (Lynparza) ................................. 172
5.7.6 Taxoid anticancer agents .............................................................................................. 173
5.7.7 Fulvestrant...................................................................................................................... 177
5.7.8 Enasidenib ...................................................................................................................... 178
5.7.9 Nonsteroidal antiandrogens (apalutamide, bicalutamide, and flutamide) ............. 181
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00005-5
© 2020 Elsevier Inc. All rights reserved.
133
134
Organofluorine Chemistry
5.7.10 BRAF and mitogen-activated protein kinase kinase enzyme inhibitors in cancer
treatment ....................................................................................................................... 183
5.8 Antiviral pharmaceuticals......................................................................................................... 185
5.8.1 Tecovirimat....................................................................................................................... 185
5.8.2 Sofosbuvir......................................................................................................................... 187
5.8.3 Ledipasvir ......................................................................................................................... 189
5.8.4 Glecaprevir and pibrentasvir .......................................................................................... 190
5.8.5 Voxilaprevir ...................................................................................................................... 194
5.8.6 Letermovir (Prevymis)...................................................................................................... 194
5.9 Fluorinated pharmaceuticals for cardiovascular diseases ..................................................... 195
5.9.1 Statin drugs ...................................................................................................................... 195
5.9.2 Ezetimibe.......................................................................................................................... 196
5.9.3 Nebivolol .......................................................................................................................... 196
5.9.4 Antiplatelet drugs ........................................................................................................... 197
5.10 Antiinflammatory pharmaceuticals ......................................................................................... 199
5.10.1 Nonsteroidal antiinflammatory agents ....................................................................... 199
5.10.2 Celecoxib ........................................................................................................................ 200
5.10.3 Corticosteroids ............................................................................................................... 200
5.11 Antidepressants......................................................................................................................... 202
References........................................................................................................................................... 204
5.1 Introduction
Incorporation of fluorine or fluorinated moieties as bioisosteres in the lead compounds has
emerged as the major focus of the drug design efforts. In 2018 nearly one-third of the FDAapproved drugs, that is, 18 out of the 59 drugs approved, were fluorine- or fluoroalkyl(aryl)
moietycontaining compounds. Due to the relatively small van der Waals radius of fluorine
(1.47 Å for fluorine; 1.20 Å for hydrogen; 1.23 Å for sp2-hybridized oxygen; and 1.43 Å for the
sp3-hybridized oxygen) and its high electronegativity (EN 5 3.98, highest of all the elements), gem-difluoromethyl (CF2) moiety is bioisosteric with respect to the oxygen in ethers
and alcohols, and trifluoromethyl (CF3) substituent is bioisosteric with respect to chloro,
bromo, and cyano moieties. It is a common practice in drug design to replace the oxidatively
unstable CH bonds by CF bonds because of the relatively stronger CF bond strength
and biochemical stability. The drug candidates appropriately modified by the fluorine and
fluoroalkyl(aryl) moieties, including CF2 and CF3 moieties, often show improved pharmacokinetic and pharmacodynamic properties. Fluorine is more lipophilic than the hydrogen,
hydroxyl, and carbonyl moieties, is not as polarizable as other halogen atoms, and exhibits
limited halogen-bonding effects. Due to these favorable steric and stereoelectronic effects,
fluorine and fluoroalkyl groups (e.g., CF2) could be used as bioisosteres of hydrogen, carbonyl, and hydroxyl groups. Furthermore, the fluoroalkyl substituents provide improved
Chapter 5 • Pharmaceutical applications of organofluorine compounds
135
lipophilicity and modulate acidity and basicity of the pharmacophores, thereby enhancing
the bioavailability of the fluorinated drug candidates.1,2 Fluorine atom is a biomimetic (bioisosteric) of hydrogen atom and thus replacement of CF3 moiety in place of CH3 moiety
would not significantly alter pharmacokinetic properties, such as P-glycoprotein (P-gp) recognition, membrane permeability, and lipophilicity. On the other hand, CF3, CF2, OCF3, or
OCF2H groups enhance oxidative stability, when placed at or adjacent to the CH bonds
that are prone to enzymatic oxidation. For example, fluorination or fluoroalkoxylation of
the aromatic ring in the taxoid compounds would result in enhanced metabolic stability and
potency (vide infra).3
Many of the blockbuster drugs, including the cholesterol-lowering drug atorvastatin
(Lipitor), are fluorinated compounds (Fig. 51). Atorvastatin was the third most prescribed
drug as of 2016.4 The structurally related statins, rosuvastatin, fluvastatin, and cerivastatin, all
have p-fluorophenyl moiety attached to the heterocyclic aromatic ring, and these statin drugs
have high affinity to the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, with
half-maximal inhibitory constant (IC50), ranging from 5 to 28 nM.5 An X-ray crystal structure of
the atorvastatin bound to HMG-CoA reductase shows orthogonal multipolar interactions6,7 of
the fluorine with the Arg590 guanidino carbon (3.1 Å) and polar (or hydrogen bonding) interactions with the Arg590 guanidino moiety and Ser661 hydroxyl group. This demonstrates the
OH
OH
F
O
O
N
O
N
N
S
O N
OH
NH
OH
OH
OH
O
F
Rosuvastatin
IC 50 = 5 nM
Atorvastatin
IC 50 = 8 nM
F
F
OH
OH
N
OH
Fluvastatin
IC 50 = 28 nM
OH
O
O
OH
O
OH
N
Cerivastatin
IC 50 = 10 nM
FIGURE 5–1 Structure of atorvastatin and structurally related statins, the widely used cholesterol-lowering drugs.
The IC50 values shown are for the inhibition of the HMG-CoA reductase; HMG-CoA, 3-Hydroxy-3-methylglutaryl
coenzyme A; IC50, half-maximal inhibitory constant.
136
Organofluorine Chemistry
FIGURE 5–2 Expanded view of the X-ray structure of atorvastatin bound to HMG-CoA reductase, showing the
multipolar and hydrogen bonding interactions of the aryl fluorine with Arg590 and Ser660 residues; multipolar
and hydrogen bond distances (Å) are shown on the dotted lines; the structure was created using UCSF Chimera
software; PDB 1HWK; HMG-CoA, 3-Hydroxy-3-methylglutaryl coenzyme A.
stabilizing effect of the aryl fluorine, involving multipolar and hydrogen-bonding interactions.
The stabilization energies for the multipolar interactions of the fluorine were estimated to be
in the order of 0.30.6 kcal/mol (Fig. 52).8
5.1.1 Bloodbrain permeability
When fluorine or fluoroalkyl groups are placed proximal to the amino groups, the basicity of
the amines is significantly attenuated, and therefore the lipophilicity and membrane permeability of these compounds are enhanced. For example, the quinuclidine 1 is a potent α7 nicotinic
acetylcholine receptor (nAChR; involved in the long-term memory) agonist, but due to its relatively high basicity, compound 1 has poor bloodbrain barrier (BBB) permeability, probably
because of the increased transporter-mediated efflux. The fluorine-substituted analog 2 has a
dramatic decrease in the basicity (ΔpKa 5 2.5), thereby substantially improved bloodbrain
penetration, as determined by a Caco-2 (human epithelial colorectal adenocarcinoma cell line)
permeability assay. Thus, the Caco-2 P-gp efflux ratios for the compounds 1 and 2 are 6.9 and
0.6, respectively (Fig. 53).9 The P-gp-mediated efflux ratios of greater than 3 are generally
indicative of the compounds being P-gp substrates and, therefore, are not retained in the brain
tissues in sufficient concentrations for the drug to be active.10 Based on this empirical criterion,
in order to be effective central nervous system (CNS) drugs, the efflux ratios should be less than
3. Although compound 2 is a relatively less potent α7 nAChR agonist than compound 1, these
results nevertheless indicate the importance of modulating the basicity of the amino groups for
improved bloodbrain permeability.9
Chapter 5 • Pharmaceutical applications of organofluorine compounds
N
N
O
N
N
1
pKa = 10.1
137
O
F
2
pKa = 7.6
Caco-2 efflux ratios: 6.9
0.6
FIGURE 5–3 Structures of quinolonequinuclidine moiety containing α7 nAChR agonists, and the effect of basicity
on the bloodbrain permeability, as measured by the Caco-2 efflux ratio (the lower the pKa, the lower the efflux
ratio, and thereby the higher the bloodbrain permeability); nAChR, Nicotinic acetylcholine receptor.
As indicated above, in order for the drug candidate to show optimal BBB penetration, the
compound should have high passive permeability across the BBB and decreased efflux transporter liability (i.e., the lower the efflux ratio, the better the BBB penetration). Substitution of
fluorine at the strategic positions increases lipophilicity and thereby increases passive permeability of the drug candidate, and also decreases basicity of the amino groups, as shown earlier in the case of an α7 nAChR agonist. Silverman and coworkers designed analogs of a lead
compound 3 (selective inhibitor of human neuronal nitric oxide synthase) with enhanced
lipophilicity through incorporation of an additional aryl CF bond in the linker fragment.
Furthermore, the basicity of the terminal tertiary amine moiety decreases with increasing ring
strain (i.e., attenuated flexibility of the amino group). The least strained amine with the openchain tertiary-amino moiety (compound 3) has the highest basicity among the series of its
analogs, N-methyl-azacyclopentane (4) and N-methyl-azacyclobutane (5; the most strained in
the series). As a result of these structural optimizations, the Caco-2 efflux ratios for compounds 3, 4, and 5 are in the decreasing order of 5.9, 2.1, and 0.8, respectively (Fig. 54).11
The selectivity of the compounds 4 and 5 toward human nitric oxide synthase are
retained or slightly enhanced (Ki 5 21 and 23 nM for compounds 4 and 5, respectively) as
compared to the parent lead compound 3 (Ki 5 30 nM). The passive permeabilities of the
compounds 4 and 5, as measured by PAMPA-BBB (parallel artificial membrane permeability
for the BBB) assay, are also enhanced as compared to the lead compound 3: 14.8 3 1026,
17.0 3 1026, 16.3 3 1026 cm/s, respectively, for compounds 3, 4, and 5.11 In general, CNS
positive drugs have effective permeability values higher than 4.0 3 1026 cm/s.11
5.1.2 Metabolic stability and bioavailability
The fluorine substitution, in general, results in improved pharmacokinetic and pharmacodynamic properties for the drug candidates. Often, the incorporation of a single fluorine on the
aryl rings provides enhanced metabolic stability and enhanced potency to the pharmaceuticals,
138
Organofluorine Chemistry
H2 N
N
N
H2 N
N
N
F
F
F
4
3
Efflux ratio (Caco-2): 2.1
Efflux ratio (Caco-2): 5.9
H2 N
N
N
F
F
5
Efflux ratio (Caco-2): 0.8
FIGURE 5–4 Optimization of hnNOS inhibitor lead compound 3 for effective bloodbrain barrier penetration;
hnNOS, Human neuronal nitric oxide synthase.
as compared to those of the structurally similar nonfluorinated compounds. Similarly,
replacement of the alkyl groups by the fluoroalkyl moieties could result in significantly
improved metabolic stability and thereby, bioavailability. As an illustrative example, sitagliptin (Januvia), a widely prescribed drug to treat diabetes, has substantially improved bioavailability as compared to the analogous pharmacophores with a methyl or ethyl substituent on
the triazole ring (6). Sitagliptin exerts its antidiabetic effect through inhibition of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Sitagliptin exerts its antihyperglycemic effect (i.e., lowering of the blood-glucose levels) by inhibiting the DPP-IV enzyme. The latter enzyme
degrades the incretins GLP-1 (glucagon-like peptide-1) and gastric inhibitory peptide, the
gastrointestinal hormones, whose function is to stimulate insulin secretion and reduce the
amount of glucose produced by the liver, as needed. Through inhibition of the DPP-IV
enzyme, sitagliptin helps elevate the incretin levels and thereby increase the insulin secretion
from the pancreatic β-cells and decrease blood-glucose levels.12
The substantially high oral bioavailability of sitagliptin (by about 76%) as compared to its
difluoromethyl (CF2H) and ethyl analogues is because of the metabolically inert trifluoromethyl (CF3) moiety in the triazole ring. The corresponding difluoromethyl and ethyl analogs
are prone to relatively fast biodegradation. Thus, whereas the bioavailability of the ethylsubstituted analog 7 is only 2% of the total administration, the bioavailability of the
Chapter 5 • Pharmaceutical applications of organofluorine compounds
139
F
F
F
NH2 O
N
N
N
CF3
Sitagliptin
Oral bioavailability:
NH2 O
N
F
IC50 for
DPP-4 inhibition:
F
F
N
F
76%
NH2 O
N
N
N
N
F
N
CH2 CH3
7
29 nM
N
N
CF2H
6
13 nM
F
37 nM
39%
2%
FIGURE 5–5 Pharmacokinetics of the antidiabetic drug sitagliptin and its structural analogs.
difluoromethyl analog 6 is relatively enhanced (39%) (Fig. 55).11 The strong CF bond of
the CF3 moiety resists biodegradation as compared to the relatively weaker CH bonds in
accordance with these observed trends in bioavailability (vide infra).
Sitagliptin has relatively improved DPP-IV inhibitory effect (IC50 5 13 nM) as compared
to the related difluoromethyl and ethyl analogs (IC50 5 29 and 37 nM for 6 and 7, respectively; Fig. 55).13 Sitagliptin illustrates a case in which the trifluoromethyl group increases
bioavailability due to its enhanced metabolic stability and at the same time is more potent,
with a relatively lower IC50 value for the DPP-IV enzyme inhibition, as compared to the
difluoromethyl and ethyl analogs.
The gem-difluoromethylene moiety in 1,3-dioxoles protects them from CYP450mediated oxidative degradation. Cystic fibrosis drugs, lumacaftor and tezacaftor, serve as
the examples of the drugs, which contain the gem-difluoro-1,3-dioxole moiety to enhance
their metabolic stability. Lumacaftor (VX-809; Vertex Pharmaceuticals) is used to treat
cystic fibrosis patients, as a combination drug with ivacaftor (also called Orkambi).14 In
cystic fibrosis the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a
cyclic adenosine monophosphatedependent anion-gate channel, is misfolded due to
the genetic defect and is unable to transport fluids across the epithelium.15 Genetic
mutation resulting in the deletion of phenylalanine at the 509 residue (F509del) is the
key factor in the misfolding of the CFTR protein.16 Lumacaftor acts as a chaperone for
the correct protein folding of the CFTR and its trafficking to the cell surface, thus restoring the ion-gate channels and thereby alleviating the symptoms of cystic fibrosis. The
3,3-difluoro-1,3-dioxole moiety in this compound helps attenuate the metabolic instability to the cytochrome P450 enzymes. In contrast, the nonfluorinated 1,3-dioxoles as well
as the catechol derivatives are prone to oxidative degradation by the CYP450 enzymes.
The CYP450 enzymes oxidize the nonfluorinated 1,3-dioxole moiety to the carbene intermediate that complexes to the CYP450 iron centers and thereby inhibit these enzymes,
whereas in the gem-difluoro analog, such carbene formation is disfavored as it cannot be
140
Organofluorine Chemistry
F
F
F
O
F
O
O
O
OH
H
N
H
N
N
O
OH
N
O F
O
HO
HO
Lumacaftor
O
O
H
H
Tezacaftor
O
CYP450
R
CYP450
O
Fe(III)
O
O
R
O
O
CYP450
R
Carbene-ligated
CYP450 (deactivated enzyme)
F
F
R
(Carbene formation is prevented and
does not deactivate the enzyme)
FIGURE 5–6 Structures of the cystic fibrosis pharmaceuticals, lumacaftor and tezacaftor; the
difluoromethylenebenzodioxole moiety is metabolically more stable to the cytochrome P450 oxidase.
readily oxidized.2 Vertex Pharmaceuticals’ next-generation CFTR potentiator, tezacaftor
(FDA-approved in 2018), is a structural analog of lumacaftor with improved bioavailability (Fig. 56).17
Fluorination of aryl rings seem to afford optimal pharmacokinetic properties for the FDAapproved pharmaceuticals baloxavir marboxil (Xofluza; ROCHE AGE; for the treatment of
influenza A and B),18 fostamatinib (Tavalisse; Regel Pharmaceuticals, Inc., for chronic
immune thrombocytopenia), and safinamide [Xadago; a monoamine oxidase-B (MAO-B)
inhibitor used in the treatment of Parkinson’s disease] (Fig. 57).19
5.1.3 ππ Stacking interactions
N-3,5-Bis(trifluoromethyl)benzylcarboxamides (e.g., in TAK-637), due to hindered rotation
across the amide CN bond, exist as atropisomers. Due to the strong electron-withdrawing
effect of the two CF3 groups, the bis(trifluoromethyl)aryl ring is electron deficient and
Chapter 5 • Pharmaceutical applications of organofluorine compounds
F
S
O
F
P
O
N
O
N
N
Me
Me
O
O
O
Me
Baloxavir Marboxil O
(Xofluza)
(for the treatment of influenza A and B)
O
H
N
N
N
O
O
O
H
N
O
Me
F
141
H
N
F
N
OH
OH
N
O
O
Me
Me
O
Fostamatinib (Tavalisse)
(for the treatment of chronic immune thrombocytopenia)
O
NH2
Me
Safinamide (Xadago)
(for the treatment of Parkinson's disease)
FIGURE 5–7 Structures of selected FDA-approved drugs consisting of fluorinated aromatics.
thereby is involved in the donor-acceptor π2π-stacking interactions with the adjacent
electron-donating aryl rings.20 This conformational bias is responsible for the excellent
neurokinin-1 (NK1) antagonistic activity of TAK-637. Presumably, similar π2π-stacking interaction is responsible for the NK1-receptor antagonistic characteristics of fosnetupitant (netupitant; Akynzeo), an FDA-approved combination drug for the treatment of acute nausea and
vomiting induced by the cancer chemotherapy (Fig. 58).21,22
5.2 Antibacterial pharmaceuticals
Organoarsenicals and sulfa drugs were among the first antibacterial drugs developed in early
1900. These highly toxic drugs were later replaced by a number of complex, naturally occurring antibiotics, including penicillin, streptomycin, and erythromycin. As a consequence of
rapid evolution of drug-resistant pathogenic bacteria, many of these antibacterials are
increasingly ineffective in many cases. Semisynthetic modifications of these antibacterials
play a dominant role in the current antibacterial drug discovery.
Erythromycin is used for Gram-positive bacterial infections. It is one of the most prescribed antibiotics and is in the United Nations’ list of essential medicines. However, erythromycin has low oral bioavailability and relatively short in vivo half-life, and is unstable
under acidic conditions. The chemical instability is attributed to the reaction of the C6 and
C12 hydroxy groups with the C9-ketone moiety, forming spiroketal derivatives.23,24
142
Organofluorine Chemistry
OOH
P
O
O
O
N
Me
N
F
N+
N
N
N
F
F
O
O
F
N
Me
F3 C
F
F
CF3
TAK-637
Fosnetupitant
FIGURE 5–8 Structures of NK1 antagonists, TAK-637, and fosnetupitant (an FDA-approved drug), illustrating the
possible π2π stacking interactions; NK1, Neurokinin-1.
9
O
O
H
HO
F
HO
OH
12 OH
OH
6
O
O
O
O
O
O
O
O
O
HO
O
OH
O
O
N
HO
O
N
O
HO
HO
Flurithromycin
Erythromycin-A
FIGURE 5–9 Structures of the broad-spectrum antibiotics, erythromycin and flurithromycin, a C8-fluorinated version
of the erythromycin-A.
Flurithromycin is a second-generation erythromycin, differing from erythromycin by the
presence of a single fluorine on the C8 carbon (Fig. 59). The fluorine enhances metabolic
stability, and bioavailability of the drug, as compared to the erythromycin. The enhanced
metabolic stability may presumably be due to the decreased basicity of the C6-hydroxy group
as well as due to the destabilization of the intermediate C9-carbocation intermediate, thereby
disfavoring the spiroketal formation.
5.2.1 Fluoroquinolones
In general, quinolone and fluoroquinolone antibiotics are among the most widely used drugs
worldwide and because of their extensive use over decades, quinolone-resistant bacterial
Chapter 5 • Pharmaceutical applications of organofluorine compounds
143
strains have steadily increased. FDA-approved fluoroquinolone antibiotics include levofloxacin (Levaquin), ciprofloxacin (Cipro), moxifloxacin (Avelox), ofloxacin, sparfloxacin, and
gemifloxacin (Factive) (Fig. 510). Although these fluoroquinolones are effective antibacterial agents and are widely used worldwide for the treatment of bacterial infections, the
potential risks posed by the use of the drugs, such as permanent disabling side effects involving tendons, muscles, joints, and the CNS, outweigh their therapeutic benefits in some cases,
according to the FDA announcements in 2016 and 2018.2527 In some serious bacterial infections, such as plague and bacterial pneumonia, the benefits of fluoroquinolone antibiotics,
however, outweigh their risks, according to these FDA guidelines. According to the FDA’s
warning about the adverse effects of fluoroquinolones in certain patients (nine aortic aneurysm events per 100,000 people per year in the general population to 300 aortic aneurysm
events per 100,000 people per year in individuals at highest risk), “the fluoroquinolone
O
O
O
F
O
F
OH
OH
N
N
N
O
Me O
N
N
HN
HN
Me
Ciprofloxacin
O
N
Me
Me
N
HO
O
O
N
O
Levofloxacin
((S)-isomer of ofloxacin)
Ofloxacin
(racemic)
Me
F
N
NH
N
HO
Me
F
O
O
Me
O
N
NH2
Sparfloxacin
FIGURE 5–10 Structures of selected FDA-approved fluoroquinolones.
Me
N
N
F
F
O
N
Gemifloxacin
O
N
N
HO
N
OH
H 2N
Norfloxacin
Me
O
F
HO
N
F
O
O
Moxifloxacin
H
NH
H
144
Organofluorine Chemistry
antibiotics can increase the occurrence of rare but serious events of ruptures or tears in the
main artery of the body, called aorta. These tears, called aortic dissections, or ruptures of an
aortic aneurysm can lead to dangerous bleeding or even death.”25 The mechanisms of the
toxicity of fluoroquinolones, and, in particular, the effect of the fluorine moiety on the toxicity, are not clearly delineated. Thus, it is now even more important to understand the mechanistic basis of the therapeutic as well as the adverse effects of these fluoroquinolone drugs,
so that improved drug-resistant and safe antibiotics could be designed.
Levofloxacin is an enantiomerically pure version [levorotatory, (S)-configuration] of oflaxacin.
Levofloxacin, moxifloxacin, and sparfloxacin show potent activity against some Gram-positive
and Gram-negative bacteria. These quinolones as well as ciprofloxacin (also active against
Gram-positive bacteria) have been widely used in respiratory tract infections, chronic bronchitis,
and community-acquired pneumonia, among other bacterial infections. The quinolone antibiotics also have favorable pharmacokinetics. Especially due to the superior pharmacokinetics of
levofloxacin, as compared to the other members of this class, a single pill-a-day suffices for the
treatment of bacterial infections.28 However, as described earlier, in some cases, these fluoroquinolone antibiotics exhibit severe adverse effects, and the recent FDA warnings recommend
the use of alternate antibiotics when other treatment options are available.
Delafloxacin (Baxdela; Rib-X Pharmaceuticals) is an FDA-approved fluoroquinolone antibiotic that is used to treat multidrug-resistant (MDR) Gram-negative and Gram-positive bacterial infections (Fig. 511). The preclinical and clinical trial data suggest delafloxacin does
not cause the drug-related adverse effects, that is, those adverse effects typically associated
with other fluoroquinolone antibiotics. It was concluded that the use of delafloxacin for treating acute, bacterial skin infections and skin structure infections in over 1400 patients for up
to 14 days is as effective as that of vancomycin with or without aztreonam.29,30 However,
delafloxacin is structurally similar to the other fluoroquinolones and therefore is susceptible
to the emergence of possible future drug-resistant newer bacterial-resistant strains. It is also
active against methicillin-resistant Staphylococcus aureus and several other fluoroquinoloneresistant bacterial strains.
O
O
F
OH
N
HO
N
Cl
F
N
H2 N
F
Delafloxacin (Baxdela)
FIGURE 5–11 Structure of delafloxacin (Baxdela), an FDA-approved antibacterial drug against multidrug-resistant
bacterial infections.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
145
H
O
N
N
O
F
O
O
H
O
H
O H
OH 2
Mg2+
H 2O
O
NH
H
O
H
OH
Ser 84
Glu88
FIGURE 5–12 Schematic illustration of moxifloxacin at the active site of the bacterial topoisomerase IV.
5.2.1.1 Mechanism of action of fluoroquinolones
The fluoroquinolones are bactericidal drugs, that is, they kill bacteria. The quinolone antibiotics inhibit DNA replication in the bacterial cells, by inhibiting the bacterial DNA gyrase (topoisomerase II) and topoisomerase IV (a type IIA topoisomerase), which are unique to the
bacterial cells but not the eukaryotic cells. The latter bacterial type II toposiomerases are heterotetrameric enzymes consisting of two A subunits and two B subunits. Human type II topoisomerases, in contrast to the bacterial type IIA topoisomerases, are homodimeric and thus are
not the targets of quinolone antibiotics.28 These topoisomerases II and IV are critical to the
bacterial DNA replication.
X-ray crystal structures of moxifloxacin bound to the topoisomerase IV show that noncatalytic Mg21 is chelated to the quinoline carbonyl and the carboxylate moieties and is bound to
four water molecules in an octahedral environment. The Mg21 bound water molecules, in
turn, are involved in hydrogen bonding with the protein Ser84 and Glu88 residues (Fig. 512).
The Mg21-promoted ππ-stacking interactions of quinolone with the base pairs, at the DNA
cleavage sites, results in the inhibition of the type IIA topoisomerase. Accordingly, mutations
at the Ser84 and Glu88 sites in topoisomerase IV give drug resistance to the quinolone drugs.31
5.2.2 Tetracyclines
Systematic structural variation of the antibiotics, through the incorporation of fluorine or fluoroalkyl substituents, provides an opportunity to design drug-resistant antibiotics, such as tetracyclines, fluoroquinolones, penicillins, cephalosporins, and carbapenems. Tetracycline antibiotics
have been used for decades to treat bacterial infections resulting from both Gram-positive and
Gram-negative bacteria. Over the years, bacteria acquired resistance to these tetracycline antibiotics. The drug resistance for tetracyclines is mostly due to the active drug efflux, and ribosomal protection afforded by the drug-resistant bacteria, the mechanisms that are most
commonly found in Gram-positive bacteria, such as S. aureus and Streptococcus spp. Some of
the widely used synthetic analogs of the naturally occurring tetracyclines for treating bacterial
infections include chlorotetracycline, doxycycline, and fluorocyclines (Fig. 513).
Eravacycline (Xerava, Tetraphase Pharmaceuticals), a tetracyclic antibiotic, consisting of a
fluorine in the D-ring, was approved by FDA in 2018 for complicated intra-abdominal
146
Organofluorine Chemistry
HO
D
OH
H
C
B
OH
Cl HO
OH N
H
H
OH N
H
O
O
A
OH
O
H
H
7
D
N
H 9
OH
O
NH2
O
OH
OH
O
OH
OH
OH
O
OH
O
Doxycycline
N
O
O
N
OH
Chlorotetracycline
Tetracycline
F
OH N
H
NH2
NH2
OH
OH
H
O
C
B
A
OH
OH
OH
O
NH2
O
Eravacycline (FDA approved in 2018)
FIGURE 5–13 Structures of some of the widely used tetracycline antibiotics; eravacycline is the next-generation
fluorotetracycline antibiotic that is active against multidrug-resistant bacterial strains.
infections in adult patients.32,33 It shows potent antibacterial activity against MDR Grampositive and Gram-negative bacterial strains. However, some bacteria, such as Enterococcus
spp., show resistance to eravacycline.
Tetraphase Pharmaceuticals’ synthesis of the eravacycline and other fluorocyclines with a
variety of the amino substituents at the C9-carbon is outlined in Fig. 514. The D-ring precursor 9 was synthesized from the 2-mexthoxy-5-fluorobenzoic acid (8), through regioselective deprotonation using s-BuLi, followed by methylation using methyl iodide, esterification
of the carboxy moiety, demethylation of the ether moiety using BBr3, followed by protection
of the phenolic hydroxy group as tert-butyloxycarbonyl derivative (t-Boc), using di(tert-butyl)
dicarbonate [(Boc)2O]. The tandem MichaelDieckmann cyclization of the fluoroarene 9
with the enone 10, followed by deprotection and installation of the C9-amino substituents
gave eravacycline. Using this general procedure, various C9-acetamido derivatives were synthesized and tested for their efficacy as antibacterial agents.33 Among many such derivatives,
eravacycline exhibited the optimal and potent antibacterial activity against MDR bacteria and
was finally approved by FDA for clinical use in 2018.
5.3 Antidiabetic pharmaceuticals
5.3.1 Sitagliptin
As described in Section 5.1, inhibitors of DPP-IV are among the effective therapeutics for
type 2 diabetes. The type 2 diabetes is characterized by hyperglycemia that leads to various
diabetes-induced complications such as diabetic retinopathy, diabetic neuropathy, and
Chapter 5 • Pharmaceutical applications of organofluorine compounds
H
1.
F
F
1. s-BuLi
CO2H
OMe
2.
3.
4.
5.
CO2Ph
Ot-Boc
O
B
A
N
O
OH
O
OBn
2. Deprotections
3. Derivatizations
9
8
F
H
H
N
O
O
N
N
10
Michael–Dieckmann annulation
CH3
MeI
Esterification
BBr 3
(Boc) 2 O
147
D
N 9
H
OH
C
B
A
OH
OH
OH
O
NH2
O
Eravacycline
FIGURE 5–14 Outline of the synthesis of eravacycline; Bn, Benzyl; (Boc)2O, di(tert-butyl)dicarbonate; t-Boc, tertbutyloxycarbonyl.
F
F
F
NH 2 O
N
N
N
N
CF3
Sitagliptin (Januvia)
DPP-IV inhibtor; antidiabetic drug
FIGURE 5–15 Structure of sitagliptin, a DPP-IV inhibitor, and a widely used antidiabetic drug.
cardiovascular complications. GLP-1 induces pancreatic secretion of insulin, and inhibits
glucagon secretion, thus reversing hyperglycemic state in the body. However, GLP-1 peptide
is rapidly cleaved by the DPP-IV enzyme in the diabetic cases. Therefore drugs targeting
inhibition of the DPP-IV enzyme provide an attractive means for the treatment of diabetes 2
cases. Sitagliptin (Januvia), a DPP-IV inhibitor, is among the widely used FDA-approved antidiabetic drugs (Fig. 515). During the optimization of the drug candidate, it was found that
the 2,4,5-trifluorophenyl substituent in sitagliptin showed relatively enhanced IC50 value
(18 nM) for the inhibition of the DPP-IV, as compared to the 2,5-difluorophenyl and
148
Organofluorine Chemistry
FIGURE 5–16 Expanded view of the X-ray structure of sitagliptin bound to DPP-IV; Phe357 and Tyr662 aromatic
rings have orthogonal π2π-stacking interactions with the electron-deficient triazole and trifluorophenyl moieties,
respectively (highlighted by arrows). Hydrogen bond distances (in Å) to the primary amino group are shown in
dotted lines. The structure was created using UCSF Chimera software, PDB 1X70.
3,4-difluorophenyl analogs (IC50 values of 27 and 128 nM, respectively).34,35 Sitagliptin
showed relatively improved oral bioavailability as compared to the other fluoroaryl derivatives, which led to its successful development of the antidiabetic drug.
An X-ray crystal structure of sitagliptin, embedded in DPP-IV shows that it is located in
the S1 hydrophobic pocket and that the electron-withdrawing trifluoromethyl triazole- and
2,4,5-trifluorophenyl moieties are involved in π2π stacking interactions with the Phe357 and
Tyr662 aromatic rings, respectively (Fig. 516). The primary amino group has hydrogen
bonding interactions with the side-chain carboxylic acids of Glu205, Glu206, and the hydroxy
moiety of Tyr662 residues.35,36
5.3.1.1 Synthesis of sitagliptin
Merck group’s green synthesis of sitagliptin is shown in Fig. 517.37 In this greener synthetic
method, as compared to the conventional multistep process,38 one-pot conversion of 2,4,5-trifluorophenylacetic acid (11) to the enamine amide 17 was achieved in high yields. Thus, the
Chapter 5 • Pharmaceutical applications of organofluorine compounds
149
CO2 + acetone
F
F
O
OH
+
O
F
O
O
O
t-BuCOCl
i-Pr 2NEt
F
F
F
Cat. DMAP/MeCN
CF3CO2 H
O
H+
13
O
12
11
OH O
Cl
H2 N
O
N
N
N
CF3
14
F
F
F
O
C
F
15
H
O
F
O
NH4 OAc
MeCN/MeOH
O
F
N
N
N
+
16
N
HN
N
CF3
N
N
CF3
F
F
F
NH2 O
F
Rh(COD) 2OTf (5 mol%)
N
N
N
17
F
NH2 O
F
N
N
N
N
CF3
Fe
P(t-Bu) 2
P(t-Bu) 2
Sitagliptin
N
CF3
99% Conversion; 95% ee
(t-Bu JOSPHOS); 10 mol%
MeOH, H 2 (90 psi, 50 °C)
FIGURE 5–17 Synthesis of sitagliptin; DMAP 5 4-(N,N-dimethylamino)pyridine.
pivaloyl anhydride of trifluorophenylacetic acid 11, formed from the in situ reaction of 11 with
pivaloyl chloride (t-BuCOCl), undergoes nucleophilic acyl substitution reaction [SN2(Ac)] with
the enolate of the Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione; 12) to give the enol 13.
The in situ reaction of 13 with trifluoroacetic acid, in the presence of the triazole salt 14, gives
the β-keto amide 16. Through kinetic studies, it was observed that the acid-catalyzed decomposition of the compound 13 gives the ketene 15, which rapidly undergoes nucleophilic addition reaction with the triazole 14 to give the β-keto amide 16. Without any further workup,
addition of NH4OAc and methanol to the reaction mixture gives the enamine amide 17. Thus,
this one-pot, multistep reaction sequence gives compound 17 directly without the necessity of
the intermediate workup procedures or compound purifications, affording greener synthetic
route to this compound. Rh(I)-catalyzed asymmetric hydrogenation of the enamine amide 17
then affords the sitagliptin in high conversions and enantioselectivity.37
150
Organofluorine Chemistry
OMe
OMe
H
H 2N
N
N
F
O
Carmegliptin
FIGURE 5–18 Structure of carmegliptin.
FIGURE 5–19 X-ray crystal structure of carmegliptin bound to the DPP-IV; hydrogen bonds are shown as dotted
lines; DPP-IV, Dipeptidyl peptidase-IV. Adapted from Mattei, P.; Boehringer, M.; Di Giorgio, P.; Fischer, H.; Hennig,
M.; Huwyler, J.; Kocer, B.; Kuhn, B.; Loeffler, B.M.; MacDonald, A.; et al. Discovery of Carmegliptin: A Potent And
Long-Acting Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes. Bioorg. Med. Chem. Lett. 2010,
20, 11091113.
5.3.2 Carmegliptin
Carmegliptin (Fig. 518) was developed as an effective DPP-IV inhibitor for treating type 2
diabetes.39,40 The fluoromethyl moiety in the carmegliptin was found to be the optimal substituent that interacts with the hydrophobic S1 pocket of the enzyme. Carmegliptin inhibits
DPP-IV with an IC50 of 6.8 nM, as compared to its nonfluorinated methyl analog with an IC50
of 13 nM.39 Furthermore, carmegliptin exhibits a unique pharmacokinetic profile with optimal renal and hepatic excretion. Phase 1 and 2 clinical studies of this compound proved it to
be a safe and orally administrable compound.
A single crystal X-ray structure of the carmegliptin, bound to the DPP-IV enzyme, shows
hydrogen-bonding interactions of the amide carbonyl oxygen with Tyr662, Asn710, and Arg125,
and that the primary amino group has hydrogen-bonding interactions with Glu206 and Glu205
residues.39 The fluoromethyl moiety occupies the hydrophobic S1 pocket of the enzyme
(Fig. 519). The amide carbonyl effectively mimics the P2-amide carbonyl of the GLP-1.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
151
FIGURE 5–20 Synthesis of carmegliptin, a DPP-IV inhibitor; DPP-IV, Dipeptidyl peptidase-IV.
OH
Me
HO
O
HO
HO
S
OH
F
HO
OH
O
Cl
O
Me
OH
Canagliflozin
Dapagliflozin
FIGURE 5–21 Structures of the SGLT-2 inhibitors, canagliflozin and dapagliflozin, the FDA-approved drugs for the
treatment of type 2 diabetes; SGLT-2, Sodiumglucose cotransporter 2.
5.3.2.1 Synthesis of carmegliptin
The synthesis of carmegliptin is shown in Fig. 520.39 Regioselective reduction of the enantiomerically pure (S)-paraconic acid (18), followed by deoxyfluorination using the
Deoxofluor [bis(2-methoxyethyl)aminosulfur trifluoride], gave the fluoromethyl lactone 19 in
67% yield for the two steps. The fluoromethyl lactone 19 was transformed into compound 20
by reaction with thionyl chloride in the presence of ZnCl2 and was then reacted with enantiomerically pure 21 to give the carmegliptin, isolated as the hydrochloride salt.
5.3.3 Canagliflozin
Canagliflozin (Invokana; Janssen Pharmaceuticals; Fig. 521) was approved by FDA in 2013
for the treatment of type 2 diabetes and to reduce the risks associated with cardiovascular
events. Type 2 diabetes increases the risks of cardiovascular dysfunction, leading to
152
Organofluorine Chemistry
exacerbation of heart failure. Canagliflozin is a sodiumglucose cotransporter 2 (SGLT-2)
inhibitor. It reduces the glycated hemoglobin (HbA1c) levels in type 2 diabetes and improves
the left-ventricular diastolic function within 3 months of treatment.41 The (fluoroaryl)thiophene moiety contributes to enhanced metabolic stability for canagliflozin. Canagliflozin
shows significant antihyperglycemic effects as compared to several analogous C-glucosides
in diabetic mice models.42 The antihyperglycemic effect of this drug is attributable to the
inhibition of SGLT-2, resulting in the decreased reabsorption of the filtered glucose.43 Some
of these flozin families of SGLT2 inhibitors (e.g., dapagliflozin) also inhibit the SGLT-2 in
the pancreatic α-cells, triggering the glucagon secretion and hepatic gluconeogenesis and
thereby decreasing plasma glucose induced by fasting.44
5.4 Anti-Alzheimer pharmaceuticals
Alzheimer’s disease (AD) has the highest global burden, with an estimated annual global
cost of US$ 818 billion. It is estimated that by 2030, the number of AD patients would rise to
over 70 million worldwide. The global cost for treating and caring for AD patients exceeds
that of other major diseases, such as cancer and diabetes.45 Whereas the number of deaths
due to cardiovascular diseases and HIV infections has dramatically reduced since 2000 due
to the state-of-the-art therapies, AD cases remain to increase as there are no pharmaceuticals that can cure AD to date (Fig. 522).
Over 90% of the AD cases are of nongenetic (i.e., sporadic) origin and the mechanisms of
the onset of sporadic AD are not well defined. According to amyloid hypothesis, the formation and accumulation of the aggregates of amyloid-β (Aβ) protein in the brains of the AD
patients are considered to be the key contributing factor for the onset of the disease. As the
neuronal activity is increased, the synapses release increasing concentrations of the soluble
100
2015
2030
1500
1000
500
Percentage change in deaths
in the United States since 2000
Estimated global cost (billion US$)
2000
Someone in the
United States develops
Alzheimer’s disease
every 66 s
75
50
25
0
–25
–50
–75
0
Alzheimer’s
disease
Cancer
Diabetes
Alzheimer’s
disease
Breast Cardiovascular
cancer
disease
HIV
FIGURE 5–22 Comparison of AD statistics with other major diseases; AD, Alzheimer’s disease. Adapted from
McDade, E.; Bateman, R.J. Stop Alzheimer’s Before It Starts. Nature (London) 2017, 547, 153155.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
153
Aβ peptide. If the rate of the breakdown of the soluble Aβ peptides is lower than that of formation, the soluble Aβ peptides are accumulated and are eventually transformed into the Aβ
aggregates, also called amyloid plaques. The Aβ plaques have further downstream effects,
including synaptic damage, tau-protein hyperphosphorylation, and mitochondrial damage.46
Excessive formation of amyloid plaques leads to overactivation of the TREM2, the gene that
expresses the microglial receptor protein TREM2 (triggering receptor expressed on myeloid
cells-2) and thereby the microglial removal of the damaged synapses and surrounding tissues. Extensive loss of the synapses along the axon results in the loss of neuronal function.
Hence, removing the amyloid plaques during the late stage of AD has no significant beneficial effect on memory restoration or on delaying the progression of AD.46
The Aβ plaque deposition occurs about 15 years earlier than the onset of the AD symptoms. Based on this hypothesis, major pharmaceutical companies developed the BACE-1
inhibitors [a β-site amyloid protein (β-amyloid) cleaving enzyme], γ-secretase inhibitors
(GSIs), and γ-secretase modulators (GSMs) toward the attenuation of the Aβ formation.
However, clinical trials of several of these pharmaceuticals targeting Aβ peptides were not
successful in reducing the AD symptoms, despite their effectiveness in attenuating the Aβ
plaque formation. It is uncertain whether Aβ is the primary causative factor or other downstream events are involved in the neurodegeneration.
According to the tau hypothesis as a causative factor for AD, Aβ-induced downstream
events lead to the tau hyperphosphorylation and formation of the paired helical filaments
that aggregate to form the intracellular neurofibrillary tangles, with consequent neuronal disintegration.47 According to the cell-cycle hypothesis as a causative factor for AD, the Aβ oligomers may induce aberrant cell-cycle reentry of neuronal cells, resulting in neuronal cell
death.48 A number of tau kinases are involved in the aberrant cell-cycle reentry of the neuronal cells. These tau kinases, when overactivated, likely due to the downstream events arising
from the Aβ peptides, lead to the aberrant cell-cycle entry.
Due to the lack of a definitive mechanistic understanding of the causative factors for the
sporadic AD, there have been no therapeutics for this disease to date. The only FDAapproved drugs, rivastigmine, galantamine, donepezil (cholinesterase inhibitors), and memantine (NMDA receptor antagonist), are used for the palliative treatment with little effect on
the memory loss and disease progression (Fig. 523).
5.4.1 BACE-1 inhibitors
Most of the current drug development by major pharmaceutical companies is based on the
BACE-1 (a β-amyloid cleaving enzyme; β-secretase) inhibitors. BACE-1 is an aspartyl protease that is involved in the formation of the brain-soluble Aβ peptide oligomers. Sequential
cleavage of the amyloid precursor protein (APP; a transmembrane protein), first by the
BACE-1 and then by γ-secretase, results in the formation of these soluble Aβ peptides, which
in turn, form neurotoxic oligomeric fibrils and aggregates, called Aβ plaques, in the brains of
affected individuals. The γ-secretase cleaves the APP at various sites between the 36 and 43
residues to give Aβ peptides of varying chain lengths. Of these Aβ peptides, the major
154
Organofluorine Chemistry
O
MeO
O
Et
N
Me
Me
N
Me
Me
O
MeO
N
Rivastigmine
Donepezil
Me
N
NH2
Me
HO
O
Galantamine
Me
O Me
Memantine
FIGURE 5–23 Structures of cholinesterase inhibitors—rivastigmine, donepezil, galantamine, and NMDA receptor
antagonist memantine—currently used as palliative treatments of AD; AD, Alzheimer’s disease.
isoforms formed are Aβ140 and Aβ142. Aβ142 is the most toxic peptide of all these Aβ
peptides, and decreasing ratios of Aβ142 to the other Aβ peptides were shown to have a
beneficial effect in attenuating the Aβ plaque formation in vivo. It was, therefore, suggested
that drug discovery strategies that target reduction of Aβ140 actually worsen the disease,
and that the selective increase in Aβ140 levels, over that of Aβ142, may, in fact, reduce
the risk of AD pathogenesis.49 On the other hand, the peptide fragments arising from the
α-secretase cleavage, followed by β-secretase cleavage, are nonneurotoxic (Fig. 524).
In normal and healthy individuals the clearance of the initially formed soluble Aβ peptides is at the same rate as their formation. On the other hand, as described earlier, when
there is an imbalance in the Aβ clearance and formation mechanisms, the brain-soluble Aβ
peptides aggregate to form the Aβ plaques in the brain tissues, resulting in the neuronal loss
and thereby cognitive decline. However, none of the drug candidates targeted at BACE-1
inhibitors were proven successful in the clinical trials.50 Merck’s phase 3 studies of verubecestat were halted because of the ineffectiveness of this drug candidate in reducing or reversing
cognitive decline and due to the drug-related adverse effects (vide infra). The clinical trials of
this drug in the early stages (prodromal) of AD were also halted because of the lack of positive outcomes. Eli Lilly and AstraZeneca’s phase 3 clinical trials on a BACE-1 inhibitor, lanabecestat (a nonfluorinated compound), were also halted due to the expected lack of positive
outcomes of this drug candidate. Eli Lilly halted its phase 3 clinical trials on the BACE-1
inhibitor atabecestat due to the liver toxicity that this drug candidate exerts (Fig. 525). All
of these BACE-1 inhibitors are effective in reducing or clearing Aβ plaques in brain and in
Chapter 5 • Pharmaceutical applications of organofluorine compounds
155
FIGURE 5–24 Schematic illustration of the formation of the Aβ oligomers and Aβ aggregates through sequential
cleavage of APP by β- and γ-secretases; Aβ, Amyloid-β; APP, amyloid precursor protein.
cerebrospinal fluid (CSF). Presumably, there is an irreversible synapse loss and neurodegeneration at the mid-to-late stages of the AD so that further reducing the formation of the Aβ
plaques has no observable effect in reducing the AD symptoms. In order to be effective AD
therapeutics the BACE-1 inhibitors should be highly selective and ideally should not inhibit
the structurally closely related BACE-2, whose inhibition leads to adverse effects. The adverse
effects caused by the BACE-1 inhibitor pharmaceuticals (that were in clinical trials) are
ascribed to their competing BACE-2 inhibition.
156
Organofluorine Chemistry
NH
F
N
HN
H
N
Me
F
O
Me
N
S O
O
N
H 2N
OCH3
Lanabcestat
O
N
N
N
H
Me
S
N
H3 C
Verubecestat (MK-8931)
F
NH2
N
Me
C
N
Atabecestat
FIGURE 5–25 Structures of verubecestat, lanabecestat, and atabecestat, the BACE inhibitors that were in the phase
3 clinical trials.
F3C
O
Cl
H
N
N
O
N
N
Me
F
Me
CF3
O
In vivo hydrolysis
NH2
CNP520
BACE-1 inhibitor; in AD prevention clinical trials
at Novartis
H 2N
N
N
Me
F
Me
CF3
NH2
22
LogD (pH 6.8) = 3.5
pKa = 7.2
FIGURE 5–26 Structures of CNP520, a drug in clinical trials for the prevention of AD in susceptible individuals, and
its metabolite 22, formed via hydrolysis of the amide moiety; AD, Alzheimer’s disease.
5.4.1.1 CNP520 as an Alzheimer’s diseasepreventive drug
Novartis is currently undertaking the early clinical trials for CNP520 (Novartis
Pharmaceuticals; Fig. 526), a highly selective BACE-1 inhibitor for normal and healthy individuals who are susceptible to the development of AD, but have not yet developed AD symptoms despite having Aβ depositions in the brains, as a preventive approach for treating
AD.50,51 CNP520 has favorable pharmacokinetic and pharmacodynamic properties with a
log D (at pH 6.8) of 3.5 and a pKa of 7.2. Apparently, the trifluoromethyl moiety reduces the
basicity of the amino moiety, such that the lipophilicity at pH 6.8 is substantially increased.
In vivo hydrolysis of CNP520 forms o-aminopyridine metabolite 22, which, unlike aniline
derivatives, has no known safety hazard.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
157
In vitro studies on animal models as well as in clinical studies of presymptomatic
patients indicate that CNP520 is an exquisitely safe therapeutic agent for the prevention of
AD at the early stages of the disease, that is, prior to the onset of the AD symptoms.
CNP520 has high selectivity for BACE-1 over BACE-2 (about threefold more selective to
BACE-1) and other structurally closely related aspartate proteases, such as human cathepsin D and human cathepsin E. Most of the BACE-1 inhibitor pharmaceuticals have equipotent selectivity against BACE-2, and thereby, leads to hair depigmentation. In animal
models, CNP520 reduced Aβ40 production by 90% and there was no depigmentation of the
hair. Unlike the amyloid-based immunotherapeutic drugs, which are associated with cerebral microhemorrhages (CMH), CNP520 did not increase CMH frequency or severity relative to vehicle-treated animals (i.e., control animal models treated with the solvent used to
dissolve the drug, e.g., saline or dimethyl sulfoxide, without using the actual drug). APP
transgenic mice exhibited reduced Aβ load and reduced neuroinflammation with the use of
the CNP520. Clinical trials of CNP520 in humans showed dose-dependent reduced levels
of Aβ and sAPPβ (soluble APP-β, a product of APP cleavage by β-secretase) in the CSF.51
An X-ray structure of the CNP520, bound to the active site of the BACE-1, shows
hydrogen-bonding interaction of the active site Asp32 and Asp228 side-chain carboxy moieties with the amidine moieties.51 The CF3 moiety adjacent to the amidine moiety exhibits
hydrogen-bonding interaction with the Asp228 side-chain carboxylic acid (2.9 Å) (Fig. 527).
5.4.1.2 Verubecestat, a BACE-1 inhibitor
Verubecestat (MK-8931; Merck & Co.), a 3-imino-1,2,4-thiadiazinane derivative (Fig. 528),
is a β-amyloid cleaving enzyme (BACE-1; an aspartyl protease) inhibitor. Verubecestat had
been in clinical trials at Merck & Co., since 2012 for the treatment of mild-to-moderate and
early-stage (prodromal) AD. It has relatively high selectivity for BACE-1, although it is nonselective over the closely related protein BACE-2. Verubecestat has high selectivity for BACE-1,
as compared to the other key aspartyl proteases, such as cathepsin D, and it lowers CSF and
brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans.52 However,
the phase 3 clinical trials on mild-to-moderate AD as well as prodromal AD were halted as
verubecestat did not have any positive outcome on patients with mild-to-moderate AD (i.e.,
it was ineffective in reducing the cognitive decline), while having drug-related adverse
effects, such as falls and injuries, sleep disturbance, and hair-color change.53
Prolonged treatment with BACE-1 inhibitors, including verubecestat, results in dendritic
spine loss, even though they help to reduce the Aβ levels in the brains of AD patients. There
are two types of dendritic spines, transient dendritic spines with a lifetime of about 4 days
and stable spines, persisting for more than 8 days. The short-lived dendritic spines are
involved in learning, while the stable dendritic spines are associated with long-term memory.
Herms and coworkers showed a significant reduction of Aβ140 as well as the dendritic
spines in the brains of mouse AD models, when treated with verubecestat. However, the loss
of spine density was recovered after verubecestat withdrawal.54 Metabolic degradation products of verubecestat, N2-desmethyl compound 23 and aniline metabolite 24, have about
158
Organofluorine Chemistry
FIGURE 5–27 Expanded view of the X-ray structure of CNP520 in complex with BACE-1 at the active site; the dotted
lines indicate hydrogen-bonding interactions of the Asp32 (with guanidine nitrogens) and Asp228 side-chain
carboxy group with the CF3 fluorine; the structure was created using UCSF Chimera software; PDB 6EQM.
100-fold less BACE-1 inhibitory activity than the verubecestat (Fig. 528). Verubecestat and
many of the other BACE-1 inhibitors having a basic amino moiety in close proximity to a
hydrophobic group inhibit cardiac delayed-rectifier K1 (IKR) channel, encoded by human
ether-a-go-go-related gene. The drug-induced inhibition of the IKR channel sometimes can
lead to arrhythmia and sudden death.52
Chapter 5 • Pharmaceutical applications of organofluorine compounds
F
N
H
N
O
NH
1 Me
HN 2 N
S O
O
Me
F
159
NH
F
N
HN
H
N
Metabolic transformation
Me
F
O
NH
S O
O
23
Verubecestat (MK-8931)
NH
HN
H 2N
+
Me
F
Me
N
S O
O
24
FIGURE 5–28 Structures of verubecestat, a BACE-1 inhibitor, and its major metabolic degradation products.
An X-ray structure of verubecestat bound to BACE-1 (Fig. 529) reveals extensive
hydrogen-bonding interactions of the amidineimino moiety with Asp289 and Asp93 sidechain carboxylic acid moieties. The aryl fluorine has hydrophobic interactions with the backbone CH bonds of the Phe169 and Tyr132 residues.52
5.4.2 γ-Secretase inhibitors and modulators
Inhibition or modulation of γ-secretase helps reduce the Aβ burden. However, GSIs have
been abandoned because of their mechanism-based inhibitory effect on various other
enzymes, resulting in severe drug-related adverse effects.55 Two of the key GSIs, semagacestat (Eli Lilly; a nonfluorinated compound) and avagacestat (BristolMyersSquibb;
Fig. 530), were tested in late-stage clinical trials but were abandoned due to the adverse
effects associated with these drug candidates. In particular, the notch-signaling inhibition by
GSIs impairs notch processing and leads to adverse effects, such as skin cancer, that were
observed in the phase 3 clinical trials of semagacestat.56 Two phase 2 trials of avagacestat
were terminated by BristolMyersSquibb in 2012, because the patients treated with this
drug had comparable disease progression and brain atrophy as compared to those treated
with a placebo. Furthermore, treatment with avagecestat resulted in adverse effects, including squamous- and basal-cell skin cancers (nonmelanoma skin cancers).57
The drug discovery effort in the area of GSIs is now shifted to GSMs due to the competing
notch-signaling inhibition of the GSIs and the consequent drug-related severe adverse
effects, including skin cancers. Many of these GSM drug candidates showed poor drug-like
properties, although they are effective GSMs and thus potential AD therapeutics. The ongoing research efforts in this area are targeted toward increasing the GSMs’ potency and efficacy with improved drug-like properties, such as relatively low c Log P (,5), high CNS
160
Organofluorine Chemistry
FIGURE 5–29 Expanded view of the X-ray structure of verubecestat bound to BACE-1 at the active site; there are
extensive hydrogen-bonding interactions of the imino-nitrogen with the Asp289 and Asp93 residues, and aryl
fluorine has hydrophobic interactions with the backbone CH bonds of Phe169 and Tyr132; the structure was
created using UCSF Chimera software, PDB 5HU1.
multiparameter optimization scores, and high sp3 character.55 The lipophilicity of the molecule should be adjusted such that it should have sufficient aqueous solubility and membrane
permeability for enhanced bioavailability. Drug candidates that have c Log P higher than 5
have poor aqueous solubility and therefore have poor oral bioavailability. Relatively higher
sp3-hybridized carbon content (preferably with a fractional sp3 character, fsp3, greater than
0.38 during the phase 1 clinical trials) gives the drug candidates natural productlike characteristics and thereby enhances their drug-like properties.58
GSMs regulate the γ-secretase activity so that the formation of the Aβ142 peptides is
attenuated. The GSMs do not show inhibitory effect on γ-secretase, and therefore the notch
Chapter 5 • Pharmaceutical applications of organofluorine compounds
161
F
OH
O
H
N
O
Me
CF3
O N
N
H
N
N
O
O
Me
N
S
NH2
O
O
Cl
Semagestat
Avagacestat
FIGURE 5–30 Structures of semagestat and avagacestat, the GSIs, whose late-stage clinical trials were abandoned;
GSIs, γ-Secretase inhibitors.
Me
N
N
N
OMe
Me
NH
Me
O
N
N
H
N
Me
N
N
N N
N
NH
H
Me Me
F
F
BMS-932481
BPN-15606
FIGURE 5–31 Structure of BMS-932481 and BPN-15606, the GSMs; GSMs, γ-Secretase modulators.
inhibition, typically associated with GSIs, is avoided. Thus, there are fewer adverse effects
with the GSMs as compared to those with GSIs. GSMs have distinct binding sites on the APP
than GSIs, and the enzyme is modulated such that the Aβ142/Aβ140 ratio is decreased,
and other relatively nontoxic, shorter Aβ peptides are formed at the expense of the neurotoxic Aβ142 peptide.59 By diverting the mechanism of formation of the neurotoxic Aβ142
to the less toxic, shorter Aβ peptides, GSMs may prove to be therapeutics for AD.
BristolMyersSquibb’s GSM, BMS-932481 (Fig. 531), modulated the Aβ peptides in
the plasma and CSFs in preclinical studies. Upon treatment with BMS-932481, the relative
levels of Aβ140 and Aβ142 were attenuated, while the levels of the relatively nontoxic
Aβ137 and Aβ138 were increased in the CSF of healthy volunteers. Therefore BMS932481 is a GSM rather a GSI. Further development of this drug was halted due to the insufficient safety margin.60
BPN-15606, a GSM modulator (Fig. 531), significantly lowers the Aβ142 levels in the
CNSs of rats and mice and reduces Aβ neuritic plaque in AD transgenic mouse model,
attenuates Aβ142, and attenuates phosphorylation of the tau protein at the threonine 181
(pThr181 Tau). This drug candidate was granted the investigational new drug status for
future human clinical trials.61 Other GSMs that progressed to clinical trials but were not
162
Organofluorine Chemistry
Cl
O
Cl
HO
OH
F
F
O
Itanapraced (CHF-5074)
Tarenflurbil (R-flurbiprofen)
FIGURE 5–32 Structures of itanapraced and tarenflurbil, the GSMs that were not successful in clinical trials; GSMs,
γ-Secretase modulators.
Me
Me
OH
O
O
OH
Cl
OH
F3 C
O
O
F
CF3
Ibuprofen
Flurbiprofen
EVP-0015962
FIGURE 5–33 Structures of NSAID-based GSMs. GSMs, γ-Secretase modulators; NSAID, nonsteroidal
antiinflammatory drug.
successful include Chiesi’s itanapraced (CHF 5074; EC50 5 40 μM) and a first-generation
nonsteroidal antiinflammatory drug (NSAID), tarenflurbil (R-flurbiprofen; EC50 5 300 μM)
(Fig. 532).62
5.4.2.1 Nonsteroidal antiinflammatory drugs as γ-secretase modulators
NSAIDs, such as sulindac sulfide, ibuprofen, and flurbiprofen (a fluorobiphenyl analog of
ibuprofen), lower the Aβ142 levels while elevating Aβ-38 levels at relatively high concentrations. Thus, these NSAIDs, when used as GSMs, have potential benefit for managing the AD
symptoms, although the first-generation NSAID-derived GSMs have relatively low potencies
and undesirable neuropharmacokinetics. As allosteric modulators, these GSMs induce conformational changes in the γ-secretase, thus modifying their effect on Aβ142 formation.63
Clinical studies of COX-1/COX-2-nonselective (e.g., naproxen) and COX-2-selective NSAIDs
(e.g., rofecoxib and celecoxib) in AD patients revealed their ineffectiveness as AD therapeutics. These NSAIDs were even suggested to be detrimental because of their inhibitory effect
on brain microglia, which help in the clearance of the Aβ peptides.64
Relatively more potent flurbiprofen analogs, such as EVP-0015962 (EnVivo
Pharmaceuticals; Fig. 533), have proven to be more effective GSMs, that is, they divert the
Aβ142-forming mechanism to the formation of shorter Aβ peptides. EVP-0015962 lowered
Chapter 5 • Pharmaceutical applications of organofluorine compounds
163
Aβ1-42 levels in human H4 neuroglioma cells with an EC50 for Aβ142 clearance of 67 nM
and increased the relatively nonneurotoxic Aβ-38 deposition by 1.7-fold.65 Although this
drug candidate has positive outcomes in the transgenic Tg2576 mice animal models, clinical trials have not been reported so far. The goal of designing the improved versions of
NSAID-derived GSMs is to enhance their GSM activity and to attenuate the NSAIDassociated cyclooxygenase (COX-1 and COX-2) inhibitory effect so that the gastrointestinal
toxicity is diminished.
5.5 Anti-HIV pharmaceuticals
HIV, a retrovirus that replicates through insertion of its genome into the host-cell DNA, is
responsible for the onset of AIDS (acquired immune deficiency syndrome) disease.
Replication of HIV virus is highly error-prone, resulting in the formation of multiple strains
of drug-resistant virus. In order to overcome the rapid drug resistance of HIV virus, combination drugs that act on multiple viral targets, consisting of the reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors, also called as highly active antiretroviral
therapy (HAART), are being developed.
In 2018 FDA approved the Gilead’s combination drug Biktarvy for the treatment of HIV
infections. Biktarvy includes two HIV nucleoside analog reverse transcriptase inhibitors,
emtricitabine (20 ,30 -dideoxy-5-fluoro-30 -thiacytidine) and tenofovir alafenamide fumarate,66,67
and an integrase strand transfer inhibitor (a class of integrase inhibitors), bictegravir68
(Fig. 534). Emtricitabine was previously marked as a triple-combination drug with tenofovir
and efavirenz by BristolMyersSquibb (approved by FDA in 2006). Efavirenz is a nonnucleoside reverse transcriptase inhibitor (NNRTI), whereas emtricitabine and tenofovir are the
nucleoside analog reverse transcriptase inhibitors; hence, the combination of these drugs in
a single dosage would minimize the viral drug resistance. Emtricitabine, tenofovir, and efavirenz, along with their fixed-dose combinations, are listed as part of the essential medicines
by the World Health Organization.69
5.5.1 Bictegravir
Bictegravir is an integrase strand transfer inhibitor. Integrases are viral enzymes that are
involved in the incorporation of the viral genome into the host DNA strand and therefore by
deactivating these integrase enzymes, HIV replication is attenuated. The hydrophobic (2,4,6trifluoromethyl)benzyl moiety in bictegravir contributes to its efficient binding to the plasma
proteins, thereby minimizing undesirable interactions with other drugs and enhancing its solubility and half-life time.70 Modeling studies showed that the trifluorobenzyl moiety exhibits
ππ hydrophobic stacking interactions with the cytosine on the 30 -end of the viral DNA.71
These calculations also showed high flexibility of the oxazepane ring, allowing enhanced conformational mobility to the molecule and thereby tight binding to various integrase strand
transferaseresistant mutants, such as G118R and S119R mutants. Three other FDA-approved
integrase strand transfer inhibitors, raltegravir, elvitegravir, and dolutegravir (Fig. 535),
164
Organofluorine Chemistry
H 2N
N
O
O
N
N
F
O
N
H
N
OH
S
F
O
H
O
O
Emtricitabine
F
F
OH
Bictegravir
O
O
O
O
P
O
N
NH
O
HO
N
F3 C
OH
N
Cl
O
N
O
NH2
N
H
O
Efavirenz
Tenofovir alafenamide fumarate
FIGURE 5–34 Structures of emtricitabine, bictegravir, tenofovir alafenamide, and efavirenz; biktarvy (Gilead Sciences)
is a triple-combination anti-HIV drug consisting of emtricitabine, bictegravir, and tenofovir fumarate, while atripia
(BristolMyersSquibb) is a triple-combination drug consisting of efavirenz, emtricitabine, and tenofovir.
O
OH
F
O
O
F
N N
N
H
N
N
N
H
N
O
N
F
O
O
O
OH
H
N
O
Raltegravir (FDA-approved integrase strand
transfer inhibitor
Dolutegravir (FDA-approved integrase strand transfer
inhibitor)
Cl
F
O
Na+ O
O
OH
O
N
OH
Elvitegravir (FDA-approved integrase strand transfer
inhibitor)
F
F
O
O
H
N
N
N
O
O
Cabotegravir
(integrase strand transfer inhibitor; in clinical
trials)
FIGURE 5–35 Structures of some of the clinically active integrase strand transfer inhibitors.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
165
potently inhibit replication of the wild-type HIV-1. However, resistant mutants can rapidly arise
when using these drugs.71 Dolutegravir is among the widely used drugs for the combination
antiretroviral therapy. Carbotegravir (Fig. 535), another structurally related integrase inhibitor, is in advanced clinical trials for the treatment of HIV-1 infections.72,73 Of particular interest,
all these integrase inhibitors have electron-acceptor fluoroaryl moieties that are vital to the
ππ hydrophobic stacking interactions with the viral DNA.
5.5.2 Doravirine
Doravirine (MK-1439; Pifeltro; Merck), an NNRTI, was approved by FDA in 2018 for the
treatment of HIV infections. It is a single-dose combination drug consisting of lamivudine and tenofovir disoproxil fumarate. This three-drug combination provides an alternative treatment strategy to the other widely used HIV drugs. Doravirine shows
superior pharmacokinetic and safety profile over efavirenz in cases involving neuropsychiatric and cutaneous adverse effects and has relatively low potential for drugdrug
interactions. 7476
An X-ray crystal structure of doravirine bound to the wild-type reverse transcriptase
shows edge-to-face ππ stacking of the aryloxy moiety with the Trp 229, and a face-to-face
ππ stacking interaction with the Tyr188. The trifluoromethyl moiety has hydrophobic van
der Waals interactions with the Tyr188 and Val189 backbone (Fig. 536).75,76 The binding
mode of doravirine to the active site is similar to that of efavirenz, except that the Tyr181 is
rotated 90 degrees in efavirenz.
5.6 Antimalarial pharmaceuticals
Malaria remains one of the deadliest infectious diseases worldwide, especially in developing and underdeveloped countries, despite the early success of the quinine-based
drugs in eradicating the disease. Artemisinin and its derivatives, including the watersoluble artesunate, showed promise in countering the drug resistance and are being used
as combination drugs with other quinine-based antimalarial agents.77 Due to the emergence of the drug-resistant plasmodium strains against the widely used antimalarial drug
chloroquine, structurally related quinoline-based drugs, such as primaquine and fluoroquinolones (the widely used antibacterial agents), have emerging interest as antimalarial
drugs (Fig. 537).78,79
5.6.1 Tafenoquine
Tafenoquine (Krintafel; GlaxoSmithKline; Fig. 537), a primaquine analog, consisting of the
5-(m-trifluoromethylphenoxy)quinoline as the pharmacophore, was approved by FDA in
2018 for the treatment of malaria and for the prevention of malaria (prophylaxis) for travelers
and people living in the malaria-endemic regions. Tafenoquine shows improved safety and
therapeutic profile as compared to the antimalarial drug primaquine and can be used against
166
Organofluorine Chemistry
FIGURE 5–36 Structure of doravirine (MK-1439; Merck & Co.), a nonnucleoside reverse transcriptase inhibitor, and
expanded view of the X-ray structure of doravirine (ball and stick), bound to the wild-type HIV reverse
transcriptase; ππ stacking of Tyr188 (face-to-face) and Trp 229 (edge-to-face) with the aryloxy moiety of
doravirine are shown as hashed lines; the structure was created using UCSF Chimera software, PDB 4NGC.
the currently drug-resistant plasmodium strains.80,81 The drug is prescribed in the racemic
form.
Tafenoquine and related 5-aryloxyquinoline analogs of the antimalarial drug primaquine
have improved metabolic stability as compared to the primaquine. In general, 5-(4-trifluoromethylphenoxy)-4-methylprimaquines are several-fold more potent inhibitors of monoamine
oxidase-A and MAO-B.82 This increased metabolic stability apparently translates into the
effectiveness of tafenoquine against the drug-resistant strains of plasmodium species.
5.6.2 Mefloquine
The mechanism of antimalarial action of the mefloquine and other quinine pharmaceuticals
has evaded the scientific community.83 Nordlund and coworkers have demonstrated the
purine nucleoside phosphorylase enzyme as the target of quinine and mefloquine drugs,
using thermal shift assay coupled with the mass spectrometry (MS-CETSA), and through
structural studies using the recombinant protein.84 Quinine and mefloquine bind to the
active site of the enzyme with nanomolar affinity, attenuating the parasite protein synthesis.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
167
FIGURE 5–37 Structures of chloroquine, primaquine, artemisinin, artesunate, artemether, mefloquine, and
tafenoquine, the antimalarial agents.
The cocrystal X-ray structure indicates that the trifluoromethyl moieties of mefloquine have
hydrophobic interactions with the active-site amino acids, stabilizing the ligandprotein
interactions (Fig. 538).84
5.7 Anticancer pharmaceuticals
5.7.1 Dacomitinib
In 2018, FDA approved dacomitinib (VIZIMPRO; Pfizer Pharmaceutical Company) for the
first-line treatment of metastatic nonsmall-cell lung carcinoma (NSCLC), arising from the
mutations in the epidermal growth factor receptor (EGFR), involving exon 19 deletion or
L858R mutation (i.e., Lys858 substituted by Arg) in the exon 21, as detected by an FDAapproved test. The tumor progressionfree survival for dacomitinib was 14.7 months, as
compared to 9.2 months when gefitinib anticancer drug was used.85 Another NSCLC drug,
lorlatinib (Lorbrena; Lorviqua; Pfizer Pharmaceuticals, Inc.) was also FDA approved in 2018
for the treatment of anaplastic lymphoma kinase (ALK) positive metastatic NSCLC
(Fig. 539).
Dacomitinib is an orally bioavailable second-generation, pan-HER tyrosine kinase (EGFRs
HER1, HER2, and HER4) inhibitor and is also an investigational drug for the treatment of
glioblastoma.86 An X-ray structure of T790M mutant EGFR bound to dacomitinib shows the
168
Organofluorine Chemistry
FIGURE 5–38 Structure of mefloquine (ball and stick) bound to PfPNP, showing hydrophobic interactions of the
trifluoromethyl moieties; The hydrophobic interactions (F-C distances ranging from 2.8 to 3.3 Å) of the CF3 groups
are shown by the dotted lines; the structure was created using UCSF Chimera software, PDB 5ZNI; PfPNP, Purine
nucleoside phosphorylase.
F
H
N
N
O
O
CH3
Cl
HN
N
N
Dacomitinib
FIGURE 5–39 Structure of dacomitinib, an FDA-approved drug for the treatment of NSCLC; NSCLC, Nonsmall-cell
lung carcinoma.
formation of a covalent bond for the cysteine-790, arising from the Michael reaction to the
α,β-unsaturated amide moiety (i.e., acrylamide moiety) of dacomitinib (Figs. 540 and
541).87 Similar cysteine adducts of the EGFR inhibitors, such as afatinib, an FDA-approved
drug for the treatment of NSCLC, were revealed through X-ray structure analysis and also
confirmed by MS.88 The role of the fluorine moieties in these compounds is apparently to
enhance the pharmacokinetic properties (i.e., increased lipophilicity and metabolic stability)
Chapter 5 • Pharmaceutical applications of organofluorine compounds
169
O
O
EGFR-Cys
O
N
O
N
EGFR L858R/T790M
S
N
N
H
O
N
HN
O
N
H
Cl
N
N
HN
Cl
F
Afatinib
F
Cysteine adduct of afatinib
F
F
EGFR- Cys797-SH
H
N
N
O
Cl
HN
N
O
N
O
CH 3
H
N
N
EGFRCys797S
O
CH 3
Cl
HN
N
N
Michael adduct of dacomitinib with Cys797-SH
of the EGFR kinase
Dacomitinib
F
O
HN
N
O
O
Cl
N
EGFR L858R/T790M
No inhibitory effect
N
Gefitinib
FIGURE 5–40 Formation of the Michael adducts of the cysteine residues with EGFR inhibitors afatinib and
dacomitinib; EGFR, Epidermal growth factor receptor.
of the drug molecules. Analogs of these compounds lacking the acrylamide moiety, such as
gefitinib (Iressa, AstraZenica, and Teva), are ineffective in inhibiting these doubly mutated
EGFR enzymes (i.e., with L858R/T790M mutations), although gefitinib is effective in inhibiting L858R mutants of EGFR and was approved by FDA (in 2003) for treating nonsmall-cell
lung cancers.
5.7.2 Lorlatinib
Standard initial treatments for NSCLC include first-line treatment with crizotinib (consisting
of a fluoroaryl moiety) or ceritinib (a nonfluorine compound). However, secondary mutations
of the ALK domain occur because of the acquired resistance to these drugs. More potent
170
Organofluorine Chemistry
FIGURE 5–41 Expanded structure of the active site region of T790M mutant of EGFR kinase, bound to dacomitinib
(ball and stick) through covalent bond formation with Cys797; the terminal pyrrolidine moiety is not revealed in
this X-ray crystal structure; the structure was created using UCSF Chimera software, PDB 4I24.
second-generation treatments have clinical benefit, although most patients develop resistance
to the second-generation tyrosine kinase inhibitors. Lorlatinib is a tyrosine kinase inhibitor
directed at the ALK-positive and c-ros oncogene 1 (ROS1) kinases (Fig. 542). Phase 1 and
phase 2 clinical trials of lorlatinib showed that it shows durable response with a median duration of response of 12.4 months for ALK-positive advanced NSCLC patients, for most of
whom CNS metastasis also progressed after the second-line of treatment with other drugs.89
The NSCLC metastasis is also transmitted to the brain, and permeation of the BBB is critical
for any pharmaceutical compound to treat the brain tumors. Positron emission tomography
studies, using the 11C- and 18F-labeled lorlatinib, demonstrated high brain permeability for
lorlatinib (see Chapter 6: Synthesis and applications of 18F-labeled compounds).90
Chapter 5 • Pharmaceutical applications of organofluorine compounds
CH 3
N
N
C N
NH
F
Cl
Cl
Cl
O
Me
H 2N
N
O S
O
N
N
N
H
NH
N
HN
F
N
Larotectinib
(Vitrakvi;
for NTRK gene fusionpositive solid tumors)
N
N
H
N
Me
N
H
N
O
O
Lorlatinib
(second-generation
drug for NSCLC)
N
C
N
N
H
N
H 2N
CH3
O
N
O
F
H 3C
Ceritinib
(first-line treatment for
NSCLC)
N N
OH
N
O
F
Crizotinib
(first-line treatment for
NSCLC)
N N
N
171
F
N
N
O
O
F
N
Talazoparib
(Talzenna; for BRCA-mutated
HER2-negative breast cancer)
Cl
H
N
O
F
F
F
Ivosidenib (Tibsovo; for acute myeloid
leukemia and cholangiocarcinoma)
FIGURE 5–42 Structures of larotrectinib, talazoparib, and ivosidenib—FDA-approved anticancer drugs.
Three other fluorine-containing heterocyclic anticancer drugs were approved by FDA in
2018: larotrectinib (Vitrakvi) for the treatment of NTRK gene fusion-positive solid tumors,
talazoparib (Talzenna) for BRCA (breast cancer)-mutated HER2-negative breast cancer, ivosidenib (Tibsovo), and ivosidenib (Tibsovo) for the treatment of acute myeloid leukemia
(AML) and cholangiocarcinoma (bile duct cancer) (Fig. 542).
5.7.3 Cobimetinib
Cobimetinib (Cotellic; Exelixis and Genentech/Roche) was approved by FDA (in 2015) for
the treatment of various cancers, including melanoma and breast cancer.91 Cobimetinib inhibits mitogen-activated protein kinase (MAPK), which is overactivated in human tumors. It is
used as a combination drug with vemurafenib (Genentech and DaiichiSankyo) for the
treatment of unresectable or metastatic BRAF V600 mutation positive melanoma (progression-free survival for 9.9 months for the combination drug versus 6.2 months for placebo
plus vemurafenib recipients). Cobimetinib in humans is metabolized by cytochrome P450
enzymes and excreted as the glucuronide conjugates, but the fluoroaryl rings are not
172
Organofluorine Chemistry
N
F
H
N
F
F
N
NH
I
O
N
OH H
O
Cl
F
F
Cobimetinib
O
HN S
O
Vemurafenib
FIGURE 5–43 Structures of cobimetinib and vemurafenib, anticancer drugs used in combination to treat melanoma.
oxidized during this P450-mediated oxidation, reflecting the enhanced oxidative stability
afforded by the aryl fluorines.91 Vemurafenib (Zelboraf; Roche) was approved by FDA in
2011 for the treatment of V600E-mutated late-stage melanoma (Fig. 543).92,93
5.7.4 Abemaciclib
Abemaciclib (Verzinio; Eli Lilly) was approved by FDA in 2017 for the treatment of breast
cancers. It is a selective CDK4 and CDK6 inhibitor and thereby deactivates the retinoblastoma protein, a key enzyme involved in cell-cycle progression, leading to the apoptosis of
tumor cells. It is the first CDK inhibitor drug for treating breast cancers.9496 The lipophilicity
enhancement afforded by fluorines in abemaciclib, with a c Log P of 5.5, allows the molecule
to bind more effectively in the ATP cleft, as compared to the other nonfluorinated CDK4/
CDK6 drugs, palbociclib (c Log P 2.7) and ribociclib (c Log P 2.3).96 X-ray crystal structure of
abemaciclib, bound to CDK6 enzyme, shows hydrogen-bonding interactions of the fluorine
with ε-amino group of the Lys43 residue (3.5 Å) and exhibits hydrophobic interactions with
Phe98 (Fig. 544).96
5.7.5 PARP inhibitors: rucaparib (Rubraca) and olaparib (Lynparza)
Rucaparib (Rubraca; Clovis Oncology) is an inhibitor of poly[adenosine diphosphate (ADP)ribose] polymerases 1 and 2 (PARP-1 PARP-2) and was approved by FDA in 2016 for treating
advanced ovarian cancers involving BRCA1 (breast cancer type 1) and BRCA2 (breast cancer
type 2) mutations.97,98 Rucaparib also suppresses the lactate dehydrogenasemediated
transformation of pyruvate to lactate in A2780 cells, resulting in the suppression of the ovarian cancer cell growth (Fig. 545).99 X-ray crystallographic structure of rucaparib complexed
to human PARP-1 shows hydrophobic interactions of the fluorine with Glu988, Ala898, and
Phe897 residues (Fig. 546).100 PARP enzymes are involved in DNA repair and their inhibition prevents DNA repairs, leading to cell death in cancers. Olaparib (Lynparza; AstraZeneca
and Merck & Co.), a nonselective PARP-1 inhibitor, was approved by FDA in 2014 for the
treatment of advanced ovarian and breast cancers with BRCA mutations.101,102
Chapter 5 • Pharmaceutical applications of organofluorine compounds
173
FIGURE 5–44 Expanded X-ray crystal structure of abemaciclib (ball and stick), bound to CDK6; the hydrogen
bonding (with Lys43) and the hydrophobic interactions (with Phe98) of the fluorines and the NH interactions with
the His100 moiety, ranging from 3.4 to 3.5 Å, are shown by the dotted lines; the structure was created using UCSF
Chimera software, PDB 5L2S.
O
O
H
N
O
HN CH3
F
NH
N
N
N
H
N
F
O
Rucaparib (Rubraca; Clovis Oncology)
Olaparib (Lynparza; AstraZeneca and Merck & Co.)
FIGURE 5–45 Structures of rucaparib and olaparib, the FDA-approved drugs for treating advanced ovarian cancers,
associated with BRCA mutations.
5.7.6 Taxoid anticancer agents
Paclitaxel (Taxol) and its synthetic analog docetaxel are among the widely used anticancer
drugs, often used as combination therapeutics along with other anticancer agents. These
compounds and various other derivatives currently in development have limited scope in
the treatment of cancers due to their lack of tumor specificity or acquired multidrug
174
Organofluorine Chemistry
FIGURE 5–46 Expanded X-ray crystal structure of rucaparib (ball and stick) bound to human PARP-1; the
hydrophobic and polar interactions of the fluorine (2.8 to 3.5 Å) are shown as dotted lines; the structure was
created using UCSF Chimera software, PDB 4RV6.
resistance. Ojima and coworkers have synthesized various fluorinated analogs of paclitaxel as
potential cancer therapeutics through the reaction of the semisynthetic taxol derivatives with
a β-lactam derivative, as shown in Fig. 547.3,103110 The fluorinated taxoids have substantially improved cell viability in MCF-7/PTX human breast cancer cells. Whereas paclitaxel
has a cell viability IC50 of about 2 μM, the m-trifluoromethoxy derivatives SB-T-121205, SB-T121405, and SB-T-121605 have IC50 values in the range of 1935 nM. These compounds and
other fluorinated versions, including m-difluoromethoxy derivatives, have comparable cytotoxicity for various cancer cell lines, and in some cases, two orders of potency magnitude
greater for drug-resistant cancer cell lines, as compared to paclitaxel. Especially with LCC6MDR breast cancer cell lines, the fluorinated versions (e.g., SB-T-121405, SB-T-121605, SB-T121705, and SB-T-121206) have substantially potent cancer-cell toxicity IC50 values of about
12.5 nM as compared to an IC50 value of 619 nM for paclitaxel.3 Furthermore, some of these
fluorinated versions, such as SB-T-121205, were able to suppress the growth, migration, and
invasion of MCF-7/PTX human breast cancer cell line, and thus prevented metastasis and
suppressed epithelialmesenchymal transition.110
5.7.6.1 Tumor-targeted drug delivery of the fluorinated taxoids
Ojima and coworkers designed a mechanism-based self-immolative disulfide linker, conjugated with biotin (a vitamin), as the tumor-targeting moiety for targeted delivery of the
Chapter 5 • Pharmaceutical applications of organofluorine compounds
175
O
O
O
NH
O
O
OH
NH
O
O
O
O
OH
O
O
O
O
OH O
O
O
OH
OH
O
O
OH O
O
O
OH
Docetaxel
Paclitaxel (Taxol)
O
TIPSO
O
O
O
R
O
O
N
O
O
OH O
O
O
NH
Ot-Bu
O
HO
O
O
OH
R
OH
O
O
O
O
OH O
O
O
OH
1. LiHMDS, THF, –40 °C
O
2. HF/Py, MeCN/Py
0 °C - RT
X
X
SB-121205;
SB-121305;
SB-121405;
SB-121605;
SB-121705;
R
R
R
R
R
= Me, X = OCF 3
= Et, X = OCF 3
= c-Pr, X = OCF 3
= NMe 2 , X = OCF 3
= OMe, X = OCF 3
SB-121206;
SB-121306;
SB-121406;
SB-121606;
SB-121706;
R
R
R
R
R
= Me, X = OCHF 2
= Et, X = OCHF 2
= c-Pr, X = OCHF 2
= NMe 2 , X = OCHF2
= OMe, X = OCHF 2
FIGURE 5–47 Structures of paclitaxel (taxol) and docetaxel; and synthesis of fluorinated versions of paclitaxel as
potent anticancer agents.
taxoids.111 Vitamin receptors are overexpressed at the cell surfaces in cancer cells, and thus
it would be expected that the biotin-conjugated drugs would selectively bind to the tumor
cells over the normal cells and then internalized through the receptor-mediated endocytosis.
The intracellularly abundant glutathione (GSH) mediates the taxoid drug release from the
biotin conjugate through a cascade of reactions, involving disulfide bond cleavage, followed
176
Organofluorine Chemistry
FIGURE 5–48 Time-resolved 19F NMR spectra for the disulfide linker cleavage and thiolactonization process of
probe 1 (2.5 mM) in 30% DMSO in D2O, beginning at 1 h after the addition of 6 equiv of GSH at 25 C with 15 min
intervals (128 scans/spectrum); DMSO, Dimethyl sulfoxide; GSH, glutathione. Adapted from Seitz, J.D.; Vineberg,
J.G.; Wei, L.; Khan, J.F.; Lichtenthal, B.; Lin, C.-F.; Ojima, I. Design, Synthesis and Application of Fluorine-Labeled
Taxoids as 19F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.
J. Fluorine Chem. 2015, 171, 148161.
by thiolactonization to give the fluorobenzothiolactone as a byproduct. The cytotoxicity of
the cancer drugs is thereby significantly attenuated.
Time-resolved 19F NMR spectroscopy allows monitoring the controlled release of the taxoid drug SB-T-12145 from its biotin-conjugated compound, BLT-F2 (Fig. 548).111
Immediately after addition of GSH, the disulfide bond of the biotin-conjugated compound
BLT-F2 is reduced to give the taxoid 3-A (in Fig. 548). The latter intermediate taxoid then
incrementally forms the fluorobenzothiolactone (structure 9 in Fig. 548), as shown by the
time-dependent increase in the intensity of the signal at δ19F 2 116.3, corresponding to the
thiolactone 9 (in Fig. 548), and a corresponding decrease in intensity of the signal at
δ19F 2 119.2, ascribed to the taxoid 3-A (in Fig. 548). The absorption at δ19F112.5 corresponds to the aryl fluorine of the fluoro-taxoid SB-T-12145, and, it overlaps with that of the
biotin conjugate BLT-F2 (Fig. 548).
Chapter 5 • Pharmaceutical applications of organofluorine compounds
177
FIGURE 5–49 Structure of the fluorouracil-phosphoramidite module, used as the building block for the automated
and modular synthesis of aptamerdrug conjugates; DMTr 5 4,40 -dimethoxytrityl.
5.7.6.2 Drug delivery through aptamerdrug conjugates
DNA aptamerdrug conjugates provide a means of delivering drug molecules with high specificity into the cancer cells. Tan and coworkers have synthesized aptamerdrug conjugates consisting of the anticancer drug, 5-fluorouracil, and a photocleavable 2-nitrobenzyl group as the
linker.112 The fluorouracil-phosphoramidite module (Fig. 549) was synthesized using solidphase synthesis, and using this module, automated and modular synthesis of aptamerdrug
conjugates was achieved at the 50 -end of the aptamer. These aptamerdrug conjugates showed
high specificity to the targeted cancer cells.
Various other drug candidates could also be incorporated in these aptamerdrug conjugates. The aptamerdrug conjugates are relatively more selective drug-delivery agents as
compared to the widely used antibodydrug conjugates. These aptamerdrug conjugates
are also stable compounds, as dry powders, and are relatively less toxic. Using this synthetic
approach, the drug molecules could be incorporated in a chained mode at the 50 -end or
incorporated at the predesigned sites on a DNA synthesizer.112 The aptamer-taxoid-based
approach is also useful for the tumor-specific drug delivery of taxoids, and for improving
aqueous solubility of the hydrophobic docetaxel.111,113,114
5.7.7 Fulvestrant
Fulvestrant (Faslodex; AstraZeneca) is an FDA-approved (approved in 2002) anticancer drug.
It is an estradiol derivative having a terminal pentafluoroethyl moiety on the side chain,
which imparts lipophilic properties to the drug (Fig. 550). Fulvestrant is used to treat hormone receptorpositive metastatic breast cancer (hormone receptors are either estrogen or
progesterone receptors). Fulvestrant is a steroidal estrogen antagonist and offers advantage
over the antiestrogen tamoxifen, as the latter compound can act as an estrogen agonist in
some cases. Thus, by downregulating the estrogen receptors (ERs), fulvestrant is active in
tamoxifen-resistant breast cancers.115 Fulvestrant also helps degrade the ERs through its
hydrophobic effect on the surface of the receptors (vide infra).
Fulvestrant is designed such that the endogenous ER ligand, 17β-estradiol, which acts as
an estrogen antagonist, is tethered to the hydrophobic side chain with a terminal fluoroalkyl
178
Organofluorine Chemistry
Me OH
Me OH
H
H
H
H
H
O
S
H
HO
HO
Estradiol (endogenous ER ligand)
F F
F
F
F
Fulvestrant
FIGURE 5–50 Structures of estradiol and fulvestrant.
moiety, the latter, mediating the ER degradation through its hydrophobic effect. Fulvestrant,
upon binding with the ERs, induces structural changes in the protein and enhances hydrophobicity, mimicking the partially unfolded protein and thereby recruiting endogenous chaperones that would unfold the protein. The unfolded protein is then shuttled for proteasome
degradation.116 Thus, fulvestrant, in addition to being an estrogen antagonist, also helps
degrade ERs through its hydrophobic effect on the surface of the receptors. As a selective ER
degrader (SERD), fulvestrant exhibits high specificity to the target protein (ER) and thereby
provides advantages over the widely used anticancer drug tamoxifen, with decreased risk of
endometrial cancer. Newer generation of SERDs address the poor oral bioavailability and
poor systemic exposure of the fulvestrant.117
5.7.7.1 Synthesis of fulvestrant
A kilogram-scale synthesis of fulvestrant is carried out, starting from the pentafluoropentanol
(25). The key step for the synthesis of fulvestrant involves the stereoselective 1,6-addition of
an organocuprate derived from 29 to the 17β-acetoxyestra-4,6-dien-3-one (30), followed by
Cu(II)-mediated aromatization of the A-ring, and alkaline hydrolysis of the ester moiety, to
give compound 32. (Fig. 551).118 The H2O2-mediated oxidation of the thio ether 32, followed by repeated recrystallizations (which also remove the unwanted 7β-isomer formed as
a minor byproduct) gave the fulvestrant, as a crystalline compound, in high purity.
5.7.8 Enasidenib
Enasidenib (Agios Pharmaceuticals; AG-221) was approved by FDA in 2017 to treat relapsed
or refractory AML. AML is characterized by attenuated cellular differentiation, through a disruption in the citric acid cycle, thereby resulting in the formation of immature cells. AML
therapies are therefore targeted to promoting cellular differentiation. Enasidenib exerts its
therapeutic effect through inhibition of the mutated version of isocitrate dehydrogenase-2
(IDH2) enzyme. The mutated form of the IDH2, found in certain cancer cells, is involved in
the reduction of the α-ketoglutarate, a product of the normal citric acid cycle, to the (R)-2hydroxyglutarate (2-HG); the wild-type IDH2 enzyme, unlike the mutated version of IDH2,
does not reduce the α-ketoglutarate to 2-hydroxyglutaric acid. The IDH2 mutations are also
found in premalignant disorders, such as myelodysplastic syndrome. Through inhibition of
Chapter 5 • Pharmaceutical applications of organofluorine compounds
HO
1. MsCl, Et3N, MeCN
CF2CF3
HO
MsO
SH
(27)
CF2CF3
26
25
HO
S
Ph3P/Br2/MeCN
CF2CF3
28
Br
S
CF2CF3
1. Mg/THF, 4–10 °C
2. CuCl, –34 °C
3.
Me
29
OAc
H
–34 °C
H
H
O
(30)
Me OAc
H
H
1. CuBr2/LiBr/Ac2O
2. NaOH
H
S
O
CF2CF3
31
Me OH
H
H
1. H2O2
H
HO
S
CF2CF3
O
S
CF2CF3
32
Me OH
17
H
H
H
HO
3
7
Fulvestrant
FIGURE 5–51 Industrial-scale synthesis of fulvestrant.
179
2. Purification
180
Organofluorine Chemistry
FIGURE 5–52 X-ray structure of enasidenib bound to IDH2 (PDB 5I96), showing the tetrel bonding between the CF3
carbon and Asp312 (distance in Å). Adapted with permission from Garcia-Llinas, X.; Bauza, A.; Seth, S.K.; Frontera,
A. Importance of R-CF3 O Tetrel Bonding Interactions in Biological Systems. J. Phys. Chem. A 2017, 121,
53715376. ©2017, American Chemical Society.
the IDH2 mutants (IC50 1020 nm), enasidenib suppresses the formation of 2-HG and
induces cellular differentiation in human AML cells in xenograft mouse models.119
Noncovalent bonding interaction between a CF3 carbon and asp-312 oxygen, also called
σ-hole tetrel bonding, was observed in the X-ray crystal structure of the enasidenib bound to
the IDH2, and this tetrel bonding was substantiated by ab initio calculations.120 In other
words the CF3 carbon is able to act as an electrophilic center, forming noncovalent bonding
interactions with the Lewis basic aspartate 312 oxygen (Fig. 552).
Synthesis of enasidenib was achieved in five steps, starting from 6-trifluoromethyl-2pyridinecarboxylic acid (33) (Fig. 553).121 Thus, 6-trifluoromethylpyridine-2-carboxylic acid
(33), upon esterification, followed by reaction of the ester 34 with biuret (imidodicarbonic
diamide) gives the 6-(6-trifluoromethyl-2-yl)-1,3,5-triazine-2,4-dione (35). Reaction of compound 35 with PCl5 in phosphoryl chloride (POCl3) gives the 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (36). Sequential aromatic nucleophilic substitution reactions (SNAr)
Chapter 5 • Pharmaceutical applications of organofluorine compounds
181
FIGURE 5–53 Synthesis of enasidenib.
of the triazine 36 with 2-(trifluoromethyl)-4-pyridinamine (37) and 1-amino-2-methyl-2-propanol
gives enasidenib.
5.7.9 Nonsteroidal antiandrogens (apalutamide, bicalutamide, and
flutamide)
Apalutamide (Erleada; Johnson and Johnson) was approved by FDA in 2018 for the treatment
of nonmetastatic castration-resistant prostate cancer (CRPC) (NM-CRPC).122 Related antiandrogens flutamide (Eulexin; Schering Plough) and bicalutamide (Casodex, AstraZeneca) were
approved by FDA in 1989 and 1995, respectively, for the treatment of metastatic prostate cancer.
Apalutamide, bicalutamide, and flutamide are nonsteroidal antiandrogens (i.e., androgen
antagonists), and the structures of all these three compounds have a trifluoromethyl group
adjacent to an electron-withdrawing moiety (CN or NO2) in the aromatic ring (Fig. 554).
182
Organofluorine Chemistry
O
F
H3 C
N
N
N
H
N
O
O
C N
S
Flutamide (Eulexin)
Apalutamide (Erleada)
C
O
O
O S
HO
N
H
N
CF3
O-
CF3
N
H
CF3
O
N+
O
H3 C N
H
F
S
N
C
N
N
CF3
O
F
Bicalutamide (Casodex)
Enzalutamide (Xtandi)
FIGURE 5–54 Structure of apalutamide (Erleada) and flutamide (Eulexin) for the treatment of nonmetastatic
castration-resistant prostate cancer.
Bicalutamide is among the widely used nonsteroidal antiandrogens for the treatment of metastatic CRPC.122 Although the prognosis of CRPC patients has significantly improved after the
introduction of these and other related drugs—including docetaxel, immunotherapy agents,
and radiopharmaceuticals—targeting multiple aspects of the disease, identifying the best
sequence of these pharmaceuticals in the combination therapy still remains a challenge.
An X-ray structure of the bicalutamide bound to the W741L mutant androgen receptor
shows a bent conformation for the bicalutamide, with an intramolecular hydrogen bonding
of the sulfonyl oxygen with the chiral hydroxy group, which also has hydrogen-bonding
interaction with Asn705 side-chain amide nitrogen (2.5 Å).123 The trifluoromethyl group has
hydrophobic interactions with Phe746, Leu873, Val746, and Met745 residues, and the cyanonitrogen is in the hydrogen-bonding distance with respect to the Arg752 side-chain nitrogen
(3.0 Å) and Gln711 side-chain oxygen (3.4 Å). Thus, the binding of the bicalutamide to the
androgen receptor is dominated mostly by hydrophobic interactions (Fig. 555).
5.7.9.1 Enzalutamide
Enzalutamide (4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin1-yl]-2-fluoro-N-methylbenzamide; Xtandi; Astellas Pharma Europe B.V.) is structurally closely
related to apalutamide. These compounds have in common the thioxo-imidazolidinone ring and
N-methyl-o-fluorobenzamide moiety. Whereas apalutamide consists of trifluoromethyl and cyano
moieties in the pyridyl ring, enzalutamide has these moieties on the phenyl ring. Enzalutamide is
approved by the European Medicines Agency (EMA) for the treatment of NM-CRPC.122
The synthesis of enzaltumide was elegantly achieved in three steps starting from 4-cyano-3trifluoromethylaniline (39). Reaction of compound 39 with thiophosgene gives the corresponding
Chapter 5 • Pharmaceutical applications of organofluorine compounds
183
FIGURE 5–55 Expanded view of the X-ray structure of R-bicalutamide (ball and stick) bound to the W741L mutant
androgen receptor; hydrogen-bonding interactions of the cyano nitrogen and the hydrophobic interactions of the
CF3 moiety are shown with dotted lines; binding of the bicalutamide to the active site is dominated by
hydrophobic interactions; the structure was created using UCSF Chimera software, PDB 1Z95.
isothiocyanates 40. The isocyanate 40 upon condensation with the β-amino ester 41 gives enzalutamide, in high yield. Compound 41, in turn, was synthesized from 2-fluoro-4-bromobenzoic
acid, involving conversion of the carboxylic acid moiety into the N-methylamide, using a mixture
of thionyl chloride and methylamine, followed by Cu(I)-catalyzed aryl-amination (Fig. 556).124
5.7.10 BRAF and mitogen-activated protein kinase kinase enzyme
inhibitors in cancer treatment
In 2018 FDA approved the combination therapy using binimetinib (Mektovi; ARRY-162; Array
BioPharma) and encorafenib (Braftovi; Novartis; Array BioPharma) for the treatment of
unresectable or metastatic melanoma, involving BRAF V600E or V600K mutations (Fig. 557).125
Encorafenib is a BRAF inhibitor and binimetinib is a MAPK kinase enzyme (MEK) inhibitor
(phosphorylating the MAPK); both drugs are developed by Array BioPharma.
184
Organofluorine Chemistry
F
O
OH
Br
1. SOCl2/DMF, CH3NH 2
O
2.
NH2
O
F
CN
CN
S
CF3 Me
CF3
Cl
Cl
Heptane, 10 °C to 46 °C
NH 2
N
15 h
92%
39
40
CuI
O
N
H
O
N
H
O
Me
41
DMSO, RT to 84 °C
C
82%
S
F
O
S
H 3C N
H
N
C
N
N
CF3
O
Enzalutamide
FIGURE 5–56 Synthesis of enzalutamide.
O
S
Br
HN
O
F
F
N
N
F
NH
H
N
N
N
O
Cl
H
N
N
OH
N
O
N
H
O
O
Binimetinib
(Mektovi)
Encorafenib
FIGURE 5–57 Structures of binimetinib and encorafenib, the combination drugs for the treatment of melanoma.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
185
Array BioPharma and Genentech have developed a clinical candidate GDC-0994 (42) as an
effective inhibitor of extracellular signal-regulated kinase kinases (ERK1/2).126 Activation of the RAS/
RAF/MEK/ERK (MAPK) signal transduction pathways is common to a large subset of human cancers, including BRAF-mutant-resistant metastatic melanoma. Although small molecule inhibitors of
BRAF and MEK, such as binimetinib and encorafenib, are currently effective in the treatment of
BRAF-mutant metastatic cancers, these drugs may have a limited duration of efficacy in some
patients due to the pathway-reactivating mutations. Selective inhibitors of ERK1/2 kinases, such as
GDC-0994, in concert with the RAF and MEK inhibition, thus may have improved efficacy against
various cancers. An analog of the GDC-0994 with a trifluoromethyl moiety in the pyrazole ring (43)
proved to be a relatively less effective ERK1/2 inhibitor (Fig. 558). The fluorochlorophenyl ring
has hydrophobic interactions with the Tyr36 side chain in the glycine-rich loop at the active site,
and the 5-aminopyrazole has hydrogen bondingstabilizing interactions with the Lys114 residue.126
5.8 Antiviral pharmaceuticals
5.8.1 Tecovirimat
Tecovirimat (ST-246; Tpoxx; SIGA Technologies) is an orally active antiviral pharmaceutical,
active against orthopoxviruses, including smallpox and monkeypox (Fig. 559). It was
F3C
N
N
N
Me
N
H
N
N
N
Cl
O
N
Me
N
H
Cl
O
N
F
F
OH
OH
GDC-0994
42
43
ERK1 IC 50 = 74 nM
ERK2 IC 50 = 52 nM
ERK1 IC 50 = 6.1 nM
ERK2 IC 50 = 3.1 nM
FIGURE 5–58 Structures of the clinical candidate GDC-0994 and its analog (as anticancer drugs).
H
H
N
O
O
O
N
H
CF 3
Tecovirimat (ST-246; Tpoxx)
(antiviral against smallpox and monkeypox)
FIGURE 5–59 Structure of tecovirimat, an antiviral drug.
186
Organofluorine Chemistry
approved by FDA in 2018 as a prophylaxis agent and for the treatment of smallpox, caused
by variola virus in adults and pediatric patients weighing greater than 13 kg. This drug was
developed by SIGA Technologies in collaboration with the US Department of Health and
Human Services, Biomedical Advances Research and Development Authority, and is stockpiled in the US strategic national stockpile as a preventive measure.127,128 Tecovirimat inhibits the activity of orthopoxvirus VP37 envelopewrapping protein, thereby preventing the
formation of the egress-competent virions and suppressing the spread of virions in the host
cells. Tecovirimat showed insignificant adverse events in a clinical study on 449 adult volunteers at a dose of 600 mg twice daily for 14 days.129 X-ray crystallographic details of this compound bound to viral proteins are not available, and the role of the trifluoromethyl moiety in
its drug action is therefore not known with certainty.
5.8.1.1 Synthesis of tecovirimat
SIGA Technologies’ synthesis of tecovirimat is outlined in Fig. 560.130 Reaction of maleic
anhydride with N-(tert-butoxycarbonyl)hydrazine, followed by deprotection, gives N-aminomaleimide 45 in good yields. Acyl nucleophilic substitution reaction of the N-aminomaleimide (45) with 4-(trifluoromethyl)benzoyl chloride gives compound 46, which undergoes
FIGURE 5–60 Synthesis of tecovirimat.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
187
DielsAlder reaction with 1,3,5-cycloheptatriene to afford the tecovirimat. In the final step
the cycloheptatriene is in reversible equilibrium with bicyclo[4.1.0]heptadiene under the
reaction conditions, and the DielsAlder reaction of the latter bicyclo[4.1.0]heptadiene with
the maleimide derivative 46 gives the tecovirimat.
5.8.2 Sofosbuvir
Sofosbuvir (Sovaldi; Gilead Sciences) is an FDA-approved orally bioavailable drug for the
treatment of hepatitis C, used as combination therapy with other small molecule inhibitors,
such as ribavirin and velpatasvir (Fig. 561). Sofosbuvir was a blockbuster drug in 2015 with
sales exceeding 5 billion US dollars.
Sofosbuvir is transformed into its active drug form, a uridine triphosphate analog, in vivo.
It is a potent nucleotide analog inhibitor of the hepatitis C virus (HCV) nonstructural protein
5B (NS5B), an RNA-dependent RNA polymerase, with an EC50 of 0.15 μM. HCV cannot replicate in the absence of the latter NS5B polymerase enzyme, and thus, most drugs developed
for treating hepatitis C are either nucleoside analog polymerase inhibitors that bind at the
active site of the enzyme (e.g., sofosbuvir) or nonnucleoside polymerase inhibitors that bind
at the allosteric site. The deficiency in the proofreading during the RNA-polymerase-initiated
RNA replication results in a high spontaneous mutation rate, necessitating combination therapy. This antiviral drug induces an S282T mutation in the NS5B, lowering the binding affinity
of the sofosbuvir-derived active cytidine-analogous triphosphate, and thereby attenuating its
replicon activity. Cytidine versions of sofosbuvir (mericitabine, 47 and 48 in Fig. 561)
inhibit the HCV NS5B protein by a similar mechanism, and some of these analogs exhibit
similar half-maximal effective concentration, EC50, as that of sofosbuvir.131 These cytidine
analogs of sofosbuvir may provide promising alternative candidates for HCV treatment,
including the treatment of HCV resulting from the drug-resistant mutation NS5B S282T,
formed through the resistance acquired from the sofosbuvir. The combination therapy using
sofosbuvir plus daclatasvir plus ribavirin for 12 or 24 weeks showed excellent outcome with
a 91%89% HCV patient survival rates in a wider patient trial.132
The active form of sofosbuvir, 20 -deoxy-20 -α-fluoro-20 -β-methyl-uridine-50 -triphosphate
(51) is formed through a series of metabolic processes in the liver. The first-pass metabolism
of sofosbuvir in the liver generates terminal carboxylic acid 49, which upon further metabolism gives the 20 -deoxy-20 -α-fluoro-20 -β-methyl-uridine-50 -phosphate 50. The latter compound, 50, is inactive in inhibiting the RNA-dependent NS5B RNA polymerase enzyme, until
it is further transformed into the triphosphate, mediated by uridinecytidine monophosphate kinase and nucleoside diphosphate kinase (Fig. 562).133 The phosphoramidate prodrug is designed to enhance its metabolic lifetime and potency, and as described above, the
active drug form 51 is released through a series of enzymatic reactions in the liver, a site
where the drug action is involved. The triphosphate 51 binds to the catalytic site of NS5B
protein, thereby resulting in the RNApolymerase chain termination. This chain termination
is presumably due to the basicity-lowering effect of the 30 -OH group by the proximal fluorine, so that its reactivity for further chain propagation is drastically reduced.
188
Organofluorine Chemistry
NH2
O
N
NH
N
O
N P O
H
O
O
O
N
O
O
O
O
Me
OH
O
O
Me
O
O
F
F
Mericitabine (cytidine analog of sofosbuvir)
Sofosbuvir
EC50 (NS5B enzyme): 0.15 μM
1.11 μM
O
NH2
N
N
O
N P O
H
O
O
O
N
O
O
Me
N
O
N P O
H
O
O
O
OH
R
NH
F
O
O
Me
O
F
48; R = e.g., Propyl
(cytidine analog of sofosbuvir)
47 (cytidine analog of sofosbuvir)
0.24 μM
EC50 (NS5B enzyme): 0.66 μM
Me
O
Me
O
NH2
N
N
O
H
N
N
HO
OH
Me O
NH
O
O
O
NH
Me
Me
N
HO
Me
O
O
N
N
NH
N
O
Ribavarin
Velpatasvir
FIGURE 5–61 Structures of sofosbuvir, mericitabine, and cytidine analogs of sofosbuvir, 47 and 48, with EC50 values
for the HCV NS5B polymerase inhibition; structures of ribavirin and velpatasvir are also shown; EC50, Half-maximal
effective concentration; HCV, hepatitis C virus.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
O
O
NH
NH
O
O
N
O
O
N P O
H
O
O
Me
N P O
H
O
O
O
Me
OH
(hydrolysis of
phosphoramidate ester)
F
N
O
HO
Liver metabolism
O
OH
189
F
49
Sofosbuvir (prodrug)
O
O
NH
NH
O
HO P O
HO
N
O
Enzyme-catalyzed
phosphorylations
O
Me
OH
N
O
O
O
HO P O P O P O
OH
OH OH
O
Me
OH
F
O
F
51
50
Active form generated
through in vivo metabolism
FIGURE 5–62 Liver metabolism in the generation of the active drug form 49 from sofosbuvir.
F F
N
N
N
N
H
O
N
H
O
HN
NH
O
H 3C
N
O
O
O
CH3
Ledipasvir
FIGURE 5–63 Structure of ledipasvir, used as a combination therapy with sofosbuvir.
5.8.3 Ledipasvir
A combination drug of sofosbuvir and ledipasvir (Fig. 563) is marketed as Harvoni
(Gilead), which is approved by FDA for adult as well as pediatric patients. Ledipasvir is active
against the HCV protein mutations, S282T, induced by sofosbuvir, and similarly, sofosbuvir
is active against the mutations induced by the ledipasvir, as a result of which HCV genotype
1infected patients are cured in 1224 weeks, with a success rate of 94%99%.133
190
Organofluorine Chemistry
5.8.3.1 Synthesis of ledipasvir
Gilead Sciences’ synthesis of ledipasvir is summarized in Fig. 564.134 A key aspect of this
synthetic strategy involves the gem-difluorination of the fluorene 1 in one step using
N-fluorobenzenesulfonimide (NFSI; 53) as the electrophilic fluorinating agent. Thus,
gem-difluorination of the fluorine 52, using NFSI in the presence of potassium hexamethyldisilazide (KHMDS), gives the gem-difluoro compound 54. Selective metalation at the aryl-I
bond in 54, using isopropylmagnesium bromide, followed by acylation with Weinreb amide
55 gives the compound 56. Alkylation of Boc-proline 57 by compound 56 gives an intermediate ketoester, which upon reaction with ammonium acetate gives the imidazole 58.
SuzukiMiyaura reaction of the compound 58 with the boronic ester 59 gives compound 60.
Deprotection of the t-Boc moiety in compound 60, followed by peptide coupling with the
N-(methoxycarbonyl)valine (61) then gives the ledipasvir.
5.8.4 Glecaprevir and pibrentasvir
Glecaprevir (ABT-493; AbbVie, Inc.) in combination with pibrentasvir (ABT-530; AbbVie,
Inc.) has been fast-track approved by FDA in 2017 for treating the major HCV genotypes 16
under the trade name Mavyret (Fig. 565). Safety and efficacy studies of Mavyret in the
phase 2 and phase 3 clinical trials showed that overwhelming majority of HCV cases (92%
100%) were completely cured after 1216 weeks of treatment.135,136 In patients with chronic
hepatitis C viral disease, the inflammation of the liver associated with this disease may result
in decreased liver function and eventual liver failure. The combination drug Mavyret is one
of the leading breakthrough therapies for treating hepatitis infections due to HCV genotype
1, a most common hepatitis infection in the United States; according to the FDA statistics,
approximately 75% of the US hepatitis infections are due to the HCV genotype 1. A realworld effectiveness study of this drug combination was assessed in Italy with 726 HCV
patients and the results showed, in general, excellent effectiveness and safety when administered for the duration of an 8-, 12-, or 16-week period.137 With a sustained virologic response
of 99.2% (with a relatively small population having posttreatment relapse), this relatively
large-scale clinical trial proved to be overall effective.137
Glecaprevir is a nonstructural protein 3/4A protease inhibitor, whereas pibrentasvir is a
nonstructural protein 5A (NS5A) inhibitor. The NS5A helps in the viral RNA replication and
viral self-assembly, and thus NS5A inhibitors are widely sought out in the antiviral drug
design, especially the combination drugs that target multiple viral proteases. The currently
available NS5B inhibitors, such as sofosbuvir, exhibit high potency only when used in combination with other complementary pharmaceuticals (such as ribavirin and interferon), as the
viral proteins develop immunity to these drugs, through relatively rapid mutations, when
the drug is given as a single component. The NS5A is proline-rich, and a large number of the
small-molecule HCV drugs targeting this protein consist of the proline- or structurally related
moiety, such as pyrrolidine. Glecaprevir has one pyrrolidine moiety, whereas pibrentasvir
has three such pyrrolidine-based bioisostere moieties. In pibrentasvir, a symmetric dimeric
version, the 6-fluorobenzimidazole serves as a linker connecting two pyrrolidine moieties.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
I
O O
S
N F
S
O O
(53)
Br
F F
1. i-PrMgCl
I
Br
2.
KHMDS, THF
O
Cl
54
52
N
( 55 )
F F
1.
t-Boc H O
N
OH
O
( 57 )
Br
K 2 CO 3 , KI
acetone
Cl
56
2.
NH
O
B
O
191
OMe
Me
F F
t-Boc H N
N
N
H
Br
58
NH 4OAc, toluene
F F
H
N
N
t-Boc
(59)
t-Boc H N
N
N
H
H H
N
N
N
t-Boc
60
Pd(OAc) 2, PPh 3, NaHCO3, DME
F F
1. HCl/dioxane/CH2 Cl2
2.
HO
O
HATU, i-Pr 2 NEt
DMF
t-Boc H N
N
N
H
H H
N
N
N
O
NHCO 2Me
Ledipasvir
NHCO 2Me
(61)
FIGURE 5–64 Synthesis of ledipasvir. KHMDS 5 potassium hexamethyldisilazide; HATU 5 [O-(7-azabenzotriazol-1yl)-N,N,N0 ,N0 -tetramethyluronium hexafluorophosphate].
The difluoroaryl moiety in pibrentasvir has an important modulating effect on the potency
and pharmacokinetics of these drugs and this drug is substantially more potent than its nonfluorinated analog. The fluorine atoms exert their enhanced potency by attenuating the
192
Organofluorine Chemistry
F
N
N
F
F
O
N
O
O
H
H
O O
H3 C
S
N
H
N
H
H3 C
NH
O
O
N
N
NH
H 3C
O
F
F
O
H
O
N
H
N
O
F
F
N
O
NH
N
N
O
O
HN
H 3C
O
CHF2
O CH
3
CH3
O
CH 3
Pibrentasvir
Glecaprevir
EC 50 for genotype 1a: 3 pM
N
R
R'
H3 C
O
F
F
O
NH
O
N
N
NH
H 3C
N
NH
N
N
O
O
HN
H 3C
O
O CH
3
CH3
O
CH 3
R = H, R' = F (62); EC50 for genotype 1a: 18 pM
R = R' = F (63); EC 50 for genotype 1a: 5 pM
FIGURE 5–65 Structures of glecaprevir and pibrentasvir, the anti-HCV drug constituents of the combination drug
Mavyret; also shown are the analogs of pibrentasvir, 62 and 63; HCV, Hepatitis C virus.
basicity of the adjacent piperidine moiety. Pibrentasvir exhibits relatively enhanced EC50
value of 3 pM for the genotype 1a.138
The basicity-attenuating effect of fluorines was clearly evident in the structure-activity
studies of the corresponding piperidine analogs 62 and 63. The IC50 value for the inhibition
of HCV stable replicons (genotype 1a) for 62 is 18 pM, whereas it is 5 pM for the difluoro
analog 63 (Fig. 565).138
Pibrentasvir is prepared in a multistep synthesis, starting from 3,4,5-trifluoronitrobenzene
(64) (Fig. 566).138,139 The nitro group facilitates the aromatic nucleophilic substitution
Chapter 5 • Pharmaceutical applications of organofluorine compounds
Pibrentasvir
FIGURE 5–66 Synthesis of pibrentasvir; HATU, O-(7-Azabenzotriazol-1-yl)-N,N,N0 ,N0 -tetramethyluronium
hexafluorophosphate.
193
194
Organofluorine Chemistry
(SNAr) of the para-fluorine in compound 64 by the piperidine-4-one acetal to give compound 65. Conversion of 65 to the corresponding vinyl triflate, followed by SuzukiMiyaura
cross-coupling affords compound 68. Consecutive SN2 reactions of 68 with the 1,4-dimesylate 69 gives the pyrrolidine product 70. Pd(0)-catalyzed BuchwaldHartwig amination of
compound 70 using N-t-Boc-prolinamide, followed by catalytic hydrogenation, gives compound 71 that undergoes acid-catalyzed dehydrative cyclization to give compound 72.
Deprotection of the Boc group in 72, followed by HATU [O-(7-azabenzotriazol-1-yl)-N,N,N0 ,
N0 -tetramethyluronium hexafluorophosphate]-mediated peptide coupling with N-methoxycarbonyl-threonine methyl ether affords the pibrentasvir.
5.8.5 Voxilaprevir
Voxilaprevir (Gilead Sciences) was approved by FDA in 2017 for the treatment of hepatitis C
in combination with sofosbuvir and velpatasvir (Vosevi). It is a nonstructural protease 3/4A
(NS3/4A protease) inhibitor (Fig. 567). A cocrystal structure of voxilaprevir with GT3 surrogate (GT1 D168Q) NS3/4A protease shows hydrophobic interaction of the macrocyclic gemdifluoromethylene moiety with the Arg155 alkyl moiety.80 Due to this hydrophobic interaction and improved metabolic stability, voxilaprevir exhibits improved potency as compared
to the compound lacking the macrocyclic gem-difluoromethylene moiety.
5.8.6 Letermovir (Prevymis)
Letermovir (Prevymis; Merck & Co.) is an orally available nonnucleoside inhibitor of the
pUL56 subunit of the viral terminase complex of cytomegalovirus (CMV) and was approved
by FDA in 2017 for the treatment of CMV-specific viral infections in allogeneic hematopoietic
stem-cell-transplant patients.140
Merck’s enantioselective synthesis of letermovir is accomplished through the bistriflamide
74 (a weak Brønsted acid)catalyzed intramolecular aza-conjugate addition reaction of the
F F
N
O
O
O
H3C
H3C
N
O
CH 3
NH
N
CH 3 O
NH
O
O
O
HN S
F O CH 3
F
Voxilaprevir
FIGURE 5–67 Structure of voxilaprevir, an NS3/4A protease inhibitor and antihepatitis drug.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
195
OTf
NHTf
NHTf
O
MeO
MeO
OTf
HN
N
F
O
HO
N
F
N
N
OMe
CF3
N
( 74 )
5 mol%
CF3
MeO
N
N
OMe
then NaOH
73
Letermovir (Prevymis)
95% (96.7:3.3 er)
FIGURE 5–68 Enantioselective Michael addition in the synthesis of letermovir.
compound 73, followed by hydrolysis of the ester moiety. Enantioselectivities as high as
96:7:3.3 were obtained using this chiral Brønsted-acid catalysis.141 This synthetic method is
amenable for the synthesis of a large variety of 3,4-dihydroquinazoline moietycontaining
compounds (Fig. 568).
5.9 Fluorinated pharmaceuticals for cardiovascular diseases
5.9.1 Statin drugs
The statin class of drugs lower cholesterol levels by inhibiting the HMG-CoA reductase, the
rate-limiting enzyme in the early stages of the biosynthesis of cholesterol. The fluorinecontaining statin drugs are the blockbuster drugs (based on the sales) and are among the
most prescribed medicines, used for the treatment of hypercholesterolemia, for preventing
cardiovascular disease. Fluorinated statin drugs include atorvastatin (Lipitor; Pfizer
Pharmaceuticals), rosuvastatin (Crestor; AstraZenica), and fluvastatin (Lescol; Novartis
Pharmaceutical Corporation) (Fig. 569). The statin drugs, atorvastatin and rosuvastatin, are
the 3rd and 37th most prescribed drugs, respectively, as of 2016.4 Other widely prescribed
nonfluorinated statins include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin
(Zocor), and pitavastatin (Livalo).
Despite the amazing success of the statin class of drugs in preventing cardiovascular diseases, a meta-analysis of the drug usage now reveals drug-related adverse effects, such as
the new onset of diabetes. By inhibiting the biosynthesis of cholesterol in the early stages,
the statin drugs decrease the levels of coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl
pyrophosphate, and dolichol—the downstream products arising from the HMG CoA reductasecatalyzed reactions. The depletion of these compounds results in the inactivation of the
intracellular insulin signal transduction pathways, which, in turn, contributes to the loss of
196
Organofluorine Chemistry
Me
Me
OH
OH
O
F
Me
O
N
OH
NH
F
O
N
N
S
Me
O N
Me
OH
Me
OH
OH
O
Rosuvastatin
Atorvastatin
F
OH
N
Me
Me
OH
OH
O
Fluvastatin
FIGURE 5–69 Structures of fluorinated statin drugs, atorvastatin, rosuvastatin, and fluvastatin.
glucose homeostasis and the drug-induced onset of type 2 diabetes. Elucidating the precise
mechanisms for the underlying development of type 2 diabetes would help in the design of a
new class of statins with minimal side effects.142,143
5.9.2 Ezetimibe
Ezetimibe (Zetia; Merck & Co.) is a nonstatin drug, used for the treatment of hypercholesterolemia and hyperlipidemia, usually in combination with other statin drugs, such as atorvastatin and simvastatin.144 It was the 144th most prescribed drug, as of 2016.4 Unlike statin
inhibitors, which inhibit the cholesterol biosynthesis in the early stages, ezetimibe is an
inhibitor of intestinal cholesterol absorption, and thus lowers the total plasma cholesterol
levels.
The enhanced metabolic stability of ezetimibe, as compared to a nonfluorinated analog
SCH 48461 (Fig. 570), is ascribed to the fluorine effect.145 The para-arylfluorine blocks the
enzymic oxidation site and apparently also acts as a bioisostere of the hydrogen and methoxy
moieties.145
5.9.3 Nebivolol
Nebivolol (Bystolic; Allergan Pharmaceuticals) was approved by FDA in 2016 for the treatment of hypertension (Fig. 571). It is a β-blocker (β-antagonist) and has a similar blood
pressurelowering effect as that of the other β-blockers, with relatively lower adverse effects.
Chapter 5 • Pharmaceutical applications of organofluorine compounds
OH
197
O
O
N
N
F
OCH 3
F
H3 CO
HO
SCH 48461
Ezetimibe
ED 50 = 2.2 mg/kg
ED 50 = 0.04 mg/kg
FIGURE 5–70 Structure of ezetimibe, used for the treatment of hypercholesterolemia and hyperlipidemia, and
comparison of its effectiveness with a nonfluorinated analog SCH 48461 in lowering the liver cholesterol ester
levels in cholesterol-fed hamsters.
F
F
O
OH
N
H
O
OH
Nebivolol
(β−blocker; to treat high blood pressure)
FIGURE 5–71 Structure of nebivolol, a β-antagonist, prescribed for the treatment of hypertension.
It enhances bioavailability for nitric oxide, through its activation of endothelial nitric oxide
synthase (eNOS) and inducible nitric oxide synthase (iNOS), and thereby exhibits vasodilatory effect. Furthermore, nebivolol functions as an antioxidant and decreases markers of oxidative stress, thereby modulating the endothelial dysfunction and lowering the
hypertension.146
5.9.4 Antiplatelet drugs
5.9.4.1 Cangrelor
Cangrelor (Kengreal; Kengrexal; The Medicines Company) is an antiplatelet drug, used
through intravenous injection. Cangrelor (Fig. 572) is a P2Y12 (an ADP receptor on platelet
cell membrane) inhibitor, and was approved by FDA in 2015 for reducing periprocedural
thrombotic events during surgery. It is a fast-acting drug as it is not a prodrug.
Vorapaxar (Zontivity; SCH 530348; Merck & Co.) is an FDA-approved (in 2014) antiplatelet drug. Vorapaxar (Fig. 572) is a thrombin receptor (protease-activated receptor PAR-1)
antagonist, and is prescribed for patients with myocardial infarction (MI) and peripheral
198
Organofluorine Chemistry
CF3
Me
S
Me
N
H
H
O
O
N
N
H
OH
O
O
H
Me
Cl Cl
OH
P
P
P
OH
O OH O OH
O
O
Cangrelor
N
Vorapaxar
F
F
HN
N
N
S
H
O
N HO
N
S
H
N
O
F
N
N
N
HO
O
OH
HO
Ticagrelor
FIGURE 5–72 Structures of cangrelor, vorapaxar, and ticagrelor, the FDA-approved antiplatelet drugs.
arterial disease. It has demonstrated benefit in the prevention of the recurrent thrombic
effects, including MI and stroke.147 Among all the known PAR-1 inhibitors, vorapaxar is the
only drug that is approved by FDA for the prevention of recurrent ischemic events in patients
with peripheral artery disease and MI.148
Ticagrelor (Brillinta; AstraZeneca; Fig. 572) is a reversible, direct-acting platelet-aggregation inhibitor. It exerts its anti-platelet-aggregation effect through allosteric inhibition of the
ADP receptor P2Y12 and is a more effective drug as compared to clopidogrel (Plavix), a nonfluorinated antiplatelet drug.149
5.9.4.2 Riociguat
Riociguat (Adempas; Bayer Pharmaceuticals; Fig. 573) is an orally available, soluble guanylate cyclase inhibitor and is a first-in-class drug, approved by FDA in 2013, for the treatment
of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension.150 Chronic thromboembolic pulmonary hypertension arises from a complication of pulmonary embolism, leading to right heart failure and death. Riociguat is recommended as a
medical therapy in the complicated, inoperable cases for treating this disease.151
Chapter 5 • Pharmaceutical applications of organofluorine compounds
199
F
N
N
N
N
H 2N
N
N
Me
NH2
O Me
O
Riociguat
FIGURE 5–73 Structure of riociguat, a drug for chronic pulmonary hypertension.
5.10 Antiinflammatory pharmaceuticals
5.10.1 Nonsteroidal antiinflammatory agents
Steroidal as well as NSAIDs are usually nonselective COX-1 and COX-2 inhibitors. Both of
these cyclooxygenases are involved in the biosynthesis of prostaglandins, the compounds
responsible for the inflammation at the sites of inflammation. Whereas COX-2 is inducible,
and expressed at the sites of inflammation, COX-1 is expressed in most tissues, including
gastrointestinal mucosa. The COX-1 inhibition, therefore, results in gastrointestinal side
effects, as observed in the prolonged use of NSAIDs, such as aspirin. The COX-1 inhibitors,
on the other hand, inhibit platelet aggregation and thus reduce the risk of cardiovascular
complications. Although selective COX-2 inhibitors eliminate the gastrointestinal side effects
associated with COX-1 inhibition, COX-2 inhibition results in the inhibition of prostacyclin
synthesis, thereby promoting thrombosis, resulting in adverse cardiovascular events, such as
heart attack and stroke.152
NSAIDs, such as aspirin (O-acetylsalicyclic acid), ibuprofen, naproxen, and flurbiprofen
(a fluorinated NSAID), are nonselective COX inhibitors and are associated with gastrointestinal side effects. Celecoxib (a fluorinated NSAID), rofecoxib (Vioxx; Merck & Co.), and valdecoxib (Bextra; Pfizer) are selective COX-2 inhibitors, thereby minimizing the gastrointestinal
adverse effects associated with the COX-1 inhibitors. Rofecoxib (used to treat osteoarthritis),
a nonfluorinated selective COX-2 inhibitor, was withdrawn from the market due to the serious drug-related adverse effects, including heart attack and stroke. Pfizer has withdrawn valdecoxib from the market due to the drug-induced heart attack and stroke risks. Celecoxib
inhibits autoimmune encephalomyelitis in COX-2-deficient mice, thus demonstrating that it
can act also exhibit COX-2-independent pathways.153 Roflumilast, an NSAID, is approved by
FDA and EMA for the treatment of inflammatory diseases, such as chronic obstructive pulmonary disease (COPD) and chronic bronchitis (Fig. 574).154
200
Organofluorine Chemistry
O
NH 2
S
O
N
F3 C
F
F
Me
OH
N
Cl
O
F
N
O
H
N
Cl
O
O
Me
Celecoxib
Flurbiprofen
Roflumilast
FIGURE 5–74 Structures of fluorinated NSAIDs—celecoxib, flurbiprofen, and roflumilast; NSAIDs, Nonsteroidal
antiinflammatory drugs.
5.10.2 Celecoxib
Celecoxib (Celebrex; Pfizer) is an NSAID, prescribed for the treatment of osteoarthritis and
rheumatoid arthritis. It is widely prescribed and is now available in the generic form after
the original patent expiration. It is the 120th best selling drug as of 2016.4 Celecoxib is a
selective cyclooxygenase-2 (COX-2) inhibitor and thereby interferes with the COX-2mediated biosynthesis of arachidonic acid, the precursor compound for the biosynthesis of
prostaglandins, which are responsible for inflammation at the sites of inflammation. As
described earlier, COX-1 is expressed in almost every tissue, whereas COX-2 is expressed at
the sites of inflammation. Thus, COX-2-selective inhibitors attenuate the inflammation at the
specific inflammation sites. The nonfluorinated COX-2-selective inhibitors rofecoxib (Vioxx;
Merck & Co.) and valdecoxib (Bextra; Pfizer), on the other hand, proved to be too hazardous
to use and are withdrawn, so that celecoxib is the only marketed COX-2 selective inhibitor
for treating rheumatoid arthritis and osteoarthritis.
An X-ray crystal structure of celecoxib at the active site of the S121P mutant (PDB 5JW1)
reveals predominant hydrophobic interactions of the CF3 moiety with the side chain CH
bonds (Fig. 575).155
5.10.3 Corticosteroids
Fluorinated steroidal antiinflammatory agents are widely prescribed for the treatment of
inflammatory skin diseases and as inhalation drugs against asthma. Some of these fluorinated steroidal antiinflammatory agents are antagonists for estrogen or the progesterone
receptors and thereby are used as anticancer agents. For example, fulvestrant, an ER antagonist, is used as a second-line therapy for advanced breast cancers. Dexamethasone, a fluorinated steroidal antiinflammatory agent is used as an antiemetic as well as an anticancer
agent for the treatment of multiple myeloma.156,157 As topical antiinflammatory agents, these
drugs are often used interchangeably for various conditions, such as skin rashes, skin allergies, and dermatitis. Some of the corticosteroids, such as fluticasone, are used as nasal
sprays for the treatment of asthma and COPD and allergic rhinitis.158,159
Chapter 5 • Pharmaceutical applications of organofluorine compounds
201
O NH
2
S
O
F3C
N N
Celecoxib
Me
FIGURE 5–75 Expanded view of the X-ray structure of celecoxib (ball and stick), bound to the S121P COX-2 mutant;
hydrophobic interactions of the CF3 moiety with the side chain CH bonds (3.43.5 Å) are shown as dotted lines;
the structure was created using UCSF Chimera software, PDB 5JW1.
Many of the corticosteroidal drugs are fluorine-containing compounds, and are used in treating various inflammatory conditions. The therapeutic effects of various fluorine-containing corticosteroidal drugs are as follows: flunisolide (AeroBid) is a corticosteroid, used for the treatment
of allergic rhinitis through its effect on the activation of glucocorticoid receptors. Amcinonide
(Cyclocort) is a topical glucocorticoid for the treatment of atopic dermatitis and allergic contact
dermatitis. Fluorometholone is a glucocorticoid used for the ophthalmic treatment of eye inflammation and various skin disorders. Desoximetasone (Topisolone) is a topical corticosteroid used
for the treatment of skin allergies, such as rashes and itching. Triamcinolone (Kenalog) is a synthetic glucocorticoid, used for the treatment of various allergies, arthritis, asthma, and COPD.
Fluticasone propionate (Flonase), a glucocorticoid, is used as a topical antiinflammatory agent
and for the treatment of asthma and COPD. Fluticasone furoate, as a combination drug with
vilanterol (a β-agonist), is used in chronic bronchitis and emphysema. Fluticasone furoate as
well as fluticasone propionate are also effective against allergic rhinitis.158,159 As of 2016, fluticasone propionate is the 16th most prescribed drug (Fig. 576).4
The synthesis of these corticosteroids, in general, involves Selectfluor-mediated fluorination of the dienol acetate (e.g., 75) to install the fluorine at C6 and ring-opening hydrofluorination of the C9C11 epoxide for installing the fluorine at C9 as the key steps (Fig. 577)
(see Chapter 2: Electrophilic reactions in the synthesis of organofluorine compounds).160 The
terminal fluoromethyl group in fluticasone is introduced by Selectfluor/Ag(I)-mediated
202
Organofluorine Chemistry
Me
O
O
Me
HO
Me 9
F
Me
HO
Me
O
O
H
O
H
F
H
F
Flunisolide
H
O
Me
O
5
Fluorometholone
Amcinonide
OH
O
O
HO
HO
Me
Me
F
Me
HO
O
HO
Me
OH
F
H
O
O
OH
H
F
O
O
HO
O
O
H
O
HO
O
HO
S
F
Me
H
O
O
F
Desoximetasone
Triamcinolone
Fluticasone propionate
O
HO
Me
F
O
O
O
Me
O
S
F
Me
HO
H
Me
H
HO
OH
Me
F
H
O
O
F
Fluticasone furoate
Dexamethasone
FIGURE 5–76 Structures of widely used steroidal antiinflammatory pharmaceuticals.
decarboxylative fluorination (see Chapter 4: Organotransition metal catalysis in the synthesis
of organofluorine compounds).161
5.11 Antidepressants
A vast majority of the antidepressant pharmaceuticals are selective serotonin reuptake inhibitors (SSRIs). The widely prescribed SSRI-based antidepressants, including fluvoxamine,
paroxetine, citalopram, escitalopram (chirally pure, S-isomer of citalopram), and fluoxetine
are fluorinated compounds (Fig. 578). The SSRIs delay the serotonin reuptake so that the
O
O
O
Me
O
HO 11
OH
H
Me
O
Me
Me
1. Selectfluor
H
AcO
O
OH
H
9
F
2. HF/H2O
OH
H
6
F
75
76
O
F
HO
Me
OH
O
Me
S O
O
Me
H
F
O
Me
HO
Me
Selectfluor, AgNO3
Acetone/H2O, 45 °C
H
–CO2
O
F
S O
O
H
Me
H
O
F
F
Fluticasone propionate
92.7%
77
FIGURE 5–77 Synthesis of corticosteroids.
CF3
F
O
HN
H3 C
O
O
O
N
N
O
O
F
NH 2
Fluvoxamine
N
Citalopram (racemic)
Paroxetine
F
N
(S)
O
F3 C
O
N
H
N
Escitalopram
((S)-Citalopram)
Fluoxetine
FIGURE 5–78 Structure of SSRI antidepressant drugs—fluvoxamine, paroxetine, citalopram, escitalopram, and
fluoxetine; SSRI, Selective serotonin reuptake inhibitor.
204
Organofluorine Chemistry
inhibitory neutotransmitter serotonin persists longer at synaptic junctions, thereby enhancing the efficacy of the neurotransmission, with concomitant decrease in anxiety disorders in
patients. SSRIs are among the most prescribed drugs, with citalopram being the 21st most
prescribed drug and fluoxetine, the 29th, as of 2016.4
Fluvoxamine (Luvox), now a generically available drug, is used for the treatment of anxiety disorders.162 It is an SSRI inhibitor and has a similar efficacy as that of paroxetine and
citalopram. Fluoxetine (Prozac; Eli Lilly), also a generically available antidepressant drug, is
listed among the United Nations’ essential drugs. In 2016 it was the 29th most prescribed
drug.4
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Rockway, T. W.; Maring, C. J.; Hutchinson, D. K.; Flentge, C. A.; Wagner, R.; Tufano, M. D.; Betebenner,
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Ng, T. I.; Krishnan, P.; Pilot-Matias, T.; Collins, C.; Panchal, N.; Reisch, T.; Dekhtyar, T.; Mondal, R.;
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6
Synthesis and applications of
18
F-labeled compounds
Chapter Outline
6.1 Introduction ............................................................................................................................... 216
6.2 Synthetic methods for radiofluorination................................................................................ 220
6.2.1 Synthesis of 18F-labeled reagents................................................................................... 221
6.3 Sharpless click reactions for positron emission tomography tracers................................... 225
6.3.1 Protein and oligonucleotide triazole positron emission tomography tracers ........... 227
6.3.2
18
F-octreotate positron emission tomography tracers for tumor imaging ................ 228
6.3.3 Strain-promoted click chemistry..................................................................................... 229
6.4 Staudinger ligation reactions for positron emission tomography tracers .......................... 232
6.5 Radiofluorination via aromatic nucleophilic substitution ..................................................... 235
6.5.1 [18F]fluoro-(1)-biotin........................................................................................................ 236
6.5.2 L-3,4-Dihydroxy-6-[18F]fluorophenylalanine (6-[18F]L-DOPA) ....................................... 238
6.5.3 γ-Aminobutyric acid transporter positron emission tomography tracers .................. 238
6.5.4 Radiofluorination of phenolic compounds ................................................................... 239
6.6 Transition metalmediated radiofluorination....................................................................... 243
6.6.1 Mn(III)-catalyzed radiofluorinations .............................................................................. 243
6.6.2 Pd-catalyzed radiofluorinations ..................................................................................... 246
6.6.3 Au(III) catalysis for the synthesis of [18F]trifluoromethyl compounds ........................ 246
6.6.4 Ni(II)-catalyzed radiofluorinations ................................................................................. 247
6.6.5 Cu(I)-catalyzed radiofluorinations.................................................................................. 250
6.7 Radiofluorination via diaryliodonium salts ............................................................................ 250
6.7.1 Cu(I)-catalyzed radiofluorination of diaryliodonium salts........................................... 252
6.7.2 Radiofluorination via iodonium ylides .......................................................................... 253
6.8 Enzymatic fluorination reactions for [18F]-labeled positron emission tomography
tracers ......................................................................................................................................... 256
6.8.1 50 -Fluoro-50 -deoxyadenosine and 5-fluororibose.......................................................... 256
6.8.2 Fluorinase-catalyzed synthesis of [18F]50 -deoxy-50 -fluoroadenosine-biotin
conjugate ......................................................................................................................... 257
6.8.3 50 -Fluoro-50 -deoxyadenosine-RGD conjugate in cancer detection .............................. 257
6.9 Positron emission tomography tracers in Alzheimer’s disease ............................................ 258
6.9.1 [18F]Flortaucipir (a neurofibrillary tangle biomarker) .................................................. 259
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00006-7
© 2020 Elsevier Inc. All rights reserved.
215
216
Organofluorine Chemistry
6.9.2 2-(4-Aminoaryl)quinoline-based 18F-labeled positron emission tomography tracers
(THK series)....................................................................................................................... 261
6.9.3 Tropomyosin receptor kinase targeted 18F-positron emission tomography.............. 263
6.10
18
F-positron emission tomography tracers in cancer diagnosis ........................................... 264
6.10.1 [18F]-(R)-lorlatinib........................................................................................................... 264
6.10.2 Cyclic RGDYK (arginine-glycine-aspartic acid-tyrosine-lysine) dimer-derived positron
emission tomography tracers ....................................................................................... 265
References........................................................................................................................................... 271
6.1 Introduction
Positron emission tomography (PET) imaging using 18F-PET tracers has emerged as a powerful diagnostic tool for cancers,1 Alzheimer disease (AD) and other neurological disorders,2
and atherosclerotic lesions.3 The preferred use of the 18F-PET tracers over the other conventionally used C-11-based PET tracers is largely due to the relatively long half-life of 18F and
the favorable pharmacokinetic properties of the organofluorine compounds. Several 18F-PET
tracers are now available either through commercial sources or via in-house synthesis at the
site of PET-administration using automated synthetic strategies. 18F isotope has a half-life of
110 min, which is significantly higher than the half-lives of the other pharmaceutically significant PET tracers: 11C (10 min), 13N (10 min), 15O (2 min), 14O (1.2 min), and decays almost
exclusively by positron emission (97% β1 emission). Furthermore, 18F isotope has relatively
the lowest positron energy of 0.635 MeV (as compared to 0.96, 1.19, and 1.723 MeV,
respectively, for 11C, 13N, and 15O) and the shortest tissue penetration range (B2 mm),
and thus the radiation toxicity to the patients receiving 18F-PET is minimal to negligible.
68
Ga (t1/2 5 68 min), 82Rb (t1/2 5 1.27 min), and 177Lu (t1/2 5 28.4 min) are among the
other radioisotopes that are used as PET tracers.
As described earlier, 18F-labeled PET imaging agents offer obvious advantage of their relatively
longer half-life times and also the feasibility of transportation of the compounds from the generating facilities to the PET-administering sites. Some of the illustrative FDA-approved PET tracers
are shown in Fig. 61. The small molecule PET tracer fluciclovine (Axumin) is FDA approved
for imaging of prostate-specific antigen (PSA) levels in prostate cancer. 177Lu DOTA-TATE
(Lutathera) and 68Ga DOTA-TATE are FDA-approved PET imaging agents for the somatostatin
receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors, and second-generation
PET tracers of these theranostics (i.e., compounds acting as PET-diagnostic as well as therapeutic
agents) with improved pharmacokinetic effects are continuously being developed.4,5
Pittsburgh compound B [(2-(4-[11C]methylamino)phenyl)6-hydroxybenzothiazole (PiB)], a
thioflavin T-derived compound,6,7 is the first FDA-approved PET tracer for PET imaging of
the amyloid plaques and is widely used. Other more recently FDA-approved 18F-labeled PET
tracers for imaging amyloid plaques include florbetaben (Neuraceq),810 flutemetamol
(Vizamyl),1012 and florbetapir (Amyvid).13,14 These radiotracers are now in routine use
along with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and PiB to monitor the extent of
Chapter 6 • Synthesis and applications of 18F-labeled compounds
217
amyloid plaque formation in cases of AD as well as other dementias that involve amyloid
pathology, such as Parkinson’s disease.
[18F]FDG is among the earliest developed 18F-PET tracers and is the first FDA-approved
18
F-labeled compound for PET imaging in the clinical settings. The [18F]FDG is being
OH
HO
O OH
HO
HO
11
CH3
NH
S
N
18
F
Pittsburgh compound B (PiB)
(for PET imagiing of Aβ levels in the brain)
18
[ F]-2-Deoxy-2-fluoro-D-glucose
(for monitoring glucose metabolism
in cancers and in the brain)
18
F
18
F
CH3
HO
O
Florbetaben (Neuraceq)
(for PET imaging of Aβ levels in the brain)
H
N
Flutemetamol (Vizamyl)
(for PET imaging of Aβlevels in the brain)
CH3
O
18
18
F
O
CH 3
NH
S
N
O
O
H
N
F
O
O
N
H
Florbetapir ( 18F-AV-45; Amyvid)
(for PET imaging of Aβ levels in the brain)
OH
NH2
Fluciclovine (Axumin)
(for PET imaging of prostate-specific
antigen (PSA) levels in prostate cancer)
OH
NH
O
O
O
N
O
(III)
M
N
NH
O
O
O
NH2
HN
N
N
H
S
N
O O
O
O
H
N
N
H
N
H
S
HN
O
OH
H 3C
OH
OH
O
O
M = 177Lu:
177
M = 68Ga:
68
Ga DOTA-TATE
(for PET imaging of somatostatin receptor-positive gastroenteropancreatic
neuroendocrine tumors
Lu DOTA-TATE (Lutathera)
(for PET imaging of somatostatin receptor-positive gastroenteropancreatic
neuroendocrine tumors)
FIGURE 6–1 Illustrative examples of the FDA-approved 18F-, 177Lu-, 68Ga-, and 11C-labeled PET tracers. PET, Positron
emission tomography.
218
Organofluorine Chemistry
widely used for monitoring glucose metabolism, and thereby in the diagnosis of cancers
and neurological disorders. Since glucose metabolism is dramatically elevated in cancerous
cells, 18F-labeled glucose allows monitoring the tumor progression and tumor metastasis. On
the other hand, unusually low levels of its uptake in the brain indicate hypometabolism in the
brain neuronal cells and therefore serve as a diagnostic marker in monitoring the extent and
progression of AD.15 Cancerous cells have abnormally high glucose metabolism and thus [8F]
FDG, in combination with computed tomography (CT) scans, would reveal the anatomical
structure along with glucose regional metabolism during a single combined scan. Thus, the
[8F]FDG PETCT scans would serve as diagnostic criterion for detecting cancers as well as for
monitoring various other pathophysiological processes.16,17 Due to its ready availability
through automated one-step synthesis, and due to its superior pharmacokinetic properties,
[18F]FDG is widely used as a PET tracer, and also as a building block for other glucosederived PET imaging agents, in the detection of and in the monitoring of the disease progression in cancer, neurological disorders, including AD and cardiovascular diseases.
Often, as described above, the PET is combined with CT (PET/CT) to gain metabolic as
well as anatomical information at the sites of lesion. Magnetic resonance imaging (MRI) in
combination with the PET gives similar and complementary information of the disease progression as that of the PET/CT, as shown in a comparative analysis of these techniques in
the diagnosis of the lung cancer (Fig. 62). Moreover, MRI technique does not involve the
patients being exposed to the ionizing radiation, unlike that for the CT, and in certain cases,
PET/MRI gives additional information. For example, the PET/MRI in lung cancers shows
both the main lesion and the lung pleural retraction (Fig. 62F), whereas PET/CT shows
only the main lesion (Fig. 62C). However, due to the current technical difficulties in the
recording of MRI, often both PET/CT and PET/MRI are recorded for a patient to gain complementary information on the sites of lesion.18 With rapid advances in the MRI, it is hoped
that the PET/MRI would completely replace PET/CT.
The FDG PET/CT has been conventionally used to monitor the clinical progress of the
nonsmall-cell lung cancers (NSCLC). Ganem and coworkers have demonstrated through
18
F-PET/CT monitoring that standardized uptake value (SUVmax) and the tumor volume of
the 18F-FDG were substantially lowered upon radiation treatment of the patients with stage
IIA left lung adenocarcinoma (a subtype of nonsmall-cell lung carcinoma).19 The SUVmax of
18
F-FDG decreased from 9.6 to 4.2 after radiation therapy, coincident with the decrease in
the tumor size. This positive correlation of the SUVmax of the 18F tracer versus the tumor size
was also demonstrated in other lung cancers, including adenocarcinoma, squamous cell carcinoma, and small-cell carcinoma.20,21
There is an emerging interest in developing clinically useful, disease-specific PET imaging
agents. For example, 6-[18F]fluoro-A-85380 binds to the nicotinic acetylcholine receptors (nAChRs)
with very high affinity and was in preclinical trials as a PET tracer for imaging nACHRs.22,23
The bloodbrain barrier penetration is an important criterion for the drug candidate to be
used as a PET tracer in the clinical settings. A comparative study using the [11C]befloxatone
(a PET tracer for the monoamine oxidase A in the brain), in in vitro as well as in vivo studies,
showed that the 6-[18F]fluoro-A-85380 PET tracer effectively penetrates the bloodbrain barrier.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
219
FIGURE 6–2 Images for a 58-year-old female with lung cancer confirmed by pathology. 18F-FDG uptake was
observed in PET images (A and D); both CT (B) and T2-weighted MRI (T2MRI) (E) showed the main lesion (shown by
the upper arrow). However, only T2MRI (E) showed the pleural retraction accompanied by lung cancer (as shown by
the lower arrow). PET/CT (C) showed only the main lesion, while PET/MR (F) showed both the main lesion and the
pleural retraction. CT, Computed tomography; [18F]FDG, 2-[18F]fluoro-2-deoxy-D-glucose; MRI, magnetic resonance
imaging; PET, positron emission tomography. Adapted from Hu, Z.; Yang, W.; Liu, H.; Wang, K.; Bao, C.; Song, T.;
Wang, J.; Tian, J. From PET/CT to PET/MRI: Advances in Instrumentation and Clinical Applications. Mol. Pharm. 2014,
11, 37983809, Copyright 2014, American Chemical Society.
This comparative PET imaging technique provides an accurate estimate of the rate constant for
the passage of the free ligand from the plasma into the brain (k1), and the rate constant for the
passage of the free ligand from the brain to the plasma (k2) (Fig. 63).24
Florbetapir (Amyvid Pharmaceutical) is an FDA-approved PET tracer for the detection of
the amyloid beta (Aβ) plaques in the brains and is among the widely used PET tracers in the
diagnosis of the AD. A florbetapir PET image of one control (i.e., non-AD case) and two AD
cases, in conjunction with Aβ antibody 4G8 immunohistochemistry, shows clear distinction
between these patients.14 The AD cases are evidenced by relatively higher uptake of the PET
tracer, indicating relatively larger areas of Aβ plaques, as also supported by the immunohistochemistry. [18F]FDG imaging is complementary to that of the other PET tracers that target
Aβ plaques or neurofibrillary tangles (NFTs), including florbetapir, as it indicates the extent
of glucose metabolism, which is inversely related to the levels of the Aβ plaques or NFTs.
Among the other selective Aβ-binding PET imaging agents that are in preclinical trials,
the [18F]FIBT, an 18F-labeled imidazo[2,1-b]benzothiazole PET tracer, has comparable
220
Organofluorine Chemistry
18
F
N
HN
O
[18F]-A85380
FIGURE 6–3 Coregistered PETMRI images representing the k1 obtained in human after intravenous injection of
[11C]befloxatone (left) and [18F]fluoro-A-85380 (right). The PET images representing the K1 are obtained as follows.
PET image obtained at 1 min postinjection (mean value between 30 and 90 s) is considered as independent of the
receptor binding. This image (in Bq/mL) is corrected from the vascular fraction (Fv in Bq/mL, considered as 4% of
the total blood concentration at 1 min) and divided by the arterial plasma input function [AUC0-1 min of the
plasma concentration, in (Bq min)/mL]. The resulting parametric image, expressed in min21, represents an index of
the K1 parameter of the radiotracer. MRI, Magnetic resonance imaging; PET, positron emission tomography. Adapted
from Mabondzo, A.; Bottlaender, M.; Guyot, A.-C.; Tsaouin, K.; Deverre, J.R.; Balimane, P.V. Validation of In Vitro
Cell-Based Human Blood-Brain Barrier Model Using Clinical Positron Emission Tomography Radioligands to Predict
In Vivo Human Brain Penetration. Mol. Pharm. 2010, 7, 18051815, Copyright 2010, American Chemical Society.
binding to the Aβ plaques as that for the PiB. [18F]FIBT, used in combination with the MRI
(PET/MRI), distinguishes an AD case from a control human subject (Fig. 64).25
6.2 Synthetic methods for radiofluorination
A variety of new synthetic methods are continually developed for the preparation of
18
F-labeled compounds,26,27 although most of the recent advances in the organofluorine synthetic routes have not yet been optimized or adapted for the synthesis of PET tracers.
Synthetic methods involving late-stage incorporation of the 18F label have obvious advantages because of the relatively short half-life of the 18F isotope.28 For example, nucleophilic
radiofluorination of α-diazocarbonyl compounds using the no-carrier-added [18F]fluoride
anion to give the corresponding [18F]fluoro carbonyl compounds is one such late-stage
fluorination strategy.29 Other late-stage radiofluorination reactions (vide infra) for the synthesis of PET tracers include Cu(I)-mediated CH fluorination of electron-rich arenes (or heteroarenes) using hypervalent iodonium reagents,30 PhenoFluor-mediated radiofluorination
of phenolic compounds,31,32 Mn(III)-catalyzed radiofluorination of aliphatic CH bonds,33
Chapter 6 • Synthesis and applications of 18F-labeled compounds
18
F
S
N
H
221
N
O
N
Me
[18F]FIBT
FIGURE 6–4 First human brain PET/MR images with [18F]FIBT. PET images of a patient with moderate AD (top) and
a subject defined as control (psychometric testing within normal limits, normal FDG PET, and normal CSF τ, τ , and
Aβ142 levels) (bottom) coregistered to their corresponding T1-weighted MPRAGE MR images as taken with the
Siemens Biograph in a fully dynamic 90 min PET/MR study. 7090 min postinjection frames are shown as axial (left),
sagittal (middle), and coronal (right) views. PET data was transformed to SUVRs using the cerebellum as reference
region (scale on left side). Images from the patient with tracer distribution typical for AD (top) show strong
contrast to images from the subject (bottom) who was cleared of any signs of neurodegeneration with a tracer
distribution typical for healthy controls. Vertical color bar indicates lookup-table “Cold” (taken from Pmod)
between ratio values of 1.0 (i.e., equality) and 2.0. AD, Alzheimer’s disease; CSF, cerebrospinal fluid; PET, positron
emission tomography; SUVRs, standardized uptake value ratios. Adapted from Hooshyar Yousefi, B.; Manook, A.;
Grimmer, T.; Arzberger, T.; von Reutern, B.; Henriksen, G.; Drzezga, A.; Foerster, S.; Schwaiger, M.; Wester, H.-J.
Characterization and First Human Investigation of FIBT, a Novel Fluorinated Aβ Plaque Neuroimaging PET
Radioligand. ACS Chem. Neurosci. 2015, 6, 428437, Copyright 2015, American Chemical Society.
Pd-catalyzed radiofluorination of arylboronic acids to give the aryl [18F]fluorides,34 and complexation of [Al]-18F or [B]-18F moieties into the macrocyclic ligands, such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) (vide infra) (Fig. 65).9,35
6.2.1 Synthesis of 18F-labeled reagents
A recent review summarizes the synthesis of the electrophilic, free radical, and nucleophilic reagents that are extensively used in the synthesis of the PET tracers.28 A vast majority of the 18F-labeled radiotracers have been synthesized through nucleophilic substitution
reactions using the [18F]fluoride anion. The [18F]fluoride ion is synthesized by the nuclear
222
Organofluorine Chemistry
1. Radiofluorination of α-diazo compounds:
α-18 F-esters and amides
mol%)
R′
FIGURE 6–5 Selected synthetic methods for the late-stage radiofluorination (vide infra).
reaction 18O(p,n)18F, by bombarding [18O]water with high-energy protons in the cyclotrons,
and this reagent is called “no-carried-added” fluoride anion since it is not contaminated
with externally added 19F-fluoride ion. The aqueous-solvated fluoride thus produced is
unreactive in the SN2 reactions and thus needs to be activated in a multistep process by
eluting the solution through ion-exchange columns with MeCN/H2O solution containing
countercations, such as K1 and R4N1. Typically, the macrocyclic Kryptofix2.2.2 cryptand
Chapter 6 • Synthesis and applications of 18F-labeled compounds
223
(a K1-complexing phase-transfer agent) is used for this purpose, and the resulting
Kryptofix-K2.2.2-18F is subsequently transferred into a polar aprotic solvents [such as acetonitrile and dimethylformamide (DMF)] or in some cases polar protic solvents (sterically
hindered alcohols, such as tert-butyl alcohol)36 for radiofluorination of the compounds
through SN2 or SNAr reactions. For example, an 18F-labeled captopril, an angiotensinconverting enzyme (ACE) inhibitor, could be synthesized in a relatively late-stage SN2 reaction using K18F/Kryptofix2.2.2 in acetonitrile. Subsequent treatment with aqueous NaOH
and neutralization would result in the hydrolysis of the ester and thioester moieties to give
the 18F-PET tracer (Fig. 66).37
O
O
O
N
S
H3 C H
MeO 2C
18
OSO 2CF3
1. K F/kryptofix-2.2.2/CH3 CN
2. NaOH (2 M)
3. HCl (conc.)
HS
N
H3 C H
HO2C
18F
[18 F]fluorocaptopril
(18 F-ACE inhibitor)
FIGURE 6–6 Synthesis of an18F-labeled captopril (ACE inhibitor). ACE, Angiotensin-converting enzyme.
For reactions with water-sensitive compounds, presynthesized acid [18F]fluorides (e.g., acetyl
[ ]fluoride, prepared from the reaction of acetic anhydride with [18F]fluoride anion) can be
used.2 Doyle and coworkers have synthesized a thermally stable, selective deoxyfluorination
reagent, PyFluor (2-pyridylsulfonyl fluoride), which is effective in the deoxyfluorination of alcohols on a preparative scale, and developed a corresponding 18F-labeled version, [18F]PyFluor,
for the radiofluorination of acohols.38 Thus, elution of the acetonitrile solution of
2-pyridylsulfonylchloride through an [18F]KF/Kryptofix-K2.2.2-containing anion-exchange cartridge gives the anhydrous [18F]PyFluor. Tetra-O-benzyl-D-glucose upon reaction with [18F]PyFluor gave 18F-labeled D-glucose derivative ([18F]FDG-benzyl ether) in 15% radiochemical
conversion. This deoxyfluorination reaction involves the initial rapid formation of the sulfonate
ester of the alcohols, followed by relatively slow SN2 reaction with the fluoride anion. The activation of alcohols toward reaction with PyFluor was achieved through the relatively sterically
crowded, nonnucleophilic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD). Minor byproducts derived from DBU or
MTBD are usually formed along with the desired PET tracers, and these impurities can be easily
separated in the final purification step (Fig. 67). Thus, [18F]PyFluor serves as an alternative
reagent to the commonly used [18F]fluoride ion, although it has not yet been automated for
the synthesis of PET tracers of radiopharmaceuticals in the clinical settings, perhaps due to the
involvement of additional steps for its preparation.
Various electrophilic and free-radical fluorinating agents can be prepared from the reaction of [18F]F2 gas with amines, alcohols, and carboxylic acids. Thus, the high electrophilic
reactivity of the elemental fluorine is tamed to provide effective radiofluorinating agents.
18
224
Organofluorine Chemistry
O O
S
Cl
N
[18F]KF/Kryptofix-K2.2.2
MeCN, 80 °C, 5 min
2-Pyridylsulfonyl
chloride
O O
S
N
[18F]PyFluor
O O
S
18
F
N
OBn
OBn
BnO
BnO
O
BnO
BnO
18F
OH
CH3
MeCN, 80 °C, 20 min
N
N
OBn
O
OBn
18
Tetra-O-benzyl-
O
O S O
[18F]F
N
F
N
D-glucose
MTBD
OBn
BnO
BnO
O
18
F
OBn
2-[ 18F]fluoro-2-deoxyglucose derivative
([18 F]FDG tetrabenzyl ether)
RCC: 15%
FIGURE 6–7 Synthesis of [18F]PyFluor and its reaction with tetra-O-benzyl-D-glucose to give the corresponding
18
F-labeled product.
The [18F]F2 is generated from the nuclear reactions 20Ne(d,α)18F and 18O(p,n)18F using the
elemental, gaseous neon, and O2, each diluted with [19F]F2 gas as the coadditive for the
extraction of the [18F]F2. The [18F]F2 produced in this manner is contaminated with
19
F-labeled F2, and therefore this reagent is called carrier-added [18F]fluorine gas. In general, radiofluorinations using the no-carrier-added [18F]fluoride reagents give relatively
higher specific activities over those using carrier-added fluorinating reagents and are thus
the preferred reagents for radiofluorination. Elemental [18F]F2 is transformed into various
electrophilic and free-radical fluorinating agents, such as 18F-labeled acetyl hypofluorite,
trifluoromethyl hypofluorite, N-fluoropyridinium salts, Selectfluor, N-fluorobenzenesulfonimide (NFSI), and N-fluoropyridin-2-one, that are useful for the radiofluorination reactions
undercontrolled reaction conditions (Fig. 68). Thus, for example, the elemental
18
F-fluorine is allowed to react with N-chloromethyl-1,4-diazabicyclo(2.2.2)octyl triflate
and (PhSO2)2NH to give [18F]Selectfluor and [18F]NFSI, respectively. These reagents can be
used in the electrophilic fluorination of enolsilyl ethers to give the corresponding
α-fluorocarbonyl compounds and fluorination of allylsilanes to give the corresponding allyl
fluorides.39 18F-labeled Selectfluor bis(triflate) achieves fluorodestannylation of arylstannanes to give the corresponding 18F-labeled aromatic fluorides.40 The reaction conditions
for the radiofluorination using 18F-selectfluor are much milder, and the radiofluorination is
more selective than for the radiofluorinations using elemental [18F]F2.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
F3 C
O
18
O
F
225
O
18
F
Trifluoromethyl hypofluorite
Acetyl hypofluorite
[18F]XeF 2
F3 C OH
O
Xe
OH
O
OSO 2CF3
18
N
F
OO O
S
N
O
Pyridine/NaOSO2 CF3
Na
18
[ F]F2
[18F]N-fluoropyridine
S
OO O
S
N
18
F
S
Cl
OSIMe3
[18F]NFSI
N
N
N
HClO4
TfO
LiOTf
Cl
O
18
N
N
F
N
[18F]FClO3
[18F]N-fluoropyridin-2-one
[1 8F]Perchloryl fluoride
18
2TfO
F
[18 F]Selectfluor
FIGURE 6–8 Conversion of the elemental [18F]F2 into various electrophilic and free-radical fluorinating agents.
Electrophilic radiotrifluoromethylation can be achieved using 18F-labeled Umemoto
reagents. Thus, a [18F]-labeled Umemoto reagent 3 can be used for the chemoselective radiotrifluoromethylation of thiol moieties in cysteine-containing peptides, to give a variety of acyclic and cyclic 18F(SCF3)-labeled peptides, such as the dipeptide 5 and cyclic RGDFC peptides
(6). The synthesis of the 18F-labeled Umemoto reagent 3 was achieved through nucleophilic
18
F[F]2 fluorination of 2-[(boromodifluoromethy)lthio]-1,10 -biphenyl (1), followed by
m-chloroperoxybenzoic acid (mCPBA)-mediated oxidative cyclization (Fig. 69).41
6.3 Sharpless click reactions for positron emission
tomography tracers
Sharpless has developed convenient synthetic route for conjugating the terminal alkynes and
azides through a modified Huisgen [3 1 2] cycloaddition reaction using Cu(I) catalysis, and
these reactions are generally referred to as the “click chemistry” or “click reactions.” In the
absence of the Cu(I) catalysis, the original Huisgen 1,3-dipolar cycloaddition requires elevated temperatures and long reaction times, and is not regioselective. The Cu(I)-catalyzed
click reactions proceed under relatively mild conditions (in some cases at ambient temperatures), under physiological conditions, and also in the cellular environments, to give exclusively the 1,4-substituted [1,2,3]triazoles. Thus, the Sharpless click reaction can serve as a
226
Organofluorine Chemistry
mCPBA/Tf2 O
[18F]KF/diCy-18-Cr-6
SCF2 Br
S
SCF2 18F
AgOTf (2 equiv)
OTf
CF2 18F
DCE, 60 o C, 20 min
1
2
3
SH
SCF2 18F
(e.g., peptide-SH)
4
Selected examples:
SCF2 [18F]
O
SCF2 18F
O
BocHN
O
N
H
CH3
O
O
HO
NH
N
H
O
NH2
N NH
H
HN
NH HN
O
O
O
cRGDFC[18F]CF3 ( 6)
Boc-Gly-CysS-[18F]CF3-OMe ( 5)
FIGURE 6–9 Electrophilic radiotrifluoromethylation of cysteine-containing peptides. DCE, 1,2-Dichloroethane; diCy18-cr-6, dicyclohexano-18-crown-6; mCPBA, m-chloroperoxybenzoic acid; Tf2O, triflic anhydride.
bioorthogonal reaction (i.e., the reaction tolerates the presence of various otherwise reactive
biomolecules, water, and oxygen) and is useful for the conjugation of 18F-labeled prosthetic
groups with biomolecules such as peptides, carbohydrates, and nucleotides. This reaction
has found wide applications in conjugation of various prosthetic organic moieties to the biologically interesting molecules, including peptides and proteins, and provides a convenient
synthetic route for the preparation of the 18F-labeled biomolecules and pharmaceuticals
(Fig. 610).42
H
R
Cu(II)SO 4 /Na-ascorbate
+
N N N
R'
or Cu(I)Br
R'
N
N N
R
R, R' = e.g., peptide, nucleotide, and 18 Flabeled substituents and pharmaceuticals
FIGURE 6–10 Sharpless click chemistry for 18F-labeling of biologically interesting molecules and pharmaceuticals.
Efficient synthetic methods for a variety of 18F-labeled azides and alkynes have been
developed, expanding the scope of the click chemistry for the preparation of various PET
imaging agents (Fig. 611).42
Chapter 6 • Synthesis and applications of 18F-labeled compounds
227
N
N
N3
18 F
O
18 F
N3
N3
18
F
n
3
18
F
N3
N3
O
N
Si
18
18
18
CO2 H
F
F
NH 2
F
p -Azidophenylalanine
O
H
N
O
N3
OH
O
NH2
N ε-Azidoethoxycarbonyl-lysine
FIGURE 6–11 Examples of 18F-labeled azide and alkyne click-chemistry precursors for the synthesis of PET tracers.
PET, Positron emission tomography.
A triazole derivative, [18F]-TBD (Fig. 612), was synthesized from the click reaction of
2-[ F]fluoroethyl azide with the N-propargyl derivative of a caspase-3 substrate. This
18
F-labeled triazole derivative was used in the dynamic PET studies of the caspase-3 activation to probe pharmacodynamics of the apoptotic cell death in vivo, and thereby to probe
the effectiveness of the apoptosis-targeted pharmaceuticals (such as cisplatin).43
18
H3 C
O
H
N
O
O
N
H
O
N-propargyl derivative of
a caspace-3 substrate
CO 2 H
H
N
H
H 3C
18
O
N3
Cu(I)
O
H
N
F
O
O
N
H
O
CO2H
H
N
18
N N
F
N
O
[18 F]-TBD
FIGURE 6–12 Synthesis of 18F-TBD, used in the PET studies of caspase-3 activation. PET, Positron emission
tomography.
6.3.1 Protein and oligonucleotide triazole positron emission
tomography tracers
The use of the oligomeric triazole, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)-methyl]amine (TBTA)
as Cu(I) chelator allows efficient coupling of alkyne or azide-substituted RNA oligonucleotides and human serum albumin to 18F-labeled alkynes or azides to give their corresponding
PET tracers (Fig. 613).44
228
Organofluorine Chemistry
O
5'-CCGCACCGCACAGCCG -3'
N
H
N3
O
S
O
+
18 F
N
CH3
RNA-oligonucleogide-N3
Ph
N
N
N
NN
N
N
NN
CuBr/TBTA/DMSO; 20 min, 10 °C
Ph
TBTA
Ph
O
O
S
18
F
N
N
O
N
N
N
H
5'-CCGCACCGCACAGCCG-3'
CH3
FIGURE 6–13 Preparation of 18F-labeled RNA oligonucleotides using click chemistry.
6.3.2
18
F-octreotate positron emission tomography tracers for tumor
imaging
Neuroendocrine tumors (also called neuroendocrine neoplasms, NENs), which occur mostly
in the digestive tract and respiratory tract, are formed from the diffuse endocrine system cells.
The NENs contain abundant SSTRs, and therefore somatostatin-based compounds are effective NEN antagonists and thus are attractive targets as PET imaging agents and also for internal radiotherapy. 177Lu- and 68Ga-based octreotate compounds, 177Lu-DOTA-TATE and
68
Ga-DOTA-TATE, are FDA-approved PET tracers as well as therapeutics (i.e., theranostics)
for these tumors.45,46 The 18F-analogs of these compounds would provide safer and relatively
more effective PET tracers. A click chemistry-derived PET tracer analog, 18F-fluoroethyl triazole
18
F-octreotate (a somatostatin analog, targeting somatostatin receptors), was synthesized
through automated synthesizer from the corresponding cyclic-hexapeptide (somatostatin;
c-CYHKTC)-derived terminal alkyne and [18F]fluoroethylazide. This octreotate-based PET tracer
showed favorable safety, imaging, and dosimetric profile for PET imaging of neuroendocrine
tumors in the human clinical trials, and further clinical trials are ongoing (Fig. 614).47
A related 18F-labeled fluoroborate analog, the cyclic peptide octreotate (a somatostatin
analog, targeting somatostatin receptors) conjugated to 18F-labeled Ammoniomethyl-trifluoroborate, called [18F]AMBF3-TATE, was synthesized through the azidealkyne click chemistry
(from the corresponding somatostatin-derived azide and trifluoroborate-derived terminal
alkyne reactants), followed by [18F]fluoride exchange of the fluoroborate moiety using microscale methods (i.e., on microfluidic chips) (Fig. 615). This 18F-PET tracer was obtained in
an overall decay-corrected radiochemical yield (RCY) of 16% in 40 min, with a radiochemical
purity greater than 99% and with high molar activity. Preclinical PET evaluations in micebearing human SSTRs (SSTR2)-overexpressing xenografts showed favorable biodistribution,
with the highest tracer accumulation in the bladder and gastrointestinal tissues.35
Chapter 6 • Synthesis and applications of 18F-labeled compounds
229
OH
NH
O
O
Ph
H
H
N
H
N
O
O
N
H
NH
NH 2
O
O
18 F
N3
HN
N
H
N
H
O
O
H
N
S
N
H
S
HN
Cu(II)SO4, Na-ascorbate
OH
O
(automated synthesizer)
O
OH
H 3C
OH
O
βAG-TOCA
OH
NH
O
18
F
Ph
N
H
N
H
N
N
N
O
O
O
O
O
H
N
N
H
NH
O
O
NH2
HN
N
H
S
N
H
N
H
S
HN
O
OH
H 3C
OH
OH
O
O
18
F-FET-βAG TOCA
(18F-octreotate)
FIGURE 6–14 Automated synthesis of 18F-octreotate, through click chemistry, as a PET tracer for neuroendocrine
tumors. PET, Positron emission tomography.
6.3.3 Strain-promoted click chemistry
Strain-promoted alkyneazide cycloaddition (SPAAC) is a variant of the Sharpless click reaction and takes advantage of the high reactivity of the strained cyclooctyne with azide moiety,
even in the absence of any Cu(I) catalysis. These SPAAC reactions are bioorthogonal as they
proceed at ambient temperature and under physiological conditions, and also in the cellular
environments, tolerating a variety of functional groups of the proteins and carbohydrates.48
This reaction is invaluable in the design of the bioorthogonal 18F-labeled probes, such as
18
F-labeled cyclic RGD (arginineglycineaspartic acid)containing peptides for PET
imaging.4952
A variety of 18F-labeled aza-dibenzocyclooctyne (ADIBO) amide derivatives, used as
18
F-labeled tagging agents, have been synthesized through conjugation of ADIBO with the
230
Organofluorine Chemistry
OH
NH
O
F
N
F B
F
O
Ph
O
N
N
N
N
H
NH
O
H
N
NH2
O
O
[18F]F–
HN
N
H
S
N
H
OH
N
H
S
(isotopic exchange on a
microfluidic chip)
O
OH
HN
H 3C
OH
Unlabeled AMBF3 -TATE
(synthesized through click reaction)
O
O
OH
NH
O
18
F
F B
F
N
Ph
O
N
N
N
O
O
H
N
N
H
NH
O
O
NH2
HN
N
H
N
H
S
N
H
S
HN
O
OH
H 3C
[18F]AMBF3 -TATE
OH
OH
O
O
FIGURE 6–15 Synthesis of 18F-labeled PET tracer [18F]AMBF3-TATE on microfluidic chips. PET, Positron emission
tomography.
18
F-labeled carboxylic acids. The latter 18F-labeled fluoroalkyl or fluoroaryl carboxylic acid
could be synthesized through the nucleophilic substitution reactions (SN2 or SNAr) using the
carrier-free [18F]fluoride source. These strained azacyclooctyne compounds serve as precursors for the synthesis of numerous 18F-PET tracers via the SPAAC of azide-derivatized substrates (e.g., peptide or protein azides) (Fig. 616).42
As an example of this strategy for the incorporation of the PET label, a dimeric RGD conjugated with ADIBO was reacted with the 18F-labeled polyethyleneglycol azide at ambient
temperature for 15 min (in aqueous ethanol) to afford the corresponding 1,2,3-triazole,
di-cRGD-PEG5-ADIBOT-18F, with a decay-corrected RCY of 92%.49 Any unreacted ADIBO
starting compound could be removed by a simple filtration through a terminal azidederivatized polystyrene resin (a process called chemoorthogonal scavenger-assisted purification), and thus this synthetic strategy does not involve a final high performance liquid
chromatography (HPLC) purification unlike most other synthetic methods for the PET
tracers (Fig. 617).
18
ADIBO-conjugated
F-synthons:
18
N
H
F
Synthesis of
18
18
N
O
F
18
5
O
N
O
N
H
N
O
O
F
N
4H
O
F-PET tracers through SPAAC:
N
N
N
N3
18
(peptide or small molecule
azides)
N
O
N
H
F
N
O
O
18
N
H
F
O
18
FIGURE 6–16 F-labeled strained azacyclooctynes as bioorthogonal precursors of the PET tracers; these strained
alkynes react at ambient temperature with azide derivatives of substrates (such as peptides, nucleotides, and
proteins) in the absence of any metal catalysts to afford the 18F-labeled compounds. PET, Positron emission
tomography; SPAAC, strain-promoted azidealkyne cycloaddition.
O
OH
O
OH
O
HN
NH
O
HN
NH
H
N
O
HN
O
O
O
HN
N
H
NH2
OH
HN
O
H
N
O
N
H
N
H
N3
HN
18
4
H
N
HN
O
HN
O
F
EtOH/H 2O (1/1); 25 °C, 15 min
O
4
PS
(ADIBO-scavenger resin); 20 min/25 °C
(for removal of unreacted ADIBO)
NH2
HN
RGDYK
O
OH
O
OH
O
NH
HN
18
F
O
O
NH
4
HN
HN
O
HN
N
H
NH2
OH
O
H
N
O
OH
N
H
N
N
N
O
O
HN
N
H
N
O
O
N3
O
NH
O
ADIBO
O
O
OH
O
N
O
O
O
O
4
N
H
O
O
HN
NH
O
H
N
O
RGDYK
HN
O
HN
NH2
HN
di-cRGD-PEG 5 -ADIBOT- 18 F
Decay corrected RCY: 92%
FIGURE 6–17 Synthesis of a cyclic RGD-linked 18F-labeled PET probe. PET, Positron emission tomography.
232
Organofluorine Chemistry
This RGD-linked 18F-tracer (di-cRGD-PEG5-ADIBOT-18F) was shown to selectively bind to
the tumors in tumor-mice models with good tumor-to-background contrast, with a relatively
high tumor uptake as compared to other major organs in PET imaging (Fig. 618).49 A
blocking experiment involving the coinjection of the corresponding unlabeled compound
showed significantly lower uptake of the labeled compound (90 min after postinjection), confirming the specific tumor uptake of the di-cRGD-PEG5-ADIBOT-18F (Fig. 618B). Further
optimization of the structural features of the latter ADIBOT-derived PET tracers may lead to
the design of the effective PET imaging agents.
6.4 Staudinger ligation reactions for positron emission
tomography tracers
Originally developed by Staudinger in 1919, the Staudinger reaction involves reduction of alkyl
or aryl azides by triarylphosphine to give the corresponding amines. Bertozzi and coworkers,
in 2000, adapted the Staudinger reaction for the bioorthogonal ligation of azides with arylphosphines to selectively form an amide bond between the reacting partners, in the presence of
complex biological environment.53,54 The reaction sequence and an overview of the mechanism are given in Fig. 619. There are two versions of the Staudinger ligation reactions: one in
which the phosphine oxide moiety is retained in the product amide (called nontraceless reaction; as shown in Fig. 619) and a variation in which the product amide does not incorporate
the phosphine oxide (traceless reaction). The traceless Staudinger ligation reaction (Fig. 620)
provides an alternative, and more efficient, approach (i.e., product does not contain the high
molecular weight phosphine moiety) for the synthesis of 18F-labeled PET tracers.
Gouverneur and coworkers synthesized β-[18F]fluoroethylamide derivatives of the N-acetylamino acids, as potential PET tracers, through the traceless Staudinger ligation of β-[18F]
fluoroethyl azide with N-acetylamino acid thioesters in RCYs of over 95%.55 This traceless
Staudinger reaction, unlike the Cu(I)-catalyzed azidealkyne cycloaddition reactions, does
not involve the metal ion impurities, and thus the resulting PET tracers are easy to purify,
although it requires relatively high temperatures (Fig. 621). Furthermore, the phosphine
reagents used in these Staudinger ligation reactions are prone to oxidation under the reaction
conditions, forming minor impurities that need to be removed by careful purification. The 2-[18F]
fluoroethylazide used in the latter reactions can be synthesized through the reaction of
2-azidoethyl tosylate with [18F]F2 in the presence of Kryptofix2.2.2 (4,7,13,16,21,24-hexaoxa1,10,diazobicyclo[8.8.8]hexacosane) at 80 C110 C, in RCYs of about 55%.27 The 2-[18F]fluoroethylazide is also widely used for the synthesis of a variety of 18F-labeled compounds through
Sharpless azidealkyne cycloaddition reactions.
Traceless Staudinger ligation reaction of 18F-labeled 2-fluoroethylazide with quinolonebased thioesters afforded the 18F-labeled PET tracers for selective binding to GABAA receptors,
with a nondecay corrected RCY of 7% and with a specific radioactivity of 0.9 GBq/μmol.56 These
fluoroalkyl 4-quinolone derivatives exhibited nanomolar to subnanomolar affinity for the
GABAA receptors (Fig. 622).
Chapter 6 • Synthesis and applications of 18F-labeled compounds
233
FIGURE 6–18 (A) In vivo evaluation of di-cRGD-PEG5-ADIBOT-18F; 3D reconstruction (upper), coronal (middle), and
transverse section (lower) combined PETCT images of the U87MG tumor-bearing mice at 30, 60, 90, and 120 min
postinjection of dicRGD-PEG5-ADIBOT-18F (1.8 MBq). (B) “Blocking” images with a coinjection of nonradioactive
di-cRGD-PEG5-ADIBOT-F (10 mg/kg). 3D, Three-dimensional; CT, computed tomography; K, kidney; PET, positron
emission tomography; T, tumor. Adapted from Kim, H.L.; Sachin, K.; Jeong, H.J.; Choi, W.; Lee, H.S.; Kim, D.W. F-18
Labeled RGD Probes Based on Bioorthogonal Strain-Promoted Click Reaction for PET Imaging. ACS Med. Chem.
Lett. 2015, 6, 402407, Copyright 2015, American Chemical Society.
234
Organofluorine Chemistry
NHR F
OR'
N N N
O
P
O
RF
O
P
R F = Fluoroalkyl/fluoroaryl
N N N
Mechanistic outline
RF
OR'
OR'
P
OR'
O
N
N
N
N
R
–N 2
P
O
P
O
N
N
RF
RF
N
O
O
O
H 2O
P
N
P
N
O H
RF
RF
HN
P
O
RF
R' O
FIGURE 6–19 Staudinger ligation reaction (nontraceless) and an overview of its mechanism.
O
X
R'
N N N
RF
P
XH
O
NHR F
R'
+
P
O
2. H 2 O
X = O/S
RF = Fluoroalkyl/fluoroaryl
X = O/S
N
Mechanistic outline
N
N
RF
–N 2
H O
O
X
P
N RF
X
R'
H2O
P
R'
N RF
O H
H 2O
FIGURE 6–20 Traceless Staudinger ligation reaction for the preparation of 18F-PET tracers. PET, Positron emission
tomography.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
O K+O
O
O
O
O
N
18 F
N3
80–110 °C, 2–15 min
O
R
[18F]F
(Kryptofix-2.2.2-K [18 F]F)
OTs
N3
N
235
N N N
18 F
S
O
THF/H2 O
PPh2
R
80 °C, 30 min
HS
Ph
O
P
18 F
N
H
RCY > 95%
Ph
Selected examples:
O
O
NH2
FIGURE 6–21 Synthesis of
N
H
N
18 F
NH 2
HN
N
H
18 F
18
F-labeled peptide analogs through traceless Staudinger reaction.
O
Ph
18F
O
S
N
H
PPh 2
N3
CH 3CN, DMF
130 °C, 15 min
O
O
18
N
H
Ph
F
N
H
GABAA receptor binding PET tracer
FIGURE 6–22 Synthesis of an 18F-labeled GABAA receptor antagonist through traceless Staudinger ligation reaction.
18
F-labeled amide derivatives of D-glucose and other alkyl amides could be synthesized
using the Staudinger ligation under relatively mild condition. The precursor 18F-labeled triarylphosphine esters were synthesized in a one-step process from the corresponding tosylates
and K[18F]F in the presence of polar protic solvents, such as tert-butyl alcohol, under phasetransfer conditions, in RCYs ranging from 2% to 65% (Fig. 623). 18F-labeled biotin derivative
was obtained using a similar procedure from the biotin-derived azide in 12% RCY.57
6.5 Radiofluorination via aromatic nucleophilic substitution
Aromatic nucleophilic substitution (SNAr) of aryl quaternary ammonium salts (7), with
electron-withdrawing groups, such as carbonyl or sulfonyl groups, ortho- or para- to the
ammonium moiety, with fluoride anion give the corresponding fluorinated compounds
236
Organofluorine Chemistry
O
O
O
TsO
18F
[18F]F– , TBAOH
4
PPh2
N
O
4
CH 3CN, t-BuOH
N
N
O
PPh2
18
N
H
90 °C, 10 min
F
5
100 °C, 10 min
O
HN
NH
H
O
O
H
S
N
4 H
N
Biotin-azide
N
N
O
N
N
O
N
OO
O
90 °C, 10 min
18
O
O
HN
NH
H
O
O
H
S
18
N
4 H
N
H
O
F
HN
O
F
5
OO
5
Biotin-PET agent
FIGURE 6–23 Staudinger ligation (traceless) of alkyl azides with 18F-labeled triarylphosphine esters. TBAOH,
Tetrabutylammonium hydroxide.
(Fig. 624). This reaction could be readily adapted to the synthesis of 18F-labeled aromatic
compounds, which, through a sequence of reactions, can be transformed to the corresponding thiol-reactive maleimides (9).58,59 These thiol-reactive maleimides are useful radiolabeled
precursors in the preparation of RGD peptide-based tracers (12) for imaging ανβ3 integrin
proteins, the transmembrane cell adhesion receptor proteins that are overexpressed in tumor
cells.60 This synthetic strategy, however, involves early-stage radiofluorination, and requires
relatively high temperatures for the radiofluorination, thus lowering RCYs of the final PET
tracers.
6.5.1 [18F]fluoro-(1)-biotin
Ipso nucleophilic aromatic substitution (SNAr) of nitro-aromatics using carrier-free [18F]F2
sources gives the 18F-labeled aromatics, at relatively high temperatures. The scope of this
radiofluorination reaction is limited to the compounds that are stable under high temperature conditions. Electron-withdrawing groups ortho- or para- to the nitro group facilitate the
nucleophilic substitution reaction. Ortho-nitropyridyl compounds can also be used in these
nucleophilic aromatic substitutions. A biotin-derived ortho-nitropyridyl ether, synthesized in
four steps starting from biotin, was reacted with Kryptofix2.2.2-complexed K[18F]F2 in
dimethyl sulfoxide at 160 C to give the 18F-labeled biotin derivative in high chemical- and
radiochemical yields, with specific activity in the range of 153 GBq/μmol (Fig. 625).61 Through
complexation of this 18F-labeled biotin to fluorescently-labeled avidin, the in vivo PET biodistribution was demonstrated in animal models, in tandem with fluorescence imaging.
FIGURE 6–24 Synthesis of [18F]fluoroarylsulfonamido-maleimide and its reaction with glutathione and thiolfunctionalized cyclic RGD peptides to give the corresponding PET tracers. PET, Positron emission tomography.
HN
NH
H
H
S
O
HN
1. EtOH/H2 SO4 , RT
NH
H
2. LiAlH 4 , DCM
OH –78°C to RT
4
3. TsCl, py, RT
O 2N
H
S
4
OTs
Biotin
O
K[18F]F-Kryptofix-2.2.2
HN
NH
H
DMSO, 160 °C, 5 min
H
S
O
4
18
F
N
18
Biotin- F PET tracer
FIGURE 6–25 Synthesis of
18
O
HO
O
O
F-labeled biotin via SNAr reaction.
DMF, 70°C, 2 h
HN
NH
H
H
S
O
4
O 2N
N
238
Organofluorine Chemistry
6.5.2 L-3,4-Dihydroxy-6-[18F]fluorophenylalanine (6-[18F]L-DOPA)
6-[18F]L-DOPA is a clinically successful PET imaging agent for the neuroendocrine tumors
(NETs).62 The synthesis of 18F-labeled DOPA was achieved through aromatic nucleophilic
substitution (SNAr) reaction of nitroaromatic 13 (with an electron-withdrawing carbonyl
group para to the NO2 moiety) using Kryptofix2.2.2-complexed K[18F]F in DMF solution,
with radiochemical conversions of 76%82%. Transformation of the benzaldehyde moiety to
the phenolic group through the BaeyerVilliger reaction, followed by deprotection of the
methoxymethyl and N-trityl (triphenylmethyl) groups afforded the 18F-labeled dopamine
(16) in high radiochemical conversion (Fig. 626).63 This synthetic method was shown to
be amenable to automation. In the automated version the sequence of reactions proceed
with an overall RCY of 20% and an enantiomeric excess of 96% of the 18F-labeled L-DOPA.63
FIGURE 6–26 Synthesis of 6-[18F]L-DOPA.
6.5.3 γ-Aminobutyric acid transporter positron emission tomography
tracers
γ-Aminobutyric acid (GABA) is one of the predominant inhibitory neurotransmitters, and dysregulation of the GABA system results in various neurological disorders such as epilepsy (seizures), schizophrenia, and autism spectrum disorder. Although benzodiazepines and other
GABA system responsive drugs are widely used in clinical practice, there are currently no
FDA-approved imaging agents for the presynaptic GABA-ergic neurons.64 Bloodbrain permeability and selective binding to the GABA receptors is a continuing challenge in this area.
Toward developing GABA transporter type 1 (GAT-1) imaging agents, [18F]fluorinelabeled compound 18 was synthesized through aromatic nucleophilic substitution reaction of the p-chlorobenzophenone derivative 17 using carrier-free [18F]fluoride anions
complexed to the Kryptofix2.2.2 with a RCY of 1% (Fig. 627).64 Hydrolysis of the
Chapter 6 • Synthesis and applications of 18F-labeled compounds
CO2Et
CO2Et
F
F
O
N
O
[18F]KF, Kryptofix-2.2.2
O
239
N
O
DMF, 130 °C, 30 min
18
Cl
F
17
18
1% RCY
CO2H
F
O
LiOH, 100 °C, 15 min
N
O
18
F
19
1% RCY
FIGURE 6–27 Synthesis of a GABA transporter type 1 (GAT-1) PET imaging agent. GABA, γ-Aminobutyric acid; PET,
Positron emission tomography.
compound 18 gives the carboxylic acid analog 19. In vivo animal studies (rhesus monkey
brain) showed that the ester 18 has significant bloodbrain permeability, whereas the carboxylic acid derivative is relatively impermeable to the brain, due to its predominant zwitterion character. However, the carboxylic acid moiety is necessary for the high affinity
binding to the GAT-1, and further studies are needed to identify the optimal PET tracers
for the GAT-1.
6.5.4 Radiofluorination of phenolic compounds
Ritter and coworkers have achieved late-stage radiofluorination of phenols using a 1,3-diaryl-2-chloroimidazolium chloride and [18F]F2, eluted through an anion-exchange column.
Otherwise tedious azeotropic drying of the 18F2 salts is not required for this radiofluorination, since the uronium salt 21 by itself, rather than the conventionally used aqueous alkaline
solution, is the eluting agent for the 18F2 ions trapped on the anion-exchange cartridge; the
18 2
F anion readily exchanges with the Cl2 anion in 21.
The mechanism of this deoxyfluorination is analogous to that of the deoxyfluorinations
achieved using PhenoFluor reagent and may involve a concerted nucleophilic aromatic
substitution (CSNAr).31 Thus, reaction of the phenolic substrates having electronwithdrawing substituents with N,N0 -1,3-bis(2,6-diisopropylphenyl)chloroimidazolium
chloride (20; CsF complex of which is commercially available as PhenoFluorMix) resulted
in the formation of the uronium salt 21. The latter uronium salt, upon passing through
the 18F2 embedded anion-exchange column, undergoes Cl2 to 18F2 anion metathesis, and
subsequent heating of the eluate-containing compound 22 (apparently an equilibrating
mixture) at 130 C forms the 18F2-labeled aromatics in good to excellent radiochemical
conversions (Fig. 628).
240
Organofluorine Chemistry
FIGURE 6–28 Radiofluorination of phenolic compounds using PhenoFluor and [18F]F2.
Although the originally developed deoxyradiofluorination of phenols is usually limited
to aromatics with electron-withdrawing substituents, Ritter and coworkers later have demonstrated that phenolic compounds with electron-releasing substituents, when complexed
with ruthenium(II), react with the N,N0 -1,3-bis(2,6-diisopropylphenyl)chloroimidazolium
chloride (28) to give the corresponding uronium salt, which upon chloride/19F2 anion
exchange on the anion-exchange column undergo deoxy-[18F]fluorination.65 In the latter
case, the Ru(II)-complexed aryloxy uronium intermediate is sufficiently electron-deficient
to stabilize the resulting Meisenheimer intermediate, even in the case of phenolic compounds with electron-donating substituents, so that the activation barrier for the deoxyfluorination is attenuated. A final rate-limiting decomplexation of the Ru(II) gives the
radiofluorinated phenolic compounds in 10%99% radiochemical conversions. The ruthenium complexes are stable to moisture and ambient atmosphere, and the radiofluorinations have large substrate scope. This radiofluorination technique is fully automated, and
a variety of biologically interesting compounds, such as 18F-labeled phenylalanine (34),
and deoxy-fluorinated versions of the drug-candidates, such as ezetimibe (35) and estrone
(36) were synthesized in micromolar scale using this technique (Fig. 629). These
Chapter 6 • Synthesis and applications of 18F-labeled compounds
Ru Cl
OH
R
(28)
R
Cl
N Ar
+ 18F
Ar N
OH
241
Cl
Ru
EtOH, 85 °C, 30 min
CH 3CN:DMSO (1:1)
125 °C, 30 min
29
Ar N
18 F
O
Cl
Ar N
N
R
R
Ar
O
18
Ru
Cl
N
Ar
R
SNAr mechanism
(Fast)
18F
Ru
F
Ru
Ar N
30
N Ar
31
O
18
F
Ru-decomplexation
Slow (rate limiting step)
R
32
Selected examples (with radiochemical conversions):
18F
OH
O
O
OMe
18
N
F
NHBoc
18F
33
F
N
O
34
98%
98%
99%
Me O
18
F-ezetimibe (35; OH replaced by
ezetimibe is a cholesterollowering drug.
18 F);
H
H
F
H
18F
88%
F-estrone (36)
FIGURE 6–29 Radiofluorination of phenols through Ru π-complexes.
synthetic methods complement other synthetic methods based on the diaryliodonium
salts and iodonium ylides (vide infra).
The radiofluorination of Ru-complexed phenols (39) was adapted, in combination with
solid-phase peptide synthesis, for the site-selective synthesis of 18F-labeled peptides on
micromolar scale, and the radiofluorination was fully automated (Fig. 630).66 This radiofluorination methodology is amenable to the synthesis of a variety of small peptides, incorporating 18F-labeled phenylalanine (tyrosine analog; 43) either at the terminus or in the
242
Organofluorine Chemistry
BF 4–
Ru+
1.
HO
38
NH2
OH
37
HO
40 W blue LED
O
O
2. Fmoc-OSu, Na2 CO3
75%
Ru
NHFmoc
O
Ru
O
O
2
O
O
2. Deprotection from
the polymer resin
39
N
O
1. SPPS
Ru
18
F
iPr
iPr
N
N
40
iPr
Cl
Cl
18 F
42
iPr
41
CF3 CO2H, iPr 3SiH, H 2 O, DTT
50°C, 10 min
18
F
43
18F
NH2
O
O
H 2N
HN
H
N
NH
N
H
O
H
N
O
18
HN
O
N
H
HO
O
O
44
F-c(RGDfk)
FIGURE 6–30 Ru(II)-mediated solid-phase synthesis (SPSS) of 18F-labeled small peptides. c(RGDfk), Cyclic
(ArgGlyAspPheLys peptide); DTT, dithiothreitol; Fmoc, 9-fluorenylmethoxycarbonyl; Fmoc-OSu,
9-Fluorenylmethoxycarbonyloxysuccinimide.
middle of the peptide sequence. For example, a cyclic ArgGlyAsp (RGD) motifcontaining peptide analog, 18F-c(RGDfk) (44), was synthesized in 25% RCY. The RGD analogs could be used as PET tracers, for example, in the monitoring of angiogenesis of tumor
cells.66
Chapter 6 • Synthesis and applications of 18F-labeled compounds
243
6.6 Transition metalmediated radiofluorination
6.6.1 Mn(III)-catalyzed radiofluorinations
Groves and coworkers have demonstrated Mn(III)(salen)OTs-catalyzed late-stage 18F-fluorination
of aliphatic CH bonds, using no-carrier-added [18F]fluoride, and used this facile-labeling synthetic strategy for the radiofluorination of a range of pharmaceutically active compounds, such as
ibuprofen (a nonselective COX inhibitor), rasagiline (MAO-B inhibitor), dopamine (neurotransmitter), celecoxib (a COX-2 inhibitor), and enalaprilat (ACE inhibitor), in moderate to high RCYs
(Fig. 631).67 The chiral Mn(salen) complexes were also shown to achieve enantioselective fluorination in some cases (up to 25% ee).
N
N
Mn (III)
O
O
Mn(III)(salen)OTs (10 mol%)
R
PhIO (1 equiv); [18F]F
H
18
R
K2 CO3 , acetone
50°C, 10 min
t-Bu
F
TsO
t-Bu
RCC: 20%–72%
t-Bu
t-Bu
Mn(III)(salen)OTs
Selected examples:
CO2 Me
O
N
18 F
18
CF3
18
F-Ibuprofen (COX inhibitor)
F
RCC: 51%
18
F-TFA-rasagiline (MAO-B inhibitor)
EtO
F3 C
N
N
NHBoc
AcO
RCC: 65%
RCC: 72%
18
F
AcO
18
SO2 CH3
F-dopamine derivative
(neurotransmitter)
O
H3 C
F
18
O
N
COCF3
N
CO2 Et
CH 218F
RCC: 46%
RCC: 23%
18
F-celecoxib analog
(COX-2 selective inhibitor)
18
F-enalaprilat (ACE inhibitor) derivative
FIGURE 6–31 Mn(salen)-catalyzed radiofluorination of aliphatic CH bonds, with some illustrative applications in
the preparation of 18F-labeled pharmaceuticals.
244
Organofluorine Chemistry
The proposed mechanism (Fig. 632) involves 18F2 exchange of the tosylate 45, followed by oxidation of the Mn(salen) 46 by iodosobenzene to give the Mn(V) complex 47.
Hydrogen atom abstraction of the aliphatic CH bond by the Mn(V) complex gives the
alkyl free-radical species (RU) that abstracts the fluorine atom from the Mn(IV)18F
N
Mn III
O
O
OTs
t-Bu
t-Bu
N
t-Bu
t-Bu
45
18
F
TsO
N
MnIII
O
O
18
F
t-Bu
t-Bu
N
t-Bu
t-Bu
PhI = O
46
18
F
Ph-I
R H
N
N OH N
Mn III
O
O
t-Bu
t-Bu
t-Bu
O
N
Mn V
O
O
18
t-Bu
t-Bu
F
t-Bu
t-Bu
47
t-Bu
49
RH
R
18
F
R.
R.
t-Bu
N OH N
Mn IV
O
O
18F
t-Bu
t-Bu
R
t-Bu
.
48
FIGURE 6–32 Aliphatic CH radiofluorination by the Mn(salen) complex: schematic outline of the reaction
mechanism.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
245
complex 48 to give the corresponding 18F-labeled compound and the Mn(III) complex
49.67 This CH activation cycle is further propagated through fluoride exchange to give the
18
F-labeled Mn(III) complex 2. These radiofluorination reactions proceed under relatively
mild conditions with a short reaction time of about 10 min to give moderate to high radiochemical conversions.
Whereas the abovementioned CH radiofluorination using the Mn(salen) complexes is
restricted to the relatively weaker benzylic CH bonds, CH radiofluorination using tetrakis
(pentafluorophenyl)porphyrin Mn(III)tosylate (Mn(TPFPP)OTs) (50) proceeds at the most
electron-rich methylene (CH2) and methine (CH) (but not at the methyl) CH bonds that
are farther removed from the electron-withdrawing groups such as carbonyl groups.68 Thus,
using Mn(TPFPP)OTs porphyrin (50)-based catalyst and iodosobenzene (PhIO) as the terminal oxidant, butyl benzoate is radiofluorinated at the distant methylene group, affording
3-[18F]fluorobutyl benzoate in about 39% radiochemical conversion. Groves and coworkers,
using this approach, synthesized a variety of 18F-labeled pharmaceutical analogs, such as
amantadine (antiparkinsonian and antiviral agent), ezetimibe (cholesterol-lowering drug),
flutamide (prostate cancer), lyrica (anticonvulsant), and 18F-labeled amino acid derivatives
(Fig. 633).68
Ar F
N
MnIII
N
N
N
Ar F
50 (10 mol%)
R18 F
R H
PhIO (1.7 eq.), K2CO 3, 18F
Ar F
–
F
TsO Ar
50
(Mn(TPFPP)OTs; Ar F = pentafluorophenyl)
acetone/ACN, 50 °C, 10 min
OAc
18
O
F
BocHN
18F
O
N
18
O
F
RCC: 19%
RCC: 39%
RCC: 31%
18
F-N-Boc-amantadine
(anti-parkinsonian and antiviral)
F
18
F-ezetimibe analog
(cholesterol-lowering drug)
O
O2 N
O
F3 C
N
H
18 F
18
NHBoc
RCC: 32%
18
18
F-flutamide derivative
(prostate cancer)
NHBoc
O
F
RCC: 22%
F-lyrica Boc protected)
(anticonvulsant)
FIGURE 6–33 Mn(III)-catalyzed radiofluorination of pharmaceuticals.
O
18
F
18
O
RCC: 29%
F-leucine derivative
(amino acid transporter)
246
Organofluorine Chemistry
6.6.2 Pd-catalyzed radiofluorinations
Ritter and coworkers have developed the late-stage electrophilic fluorination of aromatics to
give the aryl[18F]fluorides using Pd catalysis. In this transformation the electrophilic Pd(IV)[18F]F (55), generated through ligand exchange with the carrier-free [18F]fluoride anion with
the Pd(IV) complex 54, was allowed to react with the preformed arylpalladium(II) complexes
(53) to give the corresponding aryl[18F]fluorides (56).34 The Pd(IV) complex 54, in which the
polydentate tris(pyrazolyl)borate ligand helps prevent the reductive elimination in the high
valent Pd(IV) complex, was synthesized through Selectfluor oxidation of the corresponding Pd
(II) complex. Through this late-stage electrophilic fluorination, pharmaceutically interesting
compounds, such as [18F]fluorodeoxyestrone (58), were synthesized in high RCYs (Fig. 634).
Using nucleophilic radiofluorination strategy combined with Pd(0)-catalyzed fluoroalkylation
of aryl halides (or tosylates), Ritter and coworkers have synthesized 18F-difluoromethylarenes
(68) from aryl halides or tosylates (63) in three steps, involving Pd(0)-catalyzed fluoroacetophenonation of aryl halides (tosylates), followed by enolate bromination, [18F]fluoride anion
exchange of the bromide (5 min at 100 C), and potassium hydroxide (KOH)-mediated
debenzoylation (5 min at 100 C).69 A variety of functional groups on the aromatic ring, such
as carbonyl, morpholine, ester, amino, and olefinic moieties are unaffected under these reaction conditions, and this synthetic method was adaptable to the synthesis of 18F-labeled
pharmaceutically interesting compounds, such as fluoxetine (71; antidepressant), claritin
(72; antiallergic), estrone (73; a hormone), fenofibrate (cholesterol-lowering drug), and ezetimibe analogs (cholesterol-lowering drug) (Fig. 635).
6.6.3 Au(III) catalysis for the synthesis of [18F]trifluoromethyl
compounds
Toste and coworkers have synthesized 18F-radiolabeled aliphatic trifluoromethyl compounds
starting from the N-heterocyclic carbene (NHC)-stabilized alkylbis(trifluoromethyl)Au(III)
complex (74) in three steps, with the final step being the radiofluorination.70 Reaction of the
NHC-stabilized alkylbis(trifluoromethyl)Au(III) (74), synthesized via a multistep process,
with tris(perfluorophenyl)boron in the presence of trimethylsilyl bromide results in the
abstraction of the fluoride anion from the [Au]-CF3 (74) by the sterically crowded Lewis acid
(C6F5)3B forming the transient [Au]CF21 cation (75), which undergoes migratory insertion
of the [Au]R bond with concomitant bromide anion capture to give the [Au]CF2R(Br) (76).
Anion exchange of the latter compound using silver acetate, followed by reaction with
Kryptofix2.2.2-complexed [18F]fluoride anion, results in the outer-sphere (C6F5)3B-mediated
CF218F bond formation, concomitant with reductive elimination to give the 18F-labeled aliphatic trifluoromethyl compounds and the [Au](I) complex.70 Stoichiometric amounts of the Au
(III) catalyst is required for this radiofluorination, because the byproduct Au(I) cannot be
retransformed to Au(III) under these reaction conditions. Using this synthetic procedure, a
pharmaceutically interesting Bayer lead compound [18F]BAY 59-3074 was synthesized in 12%
radiochemical conversion (Fig. 636).
Chapter 6 • Synthesis and applications of 18F-labeled compounds
247
B(OH) 2
O O
S
Ar
B(OH) 2 (OAc)
N
Pd
N
52
N
R
(Ligand exchange)
OAc
51
O O
S
Ar
N
Me
2+
N
2 – OTf
18
F
Pd
N
+
N
–
N N
Pd
B
N
N N
OTf
N
N
N N
18 –
F
Pd
18-Cr-6
KHCO3 /acetone
N N
B
N
N N
H
R
Me O
Acetone, 85 °C, 10 min
56
H
55
H
F
N N
Me O
H
R
N
55
54
18
(53)
N
H
18
H
F
[Pd]
58
57
RCY = 92%
[Pd]
18
F
55
Acetone, 85 °C, 10 min
OBn
OBn
59
60
RCY = 93%
H O
BocHN
55
H
H O
BocHN
Acetone, 85 °C, 10 min
H
[Pd]
18
F
62
61
RCY = 18%
FIGURE 6–34 Pd(IV)-catalyzed radiofluorination of arylboronic acids.
6.6.4 Ni(II)-catalyzed radiofluorinations
The Pd-catalyzed radiofluorinations, despite being efficient, require longer reaction time and
high temperature for the radiofluorination and thus have limited scope in their automation.
In order to shorten the reaction time and to reduce the number of steps, Ritter and
248
Organofluorine Chemistry
50%–82% yield
ACN/PhCl (20 μL/0.2 mL)
KOH/H2 O
(45 wt.%, 40 μL)
FIGURE 6–35 Pd(0)-mediated radiofluorination at the benzylic site for preparation of pharmaceutically active
compounds, such as fluoxetine and estrone analogs.
coworkers have developed a one-step oxidative radiofluorination of the ArNi(II), using
aqueous 18F2 and a hypervalent iodonium oxidant. The intermediate Ar(18F)Ni(III) species
formed in the latter step spontaneously undergoes reductive elimination at room temperature
in less than 1 min to give high RCYs of the 18F-labeled compounds (Fig. 637).71 The air- and
Chapter 6 • Synthesis and applications of 18F-labeled compounds
249
F B(C 6 F5) 3
IPr
Au
F3C
CF3
Me3 SiBr/B(C 6F 5) 3
R
IPr
Au
F 3C
DCM or DCE
RT - 80 °C
F
C
R
IPr
F
F3 C
F
C R
Au
F
Me 3SiBr
Me3 SiF
– B(C 6 F5 )3
75
74
k[18 F]F/Kryptofix-2.2.2
IPr
Au
F3C
CF2 R
Br
IPr
AgOAc
Au
F 3C
DCM/MeOH
DCM; 8–25 min
CF2R
18
F
R
OAc
F
F
76
IPr(CF3 )Au
i-pr
IPr = i-pr
N
N
i-pr
i-pr
Selected examples:
18 F
O
O
18
O
F F
F
F
F
CF3
CN
O O
S
O
O
18
F F
F
[18F] BAY 59-3074
RCC = 31%
FIGURE 6–36 Au(III)-catalyzed synthesis of
RCC = 27%
RCC = 12%
18
F-labeled aliphatic trifluoromethyl compounds.
FIGURE 6–37 Oxidative radiofluorination of ArNi(II) complexes.
moisture-stable ArNi(II) complexes were synthesized through oxidative addition of aryl
halides to bis(cyclooctadiene)Ni(0) (Ni(COD)2), followed by sulfonamide ligand exchange.
Using this synthetic approach, Ritter and coworkers have synthesized human-injectable [18F]
fluorouracil, a PET tracer for cancer diagnosis.72
250
Organofluorine Chemistry
6.6.5 Cu(I)-catalyzed radiofluorinations
Cu(I)-catalyzed radiotrifluoromethylation, through the reaction of the in situ generated [18F]
FCF2Cu with aryl and heteroaryl iodides, gives access to the [18F]trifluoromethyl aryl and heteroaryl PET tracers.73 The [18F]FCF2Cu is formed, in situ, through the reaction of methyl
chlorodifluoroacetate (CF2ClCO2Me), [18F]F2 and CuI. Using this synthetic method, radiopharmaceuticals, such as [18F]fluoxetine (Prozac; antidepressant) and [18F]flutamide
(Eulexin, prostate cancer therapeutic), could be synthesized from the corresponding aryl
iodides with high radiochemical conversions and high radiochemical purity (Fig. 638). The
two-step synthesis of [18F]fluoxetine, with a 37% RCY, was achieved in a total reaction time
of 25 min, at 150 C. Under the similar reaction conditions, [18F]fluoxetine was synthesized
in one step, with a RCY of 55%.
[18F]fluoxetine (Prozac)
[18F]flutamide (Eulexin)
FIGURE 6–38 Cu(I)-catalyzed synthesis of [18F]fluoxetine and [18F]flutamide; TMEDA 5
tetramethylethylenediamine.
6.7 Radiofluorination via diaryliodonium salts
Aromatic nucleophilic substitution reactions of diaryliodonium salts (e.g., 7779) using
the [18F]fluoride anion give the corresponding [18F]fluoroaryl compounds. Electronreleasing groups ortho- or para- to the iodonium moiety disfavor the SNAr reactions, so the
inert aryl group in the iodonium salts should consist of electron-releasing groups (e.g.,
OMe and Me) for optimal radiochemical conversions of the diaryliodonium salts to the
desired PET tracers.74 For example, 4-[18F]fluorophenylalanne can be synthesized through
the iodonium salts, in which one of the aryl rings is p-methoxyphenyl or 2,4,6-trimethylphenyl (mesityl). The latter reaction proceeds under relatively milder conditions using Cu
(I) catalysis, and the radiofluorination does not require the use of the macrocyclic crown
ether, Kryptofix2.2.2 (Fig. 639).75 The diaryliodonium strategy has been used for the
Chapter 6 • Synthesis and applications of 18F-labeled compounds
MeO
OH
Toluene, 150 °C, 4 min
OMe
N(Boc) 2
I
O
1. [ 18F]KF/Kryptofix-K2.2.2
O
2. HI, 150 °C, 4 min
OTf
77
251
NH2
18 F
4-[ 18F]fluorophenylalanine
RCC: 40 %
MeO
I
O
O
Me
Me
OMe
NHBoc
I
Me
1. [ 18F]KF (eluted with K2 CO3/MeOH)
OTf
OH
2. MeOH evaporation
3. (CH 3 CN)4 CuOTf, DMF, 85 °C, 20 min
4. 12 M HCl/ 140 °C, 10 min
78
Me
N
O
I
OTs
79
F
N
N
N
Boc 1. n-Bu N[18 F]F, Bu NHCO ,
4
4
3
DMF, 130 °C, 10 min
2. 2 N HCl, MeCN/H2O (3:1)
100 °C, 10 min
NH2
18F
4-[ 18F]fluorophenylalanine
RCY: 53%–66%
(109 GBq/μmol)
NH
O
18 F
80
F
N
N
N
5-HT 2C receptor selective
PET tracer
RCY: 7.8% (89 GBq/μmol)
>99% radiochemical purity
FIGURE 6–39 Radiofluorination of diaryliodonium salts for the synthesis of [18F]fluoroaryl PET tracers. PET, Positron
emission tomography.
synthesis of a pyrimidine derivative 80, which exhibited relatively high specific binding to
5-HT2C receptors in vivo in the rat brain, comparable with that of lorcaserin, a FDAapproved selective 5-HT2C antagonist.76 The abnormal functioning of the latter 5-HT2C
receptors affects signaling mechanisms mediated by various neurotransmitters, including
epinephrine, GABA, glutamate, and dopamine, and results in psychiatric disorders, such as
schizophrenia, depression, and anxiety.
The diaryliodonium strategy was used in the automated synthesis of the [18F]fluorodopamine in high specific yields.77 The diaryliodonium [18F]fluoride salt, formed after anion
exchange of the corresponding triflate salt ([2-[2-[bis[(1,1-dimethylethoxy)carbonyl] amino]
ethyl]-4,5-dimethoxyphenyl](4-methoxyphenyl) iodonium triflate; Fig. 640), with the [18F]
fluoride anion, in the presence of the phase-transfer agent Kryptofix2.2.2, was thermolyzed
at relatively high temperature to afford the radiofluorinated product. The OMe and the Boc
protecting groups were removed after the radiofluorination using aqueous HI. With a slight
modification of the latter synthetic procedure, using O-ethoxymethyl protecting groups, the
radiofluorination proceeds under relatively mild conditions and facilitates the final
252
Organofluorine Chemistry
O
N(Boc)2
I+
O
–
OTf
1. Kryptofix-K2.2.2- 18F
MeCN/Toluene, 150 °C
2. HI (7.6 M), 155 °C
NH3+
HO
HO
18F
O
O
O
O
N(Boc)2
I+
O
–
1. Kryptofix-K2.2.2-18F
OTf
MeCN/Toluene, 120 °C
NH3+
HO
HO
18
F
2. HCl (4 M), 95 °C
O
18
FIGURE 6–40 Synthesis of [ F]fluorodopamine through nucleophilic aromatic substitution of aryliodonium salts.
purification.78 Through this improved procedure, [18F]fluorodopamine was obtained in
.99% radiochemical purity after recrystallization from methyl tert-butyl ether (Fig. 640).
[18F]fluorodopamine PET tracer is transported via the norepinephrine transporter and thus is
useful for the diagnostic imaging of the neuroblastoma. A pediatric neuroblastoma imaging
(PETCT) trial of this PET tracer revealed high quality images within minutes after its
injection.78
6.7.1 Cu(I)-catalyzed radiofluorination of diaryliodonium salts
Cu(I) catalysis of the diaryliodonium salts provides a convenient method for the radiofluorination of the electron-rich aromatics. The diaryliodonium(III) salts (83) could be synthesized
in situ from the corresponding electron-rich aromatics and mesityl iodonium(III) reagent
under ambient conditions, through electrophilic aromatic substitution reaction. In this reaction, TMSOTf transforms the mesityl-iodo hydroxyl moiety in 81 into a better leaving group,
forming the mesityl-iodonium triflate (82). This electrophilic iodonium cation undergoes
FriedelCrafts reaction with the aromatics to give the diaryliodonium salt 83. A Cu(I)-catalyzed radiofluorination of the diaryliodonium salt 83 at 85 C provided the 18F-labeled aromatics in high radiochemical conversions and with high specific activities.30 This synthetic
strategy is thus useful for the late-stage radiofluorination of aromatics, such as toluene, anisole, aniline, pyrrole, and thiophene derivatives, and it could be automated for the synthesis
of pharmaceutically interesting compounds, such as nimesulide (an antiinflammatory agent),
and propofol, an anesthetic compound (Fig. 641). Overall, this radiofluorination is an aryl
CH activation, the reaction proceeding through the FriedelCrafts iodination to give the
diaryliodonium(III) intermediate, which undergoes Cu(I)-catalyzed reductive elimination to
give the radiolabeled aryl fluorides.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
253
FIGURE 6–41 Synthesis of [18F]fluoroarenes using aryliodonium reagents. TMSOTf, Trimethylsilyl triflate.
6.7.2 Radiofluorination via iodonium ylides
The spirocyclic hypervalent iodonium (III) ylides (86) are bench-stable intermediates and
provide an efficient radiofluorination of nonactivated aromatics.79 They can be synthesized
from the aryl iodides in two short steps, involving the mCPBA (or oxone)-mediated oxidative
iodo-acetoxylation (or iodo-trifluoroacetoxylation) of aryl iodides to give 84, followed by
base-catalyzed condensation of 84 with the spirocyclic diester 85 to give the iodonium ylide
86. These spirocyclic iodonium ylides are resistant to decomposition and disproportionation
pathways that are usually accompanied with the conventionally used nonspirocyclic iodonium ylides, such as those based on the Meldrum’s acid. Reaction of the spirocyclic iodonium ylides with no-carrier-added [18F]fluoride ion in the presence of quaternary
ammonium salts, such as tetraethylammonium bicarbonate, proceeds in DMF at 120 C in
254
Organofluorine Chemistry
10 min to give the corresponding 18F-labeled aromatics in high RCYs. The radiofluorination
of these ylides is tolerant to a variety of functional groups in the aryl ring, such as carbonyl,
ether, amine, halogens, and nitro moieties. Aromatics with electron-withdrawing or electrondonating groups, as well as those with sterically crowded substituents, undergo radiofluorination under these conditions (Fig. 642). A possible mechanism of radiofluorination of the
iodonium ylides involves nucleophilic addition of the fluoride anion to the ylide iodine(III),
O
I
mCPBA or Selectfluor
CH3CO 2H
R
O
O
OAc
I
OAc
O
O
I
O (85)
O
Na2CO3, 25 °C
R
84
18
[ 18F]F
O
R
86
~85% yield
F
R
TEAB, DMF, 120 °C, 10 min
O
Mechanistic outline:
O
I
O
O
(88)
18
O
F
O
18
[ 18F]F
I
O
F
I
O
O
O
R
18
O
R
O
R
87
86
Selected examples:
NHCbz
18
F
18
18
F
O
F
CO2Me
O
5-[ 18F]fluorouracil
(anticancer pharmceutical)
RCC: 11%
Specific activity: 398 mCi/mmol
18
RCC: 65%
H 3C O
H
OMe
NHCO2Et
F
H
18
4-[ 18F]fluorophenylalanine
(N,O-protected)
RCC: 55%
FIGURE 6–42 Radiofluorination via spirocyclic iodonium ylides.
F
N
O
NH
N
H
F
RCC: 77%
RCC: 22%
RCC: 44%
18
18
CO2Me
H
F
[18F]fluoroestrone
RCC: 23%
F
Chapter 6 • Synthesis and applications of 18F-labeled compounds
255
followed by reductive elimination of the aryl [18F]fluoride (with expulsion of the resonance
stabilized α-iodoenolate). The spirocyclic iodonium ylides are relatively more stabilized
toward the reductive elimination of the starting materials (due to the conformational
enforcement of the stabilizing interactions between the carbonyls and iodine) as compared
to those of Meldrum’s acid (2,2-dimethyl-1,3-dioxan-4,6-dione)-derived analogous nonspirocyclic iodonium ylides. This enhanced stabilization of the ylides prevents their degradation
through reductive elimination, as is the case with Meldrum’s acid-derived (and related)
iodonium ylides, and therefore relatively higher RCYs of the [18F]fluorinated products were
realized through the use of spirocyclic iodonium ylide reagents. Furthermore, the spirocyclic
iodonium ylides are crystalline salts that could be readily synthesized from the corresponding aryl iodides or (diacetoxyiodo)arenes in a one-step process.
Pharmaceutically significant 18F-labeled PET tracers, such as [18F]fluorouracil and [18F]
fluoroestrone, and [18F]phenylalanine, were synthesized in moderate radiochemical conversions using the latter spirocyclic iodonium ylide strategy (Fig. 642). Vasdev and coworkers
have synthesized 18F-labeled lorlatinib, an anticancer drug to treat NSCLC, that is, in phase
III clinical trials, using this strategy (Fig. 644; vide infra).80
Liang and coworkers have synthesized an 18F-labeled translocator protein 18 kDa
(TSPO)-specific PET ligand, [ 18F]FDPA (93), via the spirocyclic iodonium ylide strategy,
using no-carrier-added [18F]F2, in high yield and with high specific activity.81 They have
demonstrated saturable specific binding of the [ 18F]FDPA to TSPO in the preclinical
models of brain neuroinflammation that are associated with cerebral ischemia and AD
(Fig. 643).
O
O
N N
I
OCOCF3
N N
Oxone
TFA/CHCl3
O
NEt2
O
(91)
I
OCOCF3
O
O
10% Na2CO3, EtOH
RT, 70 min
NEt2
90
89
O
N N
I
O
O
N N
O
[18F]F – (eluted from QMA cartridge)
O
NEt2
92
34% yield for the combined two steps
TBAOMs or TEAClO4 , DMF
120 ºC/15 min
18
F
O
NEt2
93 [18F]FDPA
RCC: ~20–40%
FIGURE 6–43 Synthesis of [18F]FDPA, a PET tracer for brain neuroinflammation in cases of Alzheimer’s disease and
cerebral ischemia. PET, Positron emission tomography; TBAOMs 5 tetrabutylammonium methanesulfonate;
TEAClO4 5 tetraethylammonium perchloroate.
256
Organofluorine Chemistry
6.8 Enzymatic fluorination reactions for [18F]-labeled
positron emission tomography tracers
6.8.1 50 -Fluoro-50 -deoxyadenosine and 5-fluororibose
O’Hagan and coworkers have pioneered the fluorinase-catalyzed synthesis of 50 -fluoro-50 deoxyadenosine (95) and extended this approach for the synthesis of 18F-labeled nucleosides
and their derivatives, such as 50 -fluoro-50 -deoxyinosine, 50 -deoxy-50 -fluororibose, and fluoroacetate.82 Fluorinase enzyme can be obtained in multimilligram scale through overexpression of the protein in the bacterium Streptomyces cattleya. This enzyme-catalyzed
fluorination reaction was earlier shown to proceed through a bimolecular nucleophilic substitution (SN2) mechanism with inversion of configuration at the reacting site.82,83 Singlecrystal X-ray structural studies revealed that the CS bond breakage is in concert with the
CF bond formation in the enzyme active site.83 The fluorinase-catalyzed radiofluorination
is reversible, and under optimal conditions, 18F-labeled 50 -fluoro-50 -deoxyadenosine was
obtained in over 95% RCYs. Coupling of this reaction with adenylic acid deaminase enzyme
helped shift the equilibrium toward the formation of the [18F]-5-fluoro-50 -deoxyinosine (96),
whereas coupling of the fluorination reaction with purine nucleotide phosphorylase (to give
the 18F-labeled D-ribose-1-phosphate), followed by phytase-catalyzed dephosphorylation,
afforded [18F]-5-fluoro-5-deoxyribose (97) in high RCYs (Fig. 644).
NH2
NH2
N
CH3
S
O
–O
NH3 +
N
N
F
O
N
18 F
18 –
N
N
O
+
NH3
Fluorinase
+
CH 3
L-methionine
OH OH
OH
S
–O
O
18 –
F
N
N
95
94
1. Purine nucleotide
phosphorylase
2. Phytase-catalyzed
dephosphorylation
Adenylic acid
deaminase
OH
N
N
18 F
O
OH OH
96
N
N
18 F
O
OH
OH OH
97
FIGURE 6–44 Fluorinase-catalyzed synthesis of 50 -[18F]fluoro-50 -deoxyadenosine (95), 50 -[18F]fluoro-50 -deoxyinosine
(96), and 5-[18F]fluororibose (97).
Chapter 6 • Synthesis and applications of 18F-labeled compounds
257
6.8.2 Fluorinase-catalyzed synthesis of [18F]50 -deoxy-50 -fluoroadenosinebiotin conjugate
Fluorinase enzyme is also effective in the transhalogenation reactions. Fluorinase-catalyzed
transhalogenation of 50 -chloro-50 -deoxyadenosine-PEG-biotin conjugate (99) using [18F]F2
afforded the 18F-labeled biotin conjugate (100) that has potential applications in PET imaging and as a therapeutic due to the strong affinity of the biotin to the avidin/streptavidin
(Fig. 645).84
NH2
O
N
N
N
HN
O
N
Cl
O
O
O
O
NH2
O
H
98
DMF, RT, 24 h
(+)-Biotin
NH2
N
N
Cl
O
N
HN
N
O
O
O
O
O
H
N
NH
H
H
4 S
F
pH 7.8
NH2
O
18 –
99
N
N
Fluorinase,
L-selenomethionine
O
OH OH
PyBOP, DIPEA
H
HO
4 S
OH OH
18F
NH
O
N
N
HN
O
O
O
O
H
N
H
NH
H
4 S
O
OH OH
100
FIGURE 6–45 Synthesis of biotin conjugate of the 50 -[18F]fluoro-50 -deoxydenosine-biotin conjugate.
6.8.3 50 -Fluoro-50 -deoxyadenosine-RGD conjugate in cancer detection
Fluorinase-catalyzed radiofluorination of 50 -chloro-50 -deoxy-2-ethynyladenosine (101; 69%
radiochemical conversion), followed by azidealkyne click reaction of the 18F-labeled 102
with a RGDFK cyclic peptide-derived terminal azide, 103 afforded the 18F-labeled RGDFK
conjugate 104 (Fig. 646). The latter RGD cyclic peptide conjugate was shown to selectively
bind to αvβ3 integrin, which is located primarily in the liver and intestinal walls, kidneys, and
bladder. A PETCT image of this radiotracer was consistent with that of the natural biodistribution of the αvβ3 integrin, showing its potential applications in cancer detection and in
developing effective therapeutics.85
258
Organofluorine Chemistry
NH 2
NH2
N
N
N
Cl
O
N
N
N
Fluorinase/L-selenomethionine
18
[ F]F
N
18
F
N
O
–
N
N
OH OH
OH OH
N
102
101
O
O
N
H
NH 2
NH
O
HO
HN
NH
N
H
NH
HN
O
O
O
103
NH2
N
18
F
N
N
N
N
N
N
O
OH OH
O
O
N
H
O
HO
NH
NH
NH 2
HN
N
H
NH
HN
O
O
O
104
FIGURE 6–46 Fluorinase-catalyzed synthesis of 50 -fluoro-50 -deoxyadenosine and synthesis of its RGDFK conjugate
through Cu(I)-catalyzed azidealkyne cycloaddition.
6.9 Positron emission tomography tracers in Alzheimer’s
disease
There are more than 5 million people living with AD in the United States, and there are
about 50 million AD cases worldwide. It is expected that this number would reach 75 million
by 2030 and to 132 million by 2050 worldwide as the aging population increases. It is estimated that the cost of caring for AD patients is $800 billion per year and would rise to $2 trillion by the year 2030, as the number of the AD cases continue to rise.86 AD is a devastating
neurologic disorder and is characterized by the progressive accumulations of Aβ plaques and
tau-protein aggregates, NFTs, in the brains of the affected individuals. Although the causative
factors for the AD are not clearly established, the extent of the Aβ and NFT accumulations
correlates with the progression of the AD and its associated dementia. The 11C-labeled PiB
along with three other 18F-labeled compounds, florbetaben (Neuraceq), florbetapir (Amyvid),
Chapter 6 • Synthesis and applications of 18F-labeled compounds
259
and flutemetamol (Vizamyl), are approved by the FDA for imaging Aβ plaques in the brains
(Fig. 61).87,88 These PET tracers show high specificity for binding to the Aβ plaques (see
Fig. 63 for the florbetapir PET imaging).
Among the PET tracers for selective binding to NFTs, flortaucipir-18F (T807; AV-1451; LY
3191748; Fig. 640) has emerged as the leading candidate, after its phase III clinical trials
(vide infra). Some of the quinoline-derived 18F-PET tracers, such as THK series (vide infra)
and related isoquinoline-based 18F-PET imaging agent, 18F-MK6240, are currently at various
stages of clinical trials for their selective NFT-binding.89
Eli Lilly’s flortaucipir- 18F (T807; AV-1451; LY 3191748), a selective NFT imaging
agent, is a welcome addition for the precise diagnosis of the AD, although it is not yet
approved by the FDA. Correlation between the obstructive sleep apnea syndrome and
the extent of aggregation of the Aβ and NFTs was demonstrated through the combined
use of [ 18F]Florbetaben and [18F]flortaucipir PET brain imaging.90 These PET imaging
studies showed that the obstructive sleep apnea is correlated with AD pathology ant
that this correlation is moderated by apolipoprotein E ε4 allele (APOE ε4) and body
mass index.
6.9.1 [18F]Flortaucipir (a neurofibrillary tangle biomarker)
Flortaucipir-18F (T807; AV-1451; LY 3191748; Fig. 647) shows substantial selectivity in
its binding to NFTs (tau-protein aggregates) over Aβ peptide aggregates, and the PET
brain scans are diagnostic of AD and to some extent at the prodromal stage of the AD,
also called mild cognitive impairment (MCI). Through clinical trials consisting of 710
participants, it was demonstrated that [18F]flortaucipir PET was able to discriminate AD
from other neurodegenerative diseases, such as behavioral variant frontotemporal
dementia, nonfluent variant primary progressive aphasia, semantic variant primary progressive aphasia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, Parkinson disease with or without cognitive impairment, and vascular
dementia.91 In September 2018 Eli Lilly has successfully completed the Phase III clinical
trials on the effectiveness of the Flortaucipir-18F (T807; AV-1451; LY-3191748) for PET
imaging of the brain tau-NFTs, and pending FDA approval, this PET imaging agent would
be a clinically useful biomarker for the tau-neuropathy, such as AD.92 [18F]flortaucipir
PET is also diagnostic of the chronic traumatic encephalopathy (also called traumatic
brain injury), as shown in a recent PET scan of a former football player with concussion
symptoms.93
Although flortaucipir ([18F]AV-1451) is among the most widely used PET tracers for imaging NFTs, there is substantial evidence that flortaucipir has also off-target binding, that is, it
also binds to regions other than NFTs, including monoamine oxidase A and B, pigmented
cells in the central nervous system, and elevated iron levels.94 This off-target binding of flortaucipir, as demonstrated by the PET imaging of a normal control, is localized mostly to
basal ganglia, choroid plexus (CP), and substantia nigra (SN). Similar PET imaging of AD
260
Organofluorine Chemistry
(A)
(B)
FIGURE 6–47 Two slices of representative clinical [18F]AV-1451 PET scans of a 69-year-old normal control (A) and
71-year-old tau-positive AD patient (B). Both sets of images clearly show off-target binding in the BG, CP, and SN.
The AD patient also has significant tau burden in the EC, TL, and OC. PET images are mean SUVR images
75105 min postinjection; MRI images are MP RAGE (T1 weighted) images. AD, Alzheimer’s disease; BG, basal
ganglia; CP, choroid plexus; EC, entorhinal cortex; MRI, magnetic resonance imaging; OC, occipital cortex; PET,
positron emission tomography; SUVR, standardized uptake value ratio; SN, substantia nigra; TL, lateral temporal
lobe. Adapted from Drake, L.R.; Pham, J.M.; Desmond, T.J.; Mossine, A.V.; Lee, S.J.; Kilbourn, M.R.; Koeppe, R.A.;
Brooks, A.F.; Scott, P.J.H. Identification of AV-1451 as a Weak, Nonselective Inhibitor of Monoamine Oxidase. ACS
Chem. Neurosci. 2019, 10, 38393846, Copyright 2019, American Chemical Society.
patient shows that flortaucipir has significant tau burden in the entorhinal cortex, lateral
temporal lobe (TL), and occipital cortex, in addition to the off-target binding to the SN and
CP (Fig. 647).94
Chapter 6 • Synthesis and applications of 18F-labeled compounds
261
6.9.1.1 Synthesis of [18F]flortaucipir
Pd(0)-catalyzed Stille cross coupling of N-t-Boc protected 7-bromo-5H-pyrido[4,3-b]indole
with 2-nitro-5-(trimethylstannyl)pyridine, followed by SNAr [18F]fluorination of the resulting
T807P precursor compound (7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole) with K[18F]F/
Kryptofix2.2.2 in dimethylsulfoxide (DMSO) gave the [18F]Flortaucipir in 5%10% decay
corrected RCY (Fig. 648). This radiofluorination is fully automated.95 The SNAr radiofluorination was also accomplished using similar substrates with other leaving groups, such as trimethylammonium moiety (instead of NO2).96
[ 18F]flortaucipir; T807
5%–10%
FIGURE 6–48 Synthesis of [ F]flortaucipir through end-stage SNAr radiofluorination. Boc, tert-Butyloxycarbonyl;
DCM, dichloromethane; DMAP 5 4-(N,N-dimethylamino)pyridine; HPLCSPE 5 high performance liquid
chromatography, combined with solid phase extraction.
18
6.9.2 2-(4-Aminoaryl)quinoline-based 18F-labeled positron emission
tomography tracers (THK series)
Okamura and coworkers have synthesized tau-protein aggregate (NFT) specific 18F-labeled
2-(4-aminoaryl)quinoline-based compounds [18F]-THK-5105, [18F]-THK-5117, [18F]-THK5116, and [18F]-THK-523.97 In vitro binding studies of these compounds through autoradiographic analyses of AD brain sections demonstrated the selective binding to the NFTs. Of
these compounds, [18F]-THK-5105 and [18F]-THK-5117 are promising PET tracer candidates
for tau imaging, as they do not have significant binding to other neuroreceptors, ion channels, and transporters at 1-μM concentration. The THK-series of compounds were synthesized from their corresponding tosylates using 18F-labeled KF in the presence of the
Kryptofix2.2.2, and this procedure is amenable to the automated radiosynthesis. The
optically pure (S)-[18F]-THK-5351 was also synthesized using this protocol in 46% 6 13% RCY
(radiochemical purity: 99%; specific activity: 254 6 47 GBq/mmol) (Fig. 649).98
Clinical studies of the latter optically pure compound on AD patients, along with
Pittsburg B compound (11C-PiB), showed promising results in the diagnosis of the disease
progression and had higher retention in the TL, clearly distinguishing the AD patients from
262
Organofluorine Chemistry
OH
18
OH
O
F
18
F
O
N
N
CH3
N
CH3
[18 F]-THK-5105
H
N
CH3
[18 F]-THK-5117
OH
18
F
O
18 F
O
N
[18 F]-THK-5116
N
H
N
H
N
H
[18 F]-THK-523
18
F
OH
18
F
(S)
H 2N
O
N
N
N
18
[ F]-THK-5351
H
N
N
CH3
N
[18F]-MK-6240 (Merck Laboratories)
Synthesis of THK series of PET tracers:
OH
OTHP
TsO
H
18
F
18
O
1. K F
N
N
R
R
O
K2 CO3 , Kryptofix-2.2.2
DMSO, 110 °C, 10 min
2. 2M HCl, 3 min (deprotection of THP)
N
N
R
R
[18F]-THK-5116 (R = H)
[18F]-THK-5105 (R = Me)
TsO
O
18
F
1. K18F
N
N
H
H
K2 CO3 , Kryptofix-2.2.2
O
N
DMSO, 110 °C, 10 min
[18F]-THK-523
N
H
H
18
FIGURE 6–49 Structures of the quinoline- and isoquinoline-based F-labeled PET tracers and the synthesis of the
THF series of compounds. PET, Positron emission tomography; THF, tetrahydrofuran.
the healthy controls. The [18F]-THK-5351 also showed higher contrast and lower subcortical
white matter retention that that for the [18F]-THK-5117 and is comparable to that of the
11
C-PiB.98 In a relatively larger clinical trial the compound [18F]-THK-5351 showed relatively
higher retention in the frontal, lateral temporal, superior parietal, inferior parietal, anterior
Chapter 6 • Synthesis and applications of 18F-labeled compounds
263
cingulate, hippocampus, and other regions in the brain, as compared to that of the control
age-matched subjects.99 Furthermore, these PET studies showed that the retention of the
[18F]-THK-5351 is negatively correlated with the cerebral glucose metabolism (i.e., the lower
the cerebral glucose metabolism, the higher is the NFT aggregation), as monitored by [18F]
FDG uptake, in AD and MCI cases.
The preclinical studies demonstrated improved pharmacokinetic profiles for the
S-enantiomer over the R-enantiomer for the [18F]-THK-5351 and related THK-series of compounds. [18F]-THK-5351 showed high selective binding to NFT, with low binding affinity for
white matter and rapid pharmacokinetics, and the signal-to-background ratios of [18F]-THK5351were higher than those for the [18F]-THK-105 and [18F]-THK-5117. Autoradiography on
human brain sections revealed that [18F]-THK-5351 binds with high specificity to NFTs, without any significant binding to Aβ, α-synuclein, and TDP43 (transactive response DNAbinding protein 43) deposits.98
6.9.3 Tropomyosin receptor kinase targeted 18F-positron emission
tomography
Tropomyosin receptor kinase A/B/C (TrkA/B/C) family of proteins is encoded by NTRK
genes and is responsible for the human neuronal growth, survival, and differentiation. The
downregulation of these kinases is responsible for neurological disorders, including AD, and
cancers. Larotrectinib, a TrkA/B/C inhibitor, was approved by FDA in 2018 for the treatment
of NTRK gene fusion-specific metastatic solid tumors. Bailey and coworkers have developed
a pan-Trk selective 18F-PET tracer, [18F]TRACK for in vivo Trk PET imaging. The latter compound is in clinical development (Fig. 650).100
F
N N
O
OH
N
N
HN
F
N
O
F
Larotrectinib
(TrkA, TrkB, and TrkC
inhibitor)
N
N
H
N
N
N
18
F
[18F]TRACK
Trk-targeted [18 F]-PET radiotracer
FIGURE 6–50 Structures of an anticancer drug Larotrectinib, a pan-Trk inhibitor, and [18F]TRACK, a PET tracer for
imaging human brains. PET, Positron emission tomography.
[18F]TRACK, currently in preclinical studies, is permeable to the bloodbrain barrier and
exhibits relatively faster and reversible kinetics as compared to the 11C-labeeled tradiotracer
[11C-IPMICF16] (Fig. 651).100
264
Organofluorine Chemistry
FIGURE 6–51 In vivo PET imaging of [18F]TRACK (A) and [11C]-(R)-IPMICF16 (B) in the human brain. Top row: T1MPRAGE MR images of the subject. Bottom rows: overlays of the 010, 1030, 3060, and 6090 min postinjection
(p.i.) summed SUV PET images with the MR images. Scans with both radioligands were performed in the same
healthy human subject. PET, Positron emission tomography; SUV, standardized uptake value. Adapted from Bailey,
J.J.; Kaiser, L.; Lindner, S.; Wust, M.; Thiel, A.; Soucy, J.-P.; Rosa-Neto, P.; Scott, P.J.H.; Unterrainer, M.; Kaplan, D.R.;
et al. First-in-Human Brain Imaging of [18F]TRACK, a PET Tracer for Tropomyosin Receptor Kinases. ACS Chem.
Neurosci. 2019, 10, 26972702, Copyright 2019, American Chemical Society.
6.10
18
F-positron emission tomography tracers in cancer
diagnosis
6.10.1 [18F]-(R)-lorlatinib
Vasdev and coworkers have synthesized the 18F-labeled orphan receptor tyrosine kinase
(c-ros oncogene 1 (ROS1)) inhibitor lorlatinib through their iodonium ylide strategy
(Fig. 652).80 Reaction of compound 105 (synthesized in a multistep pathway) with
Selectfluor and trimethylsilyl acetate (TMSOAc) afforded the diacetoxyiodo aryl compound
106, which was transformed into the corresponding spirocyclic iodonium ylide 108, in 36%
overall yield for the two steps. Radiofluorination of 108 was achieved using 18F-labeled
Chapter 6 • Synthesis and applications of 18F-labeled compounds
H 3C
O
N
N N
CH3
N
I
H 3C
O
N
AcO
O
Boc
I
OAc H3 C
Boc
N N
CH3
O
N Boc
H 3C
O
N
N
I
O
N
O
( 107 )
O
O
Na2 CO3
36% for two steps
106
H 3C
O
N
O
O
O
N Boc
105
O
CH3
N
Selectfluor/(Me) 3SiOAc
N
H3 C
N N
265
Boc
N
80 °C; 10 min
O
N Boc
18 F
2. HPLC purification
N
H3 C
O
Boc
108
2 mg in 400 μL of anhydrous DMF
N Boc
109
H 3C
O
N
1. 4M HCl, 90 °C, 10 min
(Boc deprotection)
N N
CH3
N
2. Neutralization to pH 5
18
(14% RCY for two steps)
CH3
1. [18F]-Et 4 NF
N
H3 C
N N
F
N
H3 C
O
110
H
N H
FIGURE 6–52 Synthesis of [18F]-(R)-lorlatinib through iodonium ylide route.
tetraethylammonium fluoride in anhydrous DMF to give the 18F-labeled (R)-larlatinib (110),
after deprotection of the Boc group, in 14% uncorrected RCY and with high radiochemical
purity. The PET imaging of the C-11-labeled lorlatinib showed its high bloodbrain permeability. Lorlatinib is the next-generation small-molecule inhibitor of the ROS1 that is undergoing phase III clinical trials for NSCLC.101 The PET assays using 11C and 18F-labeled
lorlatinib would help in establishing its biodistribution and whole-body dosimetry assessments in the clinical oncology.
6.10.2 Cyclic RGDYK (arginine-glycine-aspartic acid-tyrosine-lysine)
dimer-derived positron emission tomography tracers
6.10.2.1 FPPRGD2 (dimeric cyclic RGDYK peptide)
The integrin family of proteins, comprising 24 transmembrane receptors, helps in the integration of the cell adhesion and intracellular signaling, transmitting signals across the cell
266
Organofluorine Chemistry
membranes upon ligand binding to the receptors. The integrin protein αvβ3, among other
integrin proteins, serves as a receptor for the extracellular matrix proteins containing arginineglycineaspartic acid (RGD) sequence, and the αvb3 levels correlate with tumor metastasis and progression. The integrin αvβ3 is highly expressed in the epithelial cells of solid
tumors, whereas it is expressed in low levels in the normal cells. Radiotracers consisting of
RGD sequence-containing peptides uniquely are suited for probing the extent of tumor
metastasis and for the development of antiangiogenic drugs for tumor suppression.102104
Angiogenesis is involved in the tumor growth and progression, and the expression of αvβ3
integrin and its interaction with matrix ligands play a crucial role in the tumor angiogenesis
and metastasis. Thus, there is an emerging interest in the development of clinically useful
RGD-PET tracers for targeting αvβ3 integrin proteins.
A variety of 18F-labeled peptides incorporating RGD sequence have been synthesized and
explored for their efficacy in PET-imaging and also as potential therapeutics for cancers.27
18
F-labeled FPRGD2 (2-fluoropropanoyl-labeled PEGylated dimeric cyclic RGDYK peptide)
has been one such PET tracer that is approved by the FDA as an exploratory investigative
new drug. This PET tracer is currently in clinical trials for predicting therapeutic efficiency of
antiangiogenesis therapy in cancer patients.105,106
Synthesis of 18F-labeled FPRGD2 was achieved in a multistep synthetic strategy involving
the radiofluorination as the early step through an automated radiosynthesis.107 Nucleophilic
substitution of methyl 2-bromopropanoate using [18F]KF complexed to the phase-transfer
agent 2,2,2-Kryptofix-(2.2.2), followed by alkaline hydrolysis gave potassium 2-[18]F-fluoropropanoate (112). Reaction of the latter 18F-labeled compound, 112, with di(4-nitrophenyl)
carbonate (113), in acetonitrile at 110 oC, afforded the 4-nitrophenyl 2-[18]F-fluoropropanoate (114), which upon conjugation with the terminal amino group of the PEG-tethered
dimeric version of the cyclic peptide—arginineglycineaspartic acid-tyrosine-lysine
((RGDYK)2PEG-NH2)—gave the 18F-labeled dimeric cyclic peptide FPPRGD2 (FPP
(RGD)2).107 Under optimized conditions, this multistep process gave the PET-tracer in RCYs
of 16.9% 6 2.7% with a specific radioactivity of 114 6 72 GBq/μmol (3.08 6 1.95 Ci/μmol)
(Fig. 653). Clinical grade samples were obtained after a final HPLC purification. The
FPPRGD2 PET tracer was shown to be superior to [18F]FDG or brain MRI for imaging glioblastoma multiforme (GBM).104
6.10.2.2 [18F]FAl-NOTA-PRGD2 (18F-alfatide) and [ 68Ga]-NOTA-PRGD2
Although the FDA-approved [18F]FPPRGD2 has favorable pharmacokinetic properties for its
use as PET imaging agent to selectively bind to the αvβ3 integrin receptors, its synthesis
involves several steps, with the [18F]fluoride incorporation being at the early stage of synthesis, and thus affords relatively low RCYs. One approach of synthesizing [18F]FPPRGD2 derivatives with high RCYs is based on the late-stage incorporation of the [18F]fluoride. It involves
synthesis of the macrocyclic polyaminocarboxylates, such as NOTA (1,4,7-triazacyclononane1,4,7-triacetic acid) conjugates of the PPRGD2, followed by the complexation of the NOTA by
[18F]AlF, using AlCl3 and no-carrier-added [18F]F2. This alternative approach involving latestate incorporation of the [18F]fluoride affords improved access to the 18F-labeled PET
Chapter 6 • Synthesis and applications of 18F-labeled compounds
267
FIGURE 6–53 Synthesis the 18F-PET tracer FPPRGD2. PET, Positron emission tomography.
tracers. The aluminum fluoride complex [18F]FAl-NOTA-PRGD2 (18F-alfatide) is an analog of
the [18F]FPPRDG2, in which the 18F label was introduced at the end-stage of the synthesis
through the complexation of the [18F]fluoride anion with the in situ generated Al(III) complex of the NOTA-PRGD2.108 The side chain NOTA was conjugated with the same PEGylated
dimeric RGD peptide that was used in the synthesis of the original parent PET tracer [18F]
FPPRGD2 so as to retain the pharmacokinetic properties (Fig. 654).109 A pilot clinical study
268
Organofluorine Chemistry
O
O
O
OH
OH
N
H
NH
O
HN
H
N
NH
O
N
H
NH
O
O
O
HN
RGD
NH2OH
HN
O
18
NH
O
O
F
S
O
HN
N Al N
O
N O
O
HN
O
O
O
OH
18
F-Al-NOTA
NH HN
OH
O
O
NH
O
O
HN
H
N
HN NH2
NH
O
( F-Alfatide; Alfatide I)
O OH O
O
OH
N
H
NH
FAl-NOTA-PRGD2
18
O
HN
NH
H
N
O
O
O
HN
O
O
NHO
O
O
HN
NH2
OH
HN
RGD
H
N
O
O
O
O
O
NH
O
O
NH HN
OH
O
NH
O
O
O
N
H N
O
18
Al N
F
NO
O
O
18
F-Al-NOTA
O
HN
H
N
H
N
O
HN NH2
NH
O
FAl-NOTA-E[PEG4-c(RGDFK)]2PRGD2
[18 F]Alfatide II)
O
OH
O
O OH
N
H
NH
O
HN
O
N
H
NH HN
O
H
N
O
O
O
O
HN NH
2
OH
HN
RGD
HN
O
O
N
H
O
S
O
HN
O
N 68
Ga
O
N
O
O
O
OH
O
NH
O
18
F-Al-NOTA
NH HN
HN
H
N
O
O
O
HN NH2
NH
[ 68 Ga]-NOTA-PRGD2
FIGURE 6–54 Structures of the PRGD2-based 18F- and 68Ga-PET tracers FAl-NOTA-PRGD2 (18F-alfatide), [18F]alfatide
II, and [68Ga]NOTA-PRGD2; the [18F]fluoride and [68Ga] were introduced at the end-stage of the synthesis. PET,
Positron emission tomography.
Chapter 6 • Synthesis and applications of 18F-labeled compounds
269
of the 18F-alfatide in 13 patients with NSCLC demonstrated its high sensitivity, specificity,
and accuracy for imaging the lymph node metastases.110
Due to the neighboring group participation of the thiourea moiety, alfatide is relatively
unstable to hydrolytic degradation. In order to overcome this hydrolytic instability, a secondgeneration alfatide, called [18F]alfatide II (FAl-NOTA-E[PEG4-c(RGDFK)]2PRGD2), was developed.111 This PET tracer is well tolerated in healthy volunteers and was useful in the accurate
diagnosis of brain metastatic lesions in the clinical trials. In contrast, methods using
[18F]-FDG PET or CT were successful in about half the cases.111
A gallium analog of the alfatide I, [68Ga]-NOTA-PRGD2 (Fig. 654), in which Ga-68 was
incorporated at the end-stage of the synthesis, as in the case of the alfatide, was investigated
as a PET tracer in preclinical trials.105 The pharmacokinetic and imaging properties of the
[18F]FPPRDG2, [18F]FAl-NOTA-PRGD2 ([18F]alfatide I), and [68Ga]-NOTA-PRGD2 in the
U87MG glioblastoma xenograft models showed high tumor uptake with high target-tobackground ratios, for all three radiotracers. The latter readily synthesizable 18F-aluminumNOTA and 68Ga-NOTA PET tracers are promising PET tracers for monitoring angiogenesis
in tumor cells through their selective binding to the αvβ3 integrin receptors. Cell-binding
assays of these RGD-derived PET tracers in U87MG tumor cells revealed relatively improved
half-maximal inhibitory concentrations (IC50) for the NOTA-derived PET tracers. The IC50
values for binding to these cells were determined as 175.4, 119.2, and 82.7 nM, respectively,
for FPPRGD2, Al-NOTA-PRGD2, and Ga-NOTA-PRGD2, showing the improved efficacy for
the AlF-NOTA-ORGD2 and 68Ga-NOTA-PRGD2 over the parent FPPRGD2.105 However, the
final 18F labeling of the NOTA macrocyclic ligand proceeds at relatively high temperatures
(100 C120 C for 10 min), and thus the applications of these tracers are limited to thermally stable peptides.
6.10.2.3 NOTA-conjugated linear peptides 18F-AlF-NOTA-IF7 and 18F-Al-NOTAMATBBN
An 18F-complexed NOTA-derived polypeptide, 18F-AlF-NOTA-IF7 (Fig. 655; IF7 is a heptapeptide, IFLLWQR) was synthesized in two steps, involving peptide conjugation to the
NOTA ligand, followed by complexation with AlCl3 in the presence of the [18F]F2 source.
This 18F-PET imaging agent was found to target Anxal, a highly specific surface marker in
tumor vasculature, with good tumor uptake, and is a promising PET tracer for imaging of
cancers.112
A structurally similar linear peptide conjugated to the NOTA macrocyclic ligand, 18F-AlNOTA-MATBBN [(Fig. 655); MATBBN is a bombesin analog polypeptide], was found to
selectively bind to the gastrin-releasing peptide receptor in prostate cancer, and its tumor
uptake was relatively higher than that of 18F-FDG.113
6.10.2.4 Folate-NOTA-Al18F
An 18F-labeled PET tracer for folate receptor (FR)-expressing cancers, folate-NOTA-[18F]AlF
(Fig. 656), was synthesized by conjugating folate moiety to the macrocyclic ligand NOTA
and then heating the derived NOTA-folate in the presence of 18F2 and AlCl3 at 100 C for
270
Organofluorine Chemistry
O
O
N
O
N Al N
HO
HN
NH
O
S
NH H
N
O
18
18
NH 2
NH
O
N
H
O
F
O
H
N
N
H
O
NH
O
H
N
OH
N
H
O
F-Al-NOTA
O
O
NH2
Ile-Phe-Leu-Leu-Trp-Gln-Arg
18
O 18
F
NH O
H2N
O
H
N
O
18
NH
HN
Al N
NO
F-AlF-NOTA-IF7
O
H
N
H
N
N
H
S
O
N
H
O
O
O
O
H
N
N
H
OH O
O
NH2
H O
N
N
H
NH 2
O
H
N
O
O
F-Al-NOTA
H
N
N
H
N
O
O
N
H
O
O
N
H O
N
H
N
CH 3
NH
NH
18
H
N
F-Al-NOTA-MATBBN
FIGURE 6–55 Structures of 18F-AlF-NOTA-IF7 and 18F-AlNOTA-MATBBN PET tracers.
O
O
N
HN
H2 N
N
CO2 H
N
H
N
H
H
N
O
O
O
N
H
O
18
F
N
N
O
O
Al N
N O
Folate
FAl-NOTA
Folate-NOTA-Al18 F
O
FIGURE 6–56 Structure of folate- for FPPRGD2, Al-NOTA-PRGD2, and Ga-NOTA-PRGD2-Al18F.
15 min.114 The radiochemical synthesis and purification was achieved in a total time of
37 min to afford specific activity of 68.82 6 18.5 GBq/μmol, with a radiochemical purity of
98.3%. In vivo studies in tumor xenograft models showed that this PET tracer was comparable with the clinically established 99mTc-EC20 radiotracer. The folate-NOTA 18F-tracer was
shown to selectively bind to the FR β in the atherosclerotic plaques in the tissue samples of
mice, rabbits, and humans with ischemic symptoms and may thus be developed into clinically useful PET tracer for monitoring the atherosclerotic inflammation.3
Chapter 6 • Synthesis and applications of 18F-labeled compounds
6.10.2.5
271
18
F-fluciclovine (Axumin)
18
F-fluciclovine (Axumin), anti-1-amino-3-[18F]fluorocyclobutane-1-crboxylic acid (FACBC),
is used as an FDA-approved PET tracer for imaging suspected prostate cancer in patients
with elevated prostate-specific antigen (PSA).115 Although the 11C- or 18F-labeled choline
provides an accurate estimate of the prostate cancer relapse, choline detects only half of the
prostate cancer lesions due to the limited amount of choline uptake by the prostate cancer
lesions. On the other hand, 18F-fluciclovine is transported by two different amino acid transporters and the biodistribution of this amino acid is more favorable than that of choline.116
6.10.2.5.1 Synthesis of 18F-fluciclovine
The radiosynthesis of 18F-fluciclovine has been achieved using an automated radiosynthesis
apparatus (Fig. 657).117 In this synthetic automated procedure, the triflate 115 was allowed
to react with 18F-KF, complexed to cryptand, Kryptofix2.2.2, in acetonitrile at 85 C for
3 min to give the 18F-labeled 116. Hydrolysis of the ester moiety in 117 using aqueous NaOH
(5 min at room temperature) and deprotection of the t-Boc using aqueous HCl (5 min at
60 C) gave the 18F-fluciclovine in an overall decay-corrected RCY of 62.5% 6 1.93%.
FIGURE 6–57 Automated radiosynthesis of 18F-fluciclovine PET tracer. PET, Positron emission tomography.
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Neurofibrillary Pathology in Alzheimer Disease. J. Nucl. Med. 2016, 57, 208214.
99. Kang, J. M.; Lee, S.-Y.; Seo, S.; Jeong, H. J.; Woo, S.-H.; Lee, H.; Lee, Y.-B.; Yeon, B. K.; Shin, D. H.; Park,
K. H.; Kang, H.; Okamura, N.; Furumoto, S.; Yanai, K.; Villemagne, V. L.; Seong, J.-K.; Na, D. L.; Ido, T.;
Cho, J.; Lee, K.-M.; Noh, Y. Tau Positron Emission Tomography Using [18F]THK5351 and Cerebral
Glucose Hypometabolism in Alzheimer’s Disease. Neurobiol. Aging 2017, 59, 210219.
100. Bailey, J. J.; Kaiser, L.; Lindner, S.; Wust, M.; Thiel, A.; Soucy, J.-P.; Rosa-Neto, P.; Scott, P. J. H.;
Unterrainer, M.; Kaplan, D. R.; Wangler, C.; Wangler, B.; Bartenstein, P.; Bernard-Gauthier, V.;
Schirrmacher, R. First-in-Human Brain Imaging of [18F]TRACK, a PET Tracer for Tropomyosin
Receptor Kinases. ACS Chem. Neurosci. 2019, 10, 26972702.
101. Collier, T. L.; Normandin, M. D.; Liang, S. H.; Vasdev, N.; Collier, T. L.; Maresca, K. P.; McCarthy, T. J.;
Waterhouse, R. N.; Richardson, P.; Waterhouse, R. N. Brain Penetration of the ROS1/ALK Inhibitor
Lorlatinib Confirmed by PET. Mol Imaging 2017, 16 1536012117736669.
102. Shi, J.; Wang, F.; Liu, S. Radiolabeled Cyclic RGD Peptides as Radiotracers for Tumor Imaging. Biophys.
Rep. 2016, 2, 120.
103. Mittra, E. S.; Goris, M. L.; Iagaru, A. H.; Kardan, A.; Burton, L.; Berganos, R.; Chang, E.; Liu, S.; Shen, B.;
Chin, F. T.; Chen, X.; Gambhir, S. S. Pilot Pharmacokinetic and Dosimetric Studies of 18F-FPPRGD2: A
PET Radiopharmaceutical Agent for Imaging αvβ3 Integrin Levels. Radiology 2011, 260, 182191.
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104. Debordeaux, F.; Chansel-Debordeaux, L.; Pinaquy, J.-B.; Fernandez, P.; Schulz, J. What About αvβ3
Integrins in Molecular Imaging in Oncology? Nucl. Med. Biol. 2018, 6263, 3146.
105. Lang, L.; Li, W.; Guo, N.; Ma, Y.; Zhu, L.; Kiesewetter, D. O.; Shen, B.; Niu, G.; Chen, X. Comparison
Study of [18F]FAl-NOTA-PRGD2, [18F]FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET Imaging of
U87MG Tumors in Mice. Bioconjug. Chem. 2011, 22, 24152422.
106. ClinicalTrials.gov; Web content current as of 10/29/2019; ,https://clinicaltrials.gov/ct2/show/
NCT01806675..
107. Chin, F. T.; Shen, B.; Liu, S.; Berganos, R. A.; Chang, E.; Mittra, E.; Chen, X.; Gambhir, S. S. First
Experience with Clinical-Grade ([18F]FPP(RGD2)): An Automated Multi-Step Radiosynthesis for Clinical
PET Studies. Mol Imaging Biol 2012, 14, 8895.
108. Liu, S.; Liu, H.; Jiang, H.; Xu, Y.; Zhang, H.; Cheng, Z. One-Step Radiosynthesis of 18F-AlF-NOTA-RGD2
for Tumor Angiogenesis PET Imaging. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 17321741.
109. Wan, W.; Guo, N.; Pan, D.; Yu, C.; Weng, Y.; Luo, S.; Ding, H.; Xu, Y.; Wang, L.; Lang, L.; Xie, Q.; Yang,
M.; Chen, X. First Experience of 18F-Alfatide in Lung Cancer Patients Using a New Lyophilized Kit for
Rapid Radiofluorination. J. Nucl. Med. 2013, 54, 691698.
110. Zhou, Y.; Gao, S.; Huang, Y.; Zheng, J.; Dong, Y.; Zhang, B.; Zhao, S.; Lu, H.; Liu, Z.; Yu, J.; Yuan, S. A
Pilot Study of 18F-Alfatide PET/CT Imaging for Detecting Lymph Node Metastases in Patients with NonSmall Cell Lung Cancer. Sci. Rep. 2017, 7, 17.
111. Yu, C.; Pan, D.; Mi, B.; Xu, Y.; Lang, L.; Niu, G.; Yang, M.; Wan, W.; Chen, X. 18 F-Alfatide II PET/CT in
Healthy Human Volunteers and Patients with Brain Metastases. Eur. J. Nucl. Med. Mol. Imaging 2015,
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112. Gu, X.; Jiang, M.; Pan, D.; Cai, G.; Zhang, R.; Zhou, Y.; Ding, Y.; Zhu, B.; Lin, X. Preliminary Evaluation
of Novel 18F-AlF-NOTA-IF7 as a Tumor Imaging Agent. J. Radioanal. Nucl. Chem. 2016, 308, 851856.
113. Pan, D.; Yan, Y.; Yang, R.; Xu, Y. P.; Chen, F.; Wang, L.; Luo, S.; Yang, M. PET Imaging of Prostate
Tumors with 18F-Al-NOTA-MATBBN. Contrast Media Mol. Imaging 2014, 9, 342348.
114. Chen, Q.; Meng, X.; McQuade, P.; Rubins, D.; Lin, S.-A.; Zeng, Z.; Haley, H.; Miller, P.; Gonzalez Trotter,
D.; Low, P. S. Synthesis and Preclinical Evaluation of Folate-NOTA-Al18F for PET Imaging of FolateReceptor-Positive Tumors. Mol. Pharm. 2016, 13, 15201527.
115. Parent, E. E.; Schuster, D. M. Update on 18F-Fluciclovine PET for Prostate Cancer Imaging. J. Nucl. Med.
2018, 59, 733739.
116. Schiavina, R.; Brunocilla, E.; Martorana, G. The New Promise of FACBC Position Emission
Tomography/Computed Tomography in the Localization of Disease Relapse After Radical Treatment for
Prostate Cancer: Are We Turning to the Right Radiotracer? Eur. Urol. 2014, 65, 255256.
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an Automated Radiofluorination Apparatus; GE Healthcare Limited, 2014.
7
Materials applications of
organofluorine compounds
Chapter Outline
7.1 Introduction ............................................................................................................................... 280
7.2 Fluorinated surfactants............................................................................................................. 280
7.2.1 Perfluorocarbon nanomaterials ..................................................................................... 282
7.2.2 Fluorous catalysis ............................................................................................................. 285
7.2.3 Environmentally benign perfluorosurfactants.............................................................. 285
7.3 Fluoropolymers.......................................................................................................................... 286
7.3.1 Poly(tetrafluoroethylene) ............................................................................................... 287
7.3.2 Poly(vinylidene fluoride) ................................................................................................. 287
7.4 Fluorinated π-conjugated polymeric materials in photovoltaic devices ............................. 289
7.4.1 ππ Stacking interactions in polyfluoroaromatics ....................................................... 289
7.4.2 π-Conjugated polymers................................................................................................... 289
7.4.3 Synthesis of the fluorinated donoracceptor polymers for fullerenepolymer
solar cells .......................................................................................................................... 293
7.4.4 π-Conjugated benzodithiophenequinoxaline copolymers ....................................... 296
7.4.5 Fluorinated polymers in fullerene-free, all-polymer (organic) solar cells .................. 296
7.5 Fluorinated poly(aryl thioethers) in organic electronic materials ........................................ 298
7.6 Polymer electrolytes.................................................................................................................. 300
7.7 Fluorinated ionomers as proton-exchange membranes in fuel cells ................................... 304
7.8 Fluorinated carbon nanoparticles and nonaqueous electrolytes in lithium- and
lithium-ion batteries ................................................................................................................. 307
7.9 Fluorinated hyperbranched dendrimers: synthesis and applications .................................. 308
7.10 Fluorinated compounds in drug delivery and magnetic resonance imaging ..................... 310
7.10.1 Fluorinated curcumin analogs as 19F MRI agents ....................................................... 310
7.10.2 Polyfluorinated dendrimer amphiphiles as 19F MRI probes and drug delivery agents .... 311
7.11 Organofluorine liquid crystal materials .................................................................................. 313
7.11.1 Fluorinated dendrimer-based liquid crystals............................................................... 313
7.12 Organofluorine compounds in high-energy materials.......................................................... 313
7.12.1 N,N-Difluoramine (NF2) compounds ............................................................................ 314
7.12.2 Pentafluorosulfanyl (SF5) compounds.......................................................................... 318
References........................................................................................................................................... 321
Organofluorine Chemistry. DOI: https://doi.org/10.1016/B978-0-12-813286-9.00007-9
© 2020 Elsevier Inc. All rights reserved.
279
280
Organofluorine Chemistry
7.1 Introduction
Organofluorine compounds are ubiquitously found in a wide variety of materials, including
biomaterials, smart materials, liquid crystal displays (LCDs), solar cells, electrode and electrolyte materials in lithium-ion batteries, fuel cell membranes, and as components in numerous consumer goods. Organofluorine compounds play a key role in almost all of the modern
LCDs (vide infra). The relatively strong CF bond strength, low polarizability of the CF
bonds, and extremely low reactivity of CF bonds toward oxidizing and reducing reagents,
acids, and bases are responsible for the unique characteristics of organofluorine compounds
and fluoropolymers.
Fluorinated materials are of emerging interest in the biomedical area. Perfluorinated
hydrocarbon-based nanomaterials, because of their high oxygen solubility, are used in the
photodynamic therapy (PDT). The inadequate oxygen supply in the tumor cells hampers the
PDT. However, the oxygen-enriched perfluorocarbon-based nanomaterials, loaded with
near-infrared photosensitizers, significantly enhance the PDT efficiency, in treating cancers
(vide infra).
Fluorinated polymers are indispensable in the modern world. Fluoropolymers, such as
poly(vinylidene fluoride) (PVDF), and poly(tetrafluoroethylene) (PTFE), are ubiquitously
found in numerous consumer goods, high-tech materials, and electronics. The electron-poor
aromatic rings in polyfluoroaromatics exhibit strong ππ stacking interactions with nonfluorinated aromatic rings, forming donoracceptor (DA) complexes that are exploited in
the design of functional materials, such as solar cells. Solar cells designed from organofluorine compounds and fluoropolymers provide high power conversion efficiencies (PCE) (vide
infra). This area is exponentially progressing and may eventually become cost-effective so
that organo-based solar cells could replace the fossil fuelbased energy sources.
Fluorinated compounds such as difluoramines and pentafluorosulfanyl compounds
exhibit high energy densities, while having relatively low shock sensitivities, and therefore
are of emerging interest in the area of high-energy oxidizers and materials. Efficient synthetic
methods for these high-energy fluorine-containing compounds are therefore of considerable
interest (vide infra).
7.2 Fluorinated surfactants
Surfactant molecules with perfluoroalkyl chains are biologically inert, exhibit enhanced
hydrophobicity, and dissolve oxygen in relatively high concentrations. The perfluoroalkyl
group is hydrophobic as well as lipophobic, and thereby the perfluoroalkylated surfactants
are among the most effective surface-active agents, lowering the surface tension of the water
more effectively than the corresponding hydrocarbon analogs. In some cases, mixtures of the
fluorinated and nonfluorinated surfactants could be used to make them cost-effective. The
mixtures of fluorinated and nonfluorinated surfactants also have the dual advantage of
Chapter 7 • Materials applications of organofluorine compounds
281
attenuated surface tension (owing to the fluorosurfactants), and diminished interfacial tension between the water and oil (owing to the hydrocarbon surfactants).
A variety of fluorinated zwitterionic, nonionic, and anionic surfactants derived from naturally occurring amino acids, carbohydrates, and lipids, with varying lengths of perfluoroalkyl
chain length (Fig. 71A), have found a range of biomedical applications, including in ultrasound imaging, oxygen transport, blood substitutes, tissue engineering, and drug delivery.1
As an alternative to the use of pre-existing surfactants, Swager and coworkers elegantly demonstrated the rapid production of surfactants and double emulsions through reversible, spontaneous imine formation of the amines (e.g., primary amino groups of lysine residues of proteins
or poly(ethylene glycol)-derived terminal amines) and perfluoroalkyl aldehydes at the oilwater
interface. This in situ imine surfactant formation with biologically interesting molecules, such as
antibodies, is potentially useful for the biosensing applications (Fig. 71B).2
Industrially used fluorinated surfactants, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), contain hydrophilic head groups and lipophobic perfluoroalkyl
moieties as tails, and are used in the stabilization of various emulsions and vesicles
(Fig. 72). Because of their excellent performance as emulsifiers, the perfluorosurfactants
PFOA and PFOS have found numerous applications in consumer goods and pharmaceutical
industries. For example, the PFOA and PFOS are components of food packaging materials,
nonstick cookware, fire extinguishing materials, coatings, and drug delivery agents. However,
because of the slow degradation of these fluorosurfactants in the environment, they are persistent in the environment for long durations and pose toxicity hazards in humans and animals. The long-chain perfluorinated compounds were shown to have endocrine disrupting
effects. Therefore the use of the long-chain perfluorosurfactants is discontinued in the
United States, and there is an urgent need to develop alternative natural productderived
surfactants to replace the PFOA and PFOS.3
Emulsion of perfluorotributylamine or perfluorodecalin in albumin was originally developed as a blood substitute and was sold under the trade name “Fluosol.” Although Fluosol
was approved by FDA, its use in medical applications was halted due to the technical difficulties of handling this emulsified blood substitute. The efficient oxygen transport achieved
by the perfluorocarbon emulsions prompted the development of perfluorocarbon emulsionbased tissue engineering, which is useful, especially in the cardiac tissue engineering.
Similarly, oxygent an emulsified form of perfluorooctyl bromide, when added to the tissue
culture media provides enhanced oxygen transport.4,5 Early preclinical and clinical trials of
Oxygent showed that a relatively low dose of 1.35 g/kg of Oxygent, used as an alternative to
the intraoperative blood transfusion, was able to compensate the ongoing blood loss.6
Oxygent is approved in Russia as an oxygen carrier for hemorrhagic shock and perfusion of
human organs. Furthermore, fluorinated surfactants solubilize the organofluorine compounds as emulsions and thereby find applications in biomedical areas, including in drug
delivery and tissue engineering. Biocompatible fluorosurfactants could be readily synthesized
from the naturally occurring carbohydrates, amino acids, and lipids, and their physiochemical and biochemical characteristics could be modulated by the nature and number of the
fluoroalkyl moieties.
282
Organofluorine Chemistry
(A) Surfactants based on naturally occurring compounds:
O
RF
O
NH 3 +
O
N(CH 3 )3
O
O
R F = e.g., C 9 F19
R F-lysine
R F-phosphocholine
O
P
O
O
RF
n
O
O
OH R F
n
O
O
O
O
O
HO
HO
RF
OH
O
P
R F = C 8 F17
RF
O
O
NH 3 +
R F-glycine
OH
RF
O
O
R F = e.g., C 4F 9
HO
HO
O
H
N
RF
OH
O
P
O
O
O
O
N(CH 3 )3
RF
R F = e.g., C 8F 17
n
RF = e.g., C6 F13
RF-D-glucose
n = e.g., 5; R F = e.g., C 4 F9
RF-D-glucophospholipid
R F-phosphotidylcholine
(B) In situ formation of the fluorocarbon surfactants:
H
O
O
n
NH 2
+
H
F
+
F
O
F F F F
O
F F F F F F
H 3C
F
F F F F F F
H 3C
O
F F F F F F
O
n
HF
H 3C
O
H
F
NH 2
F F F F
F
O
N
n
F F F F F F
Fluorocarbon–imine surfactant
FIGURE 7–1 Structures of typical perfluoroalkyl-derived surfactants based on α-amino acids, carbohydrates, and
phosphatidylcholine (A); and in situ formation of the imine surfactants (B).
7.2.1 Perfluorocarbon nanomaterials
Perfluorinated hydrocarbon nanomaterials have found applications in the PDT. In PDT, cancer cells are destroyed by reactive, singlet oxygen (1O2) species that is produced upon photoirradiation in the presence of a photosensitizer. However, due to the inadequate oxygen
Chapter 7 • Materials applications of organofluorine compounds
F F F F F F
F F F F F F
F
O
F
Br
F F F F F F F F
F
OH
F F F F F F F F
F F F F F F F F
Perfluorooctyl bromide
(Oxygent)
283
SO 3H
F F F F F F F F
PFOA
PFOS
FIGURE 7–2 Structures of perfluorooctyl bromide, a constituent of the oxygen-carrier biomaterial, Oxygent, and
the widely used, but now phased out perfluorinated surfactants, PFOA, and PFOS. PFOA, Perfluorooctanoic acid;
PFOS, perfluorooctanesulfonic acid.
supply (hypoxic), the efficacy of the PDT is significantly hampered. Cheng and coworkers
have designed an oxygen self-enriching PDT, by loading the near-infrared photosensitizer,
IR780, and the perfluorocarbon nanodroplets into the lipid vesicles. Due to the relatively high
concentration of oxygen in the perfluorocarbon nanoparticles, and because of the relatively longer lifetime of the singlet oxygen (1O2) in perfluorocarbons, the photodynamic efficiencies of
this novel system are enhanced, resulting in elevated cytotoxicity to tumor cells (Fig. 73).7
IR780
Laser irradiation
1
O2-enriched
perfluorocarbon
O2
Tumor cell apoptosis
(singlet
oxygen)
N
Cl
N
I
IR780; photosensitizer
FIGURE 7–3 Schematic illustration of the photodynamic therapy using the oxygen-enriched perfluorocarbon materials;
laser irradiation of the coencapsulated oxygen-enriched perfluorocarbon materials and the IR780 photosensitizer
generates the cytotoxic singlet oxygen in relatively high concentrations and thereby results in the tumor suppression.
Because of the high oxygen solubility and transport properties of the fluorinated amphiphilic micelles, fluorinated nanoplatforms offer unique opportunities in designing therapeutics for the PDT.8,9 For example, the fluorinated nanoplatforms of spherical micelles,
284
Organofluorine Chemistry
consisting of copolymers of poly(ethylene glycol) (PEG) and perfluorophenyl methacrylate,
tethered to the amino-porphyrins (as amide derivatives), such as tetrakis(4-aminophenyl)porphyrin (PEG-b-PPFMA/porphyrin), have high oxygen solubility. In these fluorinated
nanomaterials, conjugated to the porphyrin photosensitizers, the production efficacy of the
singlet oxygen was enhanced with increase in the ratio of the pentafluorophenyl to the porphyrin moieties.10 In vitro photocytotoxic experiments revealed high efficacy of the
porphyrin-conjugated fluorinated nanoplatforms.
NH2
Me CN
PEG
O
Me
Me
x
O
O
z
O
F
F
O
NH N
N
H
NH2
N HN
F
F
F
NH 2
porphyrin
PEG-b-PPFMA/porphyrin
Nanoparticulate perfluorooctyl bromide, stabilized by albumin, is an effective oxygen carrier
and could be used in the tumor-specific delivery of oxygen, thereby leading to the effective cancer
therapeutics.11 The hypoxic microenvironment of the solid tumors limits the therapeutic effectiveness of the anticancer drugs and radiotherapy. In radiotherapy, abundant oxygen supply is essential for the production of reactive oxygen species that promotes the cancer cell destruction.
Furthermore, the perfluorocarbon-based nanoparticles, such as those derived from perfluorotributylamine, have platelet inhibition capability, and thereby increase tumor blood vessel permeability
to red blood cells and promote excessive oxygen delivery at the tumor sites.12,13 On the other
hand, the perfluorinated nanoparticles, because of their high affinity for oxygen, deplete oxygen
concentrations in the tumor cells with high efficiency. Furthermore, fluorocarbons, such as perfluorotributylamine, form spherical nanoparticles when ultrasonically emulsified with human
serum albumin and IR780, a near-infrared photosensitizer. These nanoparticles, because of their
high oxygen affinity, enhance hypoxic environment in the tumor cells and also have enhanced
tumor permeability. The perfluorinated nanoparticles, when used in combination with hypoxiabased agents, such as anaerobic bacteria and bioreductive prodrugs, promote hypoxic environment in the tumor cells, upon irradiation with an 808 nm laser, and thereby enhance the efficacy
of hypoxia-based bacterial cancer therapies.13
Small molecule fluorocarbon-based microbubbles are produced through ultrasonication
in the presence of perfluorosurfactants. These microbubbles, consisting of fluorinated inner
gas surrounded by the perfluorosurfactants (or other naturally occurring emulsifying agents),
Chapter 7 • Materials applications of organofluorine compounds
285
have found therapeutic applications, primarily in the cardiovascular diagnosis, tumor diagnosis, tissue engineering, and also as ultrasound-targeted drug and gene delivery agents.14,15
7.2.2 Fluorous catalysis
Perfluorosurfactants also can be used to catalyze a variety of organic reactions. The perfluorosurfactants enable the reactions in water or in supercritical CO2 through their propensity
for the formation of emulsion and thus serve as green catalysts, minimizing the production
of the environmental waste. The perfluorosurfactant-based catalysts can be used in aqueous
or supercritical CO2 media, replacing the conventionally used organic solvents, and thus
would lead to a substantial decrease in the environmental E factor (kg of waste produced/kg
of products formed).16 As an illustrative example, the copolymerization of carbon monoxide
and ethylene in supercritical CO2 medium, in the presence of a fluorous Pd(II) catalyst
PdClMe(dfppp) and silver tetrafluoroborate (AgBF4), gives the poly(ethylene ketone), in the
absence of any organic solvents (Fig. 74).17
P
Cl
H
H
+ CO
H
H
P
Pd
C 6 F13
Me
C 6 F13
O
(PdClMe(dfppp)
n
Supercritical CO 2 , AgBF4
FIGURE 7–4 Fluorous Pd(II) catalysis in supercritical CO2 for the copolymerization of ethylene and carbon monoxide.
7.2.3 Environmentally benign perfluorosurfactants
The use of environmentally less hazardous perfluorosurfactants, those with short-chain perfluoroalkyl moieties (C4C6) and perfluoroalkoxy ethers that are more easily degraded, are
potentially useful alternatives to the long-chain perfluorosurfactants,18 although they are relatively less effective as emulsifying agents as compared to PFOA and PFOS. Sodium salts of
(trifluoromethoxy)alkyl sulfonic acids (1), (p-trifluoromethylphenoxy)alkyl sulfonic acids (2),
and N,N-bis(trifluoromethyl)aminoalkyl sulfonic acids (3) exhibit relatively low surface tension, comparable to that for the PFOA.18,19 Oligomers of hexafluoropropylene oxide (4) are
also potential alternative biodegradable surfactants (Fig. 75).20 The biodegradation studies
of the 10-(trifluoromethoxy)decyl sulfonate (5) shows the formation of the intermediate degradation products, 10-(trifluoromethoxy)decanoic acid (6), (trifluoromethoxy)acetic acid (7),
and the transiently formed unstable product, trifluoromethanol. A minor pathway involving
the formation of β-keto-10-trifluoromethoxy)decanesulfonic acid was also detected, showing
the involvement of the β-oxidation pathways in the biodegradation of these alternative fluoroalkyl surfactants (Fig. 74).19
286
Organofluorine Chemistry
F3 C
O
SO3 – Na+
n
F 3C
O
SO3– Na +
n
F3C
CF3
N SO3 – Na+
F F F F
F
n
F
n = 8–12
1
F3 C
2
–
O
+
SO3 Na
10
O
CO2H
9
CF3
OH
n
O
4
3
Desulfonative oxidation of
terminal carbon
O
F3 C
β-Oxidation
Observed by LC/MS
5
F3 C
n = 8–12
n = 8–12
O
6
CO2H
CF3OH
7
(Observed by LC/MS)
FIGURE 7–5 Structures of some of the potentially biodegradable alternatives to the PFOA and PFOS surfactants,
and proposed biodegradation pathway for the ω-(trifluoromethoxy)decylsulfonate salt.19 PFOA, Perfluorooctanoic
acid; PFOS, perfluorooctanesulfonic acid.
7.3 Fluoropolymers
Fluoropolymers revolutionized the polymer industry since the beginning of the early 20th century. The fluoropolymers that have found wide industrial applications include PTFE (Teflon),
PVDF, poly(vinyl fluoride), poly(chlorotrifluoroethylene) (PCTFE), poly(chlorotrifluoroethyleneco-ethylene), poly(tetrafluoroethylene-co-ethylene), and Nafion (a perfluorinated ion-exchange
membrane, vide infra).
Fluoroalkyl-derived copolymers were shown to be ideal photoresist materials, especially
in the 157 nm lithography, as the fluorinated polymers are transparent at 157 nm. Due to the
acidity enhancing effect of the perfluoroalkyl moieties, α-trifluoromethyl alcohols are as
acidic as phenolic compounds and are soluble in mild aqueous bases, so that they could be
easily washed out with aqueous bases after the photochemical irradiation. A variety of fluoropolymers were designed for the photoresist lithography.21 The trifluoromethylated photoresist material 12 is one such example. Poly(vinyl alcohol-co-trifluoromethyl vinyl alcohol), 11,
was synthesized through azobis(isobutyronitrile) (AIBN)-initiated free-radical copolymerization of vinyl acetate (8) and α-trifluoromethylvinyl acetate (9), followed by hydrolysis.
Protection of the alcohol moieties to tetrahydropyranyl ether then gives the photoresist
material 12, which is acid-cleavable under photoresist lithography conditions to give the
polymer 11 (Fig. 76). The α-trifluoromethyl alcohol moiety in the polymer 11, being as
acidic as phenolic compounds, reacts with mild bases, such as tetramethylammonium
Chapter 7 • Materials applications of organofluorine compounds
CF3
+
OAc
AIBN
n
n
H OAc
F 3C OAc
OAc
8
9
O
10
H3O +
287
n
H OHn F3C OH
11
n
H O n F C O
3
O
O
12
FIGURE 7–6 Synthesis of a photoresist material, the copolymer of vinyl acetate and α-trifluoromethylvinyl acetate.
hydroxide, to give the water-soluble salts. Thus, the polymer 11 is readily removed by 0.26N
aqueous tetramethylammonium hydroxide during the subsequent development stage.21,22
Furthermore, fluoropolymers have high solubility in supercritical CO2. Carbon dioxide
is relatively nontoxic and nonflammable and is abundantly available. CO2 is also fluorophilic and, therefore, supercritical CO2 can be used in the polymerization of fluoroolefins.
Thus, the supercritical CO2 serves as a green solvent for the polymerization of fluoroolefins, such as trifluoroethylene, vinylidene fluoride, and fluoroalkyl acrylates.2325
Composite materials of poly(propylene) and PTFE, foamed with supercritical CO2, are
superhydrophobic and are potentially suitable for a large scale oil recovery from the contaminated water.26
7.3.1 Poly(tetrafluoroethylene)
PTFE (Fig. 77) is synthesized through free-radical polymerization of tetrafluoroethylene.
A range of free-radical initiators, such as ammonium persulfate, benzoyl peroxide, trimethylene oxide, and di-tert-butyl peroxide, were used in the polymerization of the tetrafluoroethylene to give the PTFE. This polymer is chemically inert to strong acids, and has exceptionally
high thermal stability, and thereby has found numerous applications, for example, in the
manufacture of electric insulators and dielectrics, pyrotechnics, lubricants, hydrophobic
coatings, and coated fabrics. The biomedical applications of PTFE include vascular grafts,
stents, and coatings on surgical devices. Unfortunately, PTFE polymeric materials are not
recyclable, unlike other polymeric materials, and therefore have large environmental impact.
Despite the recent trend in replacing the fluoropolymers by environmentally sustainable
polymers, some of the PTFE polymers are hard to replace.27
7.3.2 Poly(vinylidene fluoride)
PVDF is an industrially produced polymer and has numerous materials- and biomaterials
applications. This polymer exhibits piezoelectric properties, converts electrical energy into
288
Organofluorine Chemistry
Free-radical
polymerization
F
F
F F
F
n
F F
F
PTFE
Tetrafluoroethylene
Free-radical
polymerization
F
H
F F
F
n
H
PVDF
Vinylidene fluoride
F
F
H
H
F
Vinylidene fluoride
Trifluoroethylene
F
+
H
Vinylidene fluoride
F F
F
n
Poly(VDF–trifluoroethylene)
Free-radical
polymerization
F
F
F F
H F
F
H
H
F
+
Free-radical
polymerization
F
CF3
Hexafluoropropene
F F
F F
F CF3
n
Poly(VDF–hexafluoropropene)
FIGURE 7–7 Synthesis and structures of PTFE, PVDF, and some of its industrially significant copolymers. PTFE, Poly
(tetrafluoroethylene); PVDF, poly(vinylidene fluoride).
mechanical energy and vice versa, and thus has found extensive industrial applications in
the manufacture of smart materials. The PVDF also exhibits ferroelectric, hydrophobic, and
oleophobic properties and is chemically inert to strong acids. It has found, therefore, numerous industrial applications, for example, in coatings, functional membranes for water treatment, aeronautics, and biomedical applications.28 As smart materials, the PVDF and its
copolymers have the ability to change their shape and size when subjected to the electric
fields, reversibly converting mechanical strain into electrical signals.29 Copolymerization of
trifluoroethylene with vinylidene fluoride gives poly(VDF-trifluoroethylene), and the latter
Chapter 7 • Materials applications of organofluorine compounds
289
copolymer is one of the major commercially viable smart materials, along with PVDF. The
copolymer of vinylidene fluoride and hexafluoropropene (poly(VDFhexafluoropropene)
shows improved hydrophobic and mechanical properties as compared to PVDF. The latter
copolymer exhibits lower crystallinity than that of PVDF and is also used as a membrane
separator in lithium-ion batteries (Fig. 77).
7.4 Fluorinated π-conjugated polymeric materials in
photovoltaic devices
7.4.1 ππ Stacking interactions in polyfluoroaromatics
Polyfluoroaromatics as composites with nonfluorinated aromatics exhibit improved thermal and chemical stabilities because of the high CF bond strengths and also due to the
electrostatic ππ stacking interactions of the perfluoroaryl groups with the nonfluorinated
aromatics.30,31 The existence of ππ stacking interactions of the fluorinated and nonfluorinated aromatics (as in the case of aggregate 15) is unambiguously evident from
the markedly increased melting point of 250 C252 C for the 1:1 molar mixture of perfluorotriphenylene (14, mp 109 C) and triphenylene (13, 199 C) (Fig. 78).32 These
arylfluoroaryl ππ stacking interactions often result in improved physicochemical and
thermochemical characteristics for the polymeric materials. For example, Grubbs and
coworkers have confirmed the existence of these π_π stacked complexes, through differential scanning calorimetry (DSC), using the polynorbornene polymer 16, having the sidechain triphenylene moieties. A 1:1 mixture of the latter polynorbornene polymer and perfluorotriphenylene (14) exhibits a Tg of 123 C, whereas the polymer 16 alone, in the
absence of the perfluorotriphenylene (14), exhibits a glass transition temperature of
41 C.33 Thus, through addition of small perfluorinated molecules, such as 14, polymers
displaying only a glass transition could be transformed into crystalline materials. This
ππ stacking interactions in fluoroaromatics plays an important role in the organic solar
cells (vide infra).
7.4.2 π-Conjugated polymers
Fluoride-initiated copolymerization of 1,4-phenylene bis(trimethylsilylethyne) (17) with perfluorobenzene gives the corresponding copolymer 18, with high regioselectivity; the reaction
proceeds through the aromatic nucleophilic substitution (SNAr) of the fluorines at the 1,4positions in the perfluorobenzene (Fig. 79).34 The number average molecular weights (Mn)
of these polymeric materials are in the range of 34153 kDa. These poly(arylene ethynylene)
materials are commonly used as active components in various materials applications, such
as solar cells, sensors, organic light-emitting diodes, and field effect transistors.35,36
Fluorinated poly(thienothiophene (TT)-co-benzodithophene (BnDT)) polymers (e.g.,
PTBF1, PTBF2; Fig. 7-10), when used as composite materials with fullerenes, exhibit semiconducting properties, and their photovoltaic efficiencies could be tailored by the
290
Organofluorine Chemistry
F
F
F
F
H
H
H
H
π–π Stacking interactions
of polyfluoroaryl–aryl rings
F
F
F
F
F
F
F
F
+
F
F
F
1:1
F
F
F
F
15
14
13
F
mp 250–252 °C
mp 109 °C
O
F
n
O
F
F
F
F
F
1:1
T g = 123 °C
+
F
F
F
F
F
14
F
F
F
F
F
F
F
mp 199 °C
F
F
16
T g = 41 °C
FIGURE 7–8 ππ Stacking interactions of polyfluorinated aryl rings with nonfluorinated aromatics and its
usefulness in the design of task-specific polymeric materials.
Chapter 7 • Materials applications of organofluorine compounds
F
OR
RO
F
SiMe 3
Me 3Si
F
F
TBAF or CsF
F
–Me 3SiF
F
OR
RO
291
17
RO
OR
F
F
RO
OR
F
F
n
18
FIGURE 7–9 Transition metalfree copolymerization in the synthesis of fluorinated poly(arylene ethynylene)
copolymers.
stereoelectronic effect of the substituents on the polymer backbone.37 A vast majority of the
polymeric materials used in the solar cell applications have alternating DA moieties. In
most cases, electron-withdrawing moieties, such as fluorines, are attached to the acceptor
moieties. The electron-withdrawing effect of the fluorine(s) lowers the HOMO as well as
LUMO energy levels of the polymers, with HOMO lowering being relatively greater than for
the LUMO. This relatively greater energy-lowering effect of the HOMO, as compared to the
LUMO, results in the increase of the polymer HOMOLUMO gap, as well as increase in the
HOMO (polymer)LUMO (fullerene) energy difference, thereby increasing the solar cell
open-circuit voltage (Voc). This increase in the solar cell open-circuit voltage (Voc), due to
the enhanced HOMO (polymer)LUMO (fullerene) energy difference, translates into the
increased PCE of the solar cells.38 Thus, fluorination of the π-conjugated polymers offers a
viable strategy for the design of the polymer solar cells that can deliver up to .7% (and even
up to 13% in some all-polymer solar cells) efficiency (vide infra).36,39
Fluorine has obvious advantages in the solar cell applications, as it has highest
electronegativity of all the elements (Pauling EN of fluorine 5 3.98) and its van der
Waals radius is only 20% greater than for the hydrogen. It is also electron-donating
through resonance, somewhat counteracting the electronegative effects. Noncovalent
interactions involving hydrogen bonds of fluorine to neighboring nitrogen, oxygen, and
sulfur atoms can alter the physicochemical properties of the polymeric materials, especially in thin-film-based devices used in organic solar cells. The DA polymers are
typically used as electron-donating components along with fullerene-based compounds
as electron-accepting components in the bulk heterojunction (BHJ) solar power cells.
However, there is also increasing interest in developing all-polymer solar power cells that
can rival in their PCE.40 As described earlier, in most of the fluorinated polymers used in
the organic solar cells to date, fluorines are placed on the electron-acceptor unit of the
DA polymers. You and coworkers broadly classified these fluorinated acceptor units
292
Organofluorine Chemistry
N
S
N
N
F
F
R
N
F
Benzothiadiazole
(BT)
N
F
Benzotriazole
(TAZ)
R
R
N
N
F
F
R
O
O
F
S
S
Quinoxaline
(Qx)
Thienothiophene
(TT)
Illustrative polymers consisting of the above moieties:
R
R
S
S
R
F
F
F
F
S
R
S
n
R = 3-butylnonyl
R1 = 2-butyloctyl
n
PBnDT-DTffBT
R1
S
S
N S
N
S
R
R1
N N
N
S
R
PBnDT-XTAZ
R2 O
F
S
O
OR 2
N
S
OR
N
O
S
S
S
F
S
F
S
S
S
OR
F
n
R1
n
PTBFF1
(R = 2-ethylhexyl)
PBQ-4
O
O
F
S
PTBF1
S
S
S
S
S
OMe
OMe
S
S
OMe
OMe
F
OMe
OR
F
OMe
F
n
n
PTBF2
FIGURE 7–10 Donoracceptor (DA) polymers with fluorinated acceptor moieties; one example of a polymer with
a fluorinated donor moiety, PTBF2, is also shown.
Chapter 7 • Materials applications of organofluorine compounds
293
into four classes: those based on benzothiadiazole (BT), benzotriazole (TAZ), quinoxaline, and thienothiophene moieties (Fig. 710).36 Among these polymeric materials, BT
acceptor-based DA copolymers are widely used in solar cell applications.39 In addition
to the energy lowering of the HOMO and LUMO levels, fluorine atoms also increase the
planarity of the polymer chains, thereby increasing maximum absorption coefficient relative to the nonfluorinated polymers, due to the hydrogen bonding and electrostatic ππ
stacking interactions. Furthermore, fluorination of the DA polymers enhances their miscibility with the widely used electron-acceptor fullerene, phenyl-C61-butyric acid methyl
ester (PC61BM; PCBM, Fig. 712). When nonfullerene acceptors (as in the case of the allpolymer solar cells) are used in conjunction with the π-conjugated fluorinated DA polymers, PCE of up to 13.1% could be achieved (vide infra).40
Fluorination of the donor moieties in the DA polymers (which are used in the
fullerene-based BHJ solar cells), as in the case of the fluorination of the acceptor moieties,
also results in the lowering of the HOMO and LUMO energy levels and in the enhancement
of the crystallinity and backbone planarity of the polymeric materials. However, the beneficial effects of the fluorination of the donor moieties, unlike that for the acceptor moieties,
are not quite generally observed.36 The DA polymers most widely used in these applications consist of benzodithiophene (BnDT), thiophene, and benzene moieties. Some of the
examples of these polymers are shown in Fig. 711. The fluorines in the PTBF3 polymers
have detrimental effects on the polymer photochemical stability. The fluorine-containing
PTBF3 polymers also have decreased compatibility with the fullerene-based electron acceptor, phenyl-C71-butyric acid methyl ester, PC71BM, as these polymers show phase separation in their BHJ solar cells.37 On the other hand, copolymerization of 2,3-difluorothiophene
with the electron-rich BnDT-derived monomer affords the copolymer P2FT, which showed
improved open-circuit voltage (Voc) and other favorable characteristics in its fullerenebased BHJ.41 When fluorinated benzene was used as a π-conjugated linker connecting the
thiophene donor moieties, as in the case of PDTBz-4F, the performance of the fullerenebased BHJ was dependent on the number of the fluorines on the benzene moiety. For
example, the mono-, and difluorinated analogs show favorable attributes to the solar cell
performance, while the tetrafluorinated derivative PDTBz-4F has adverse effects on the morphology of the active layer and exhibits decreased solubility and phase separation with
PC71BM.42
7.4.3 Synthesis of the fluorinated donoracceptor polymers for
fullerenepolymer solar cells
Stille-coupling condensation polymerization of the distannylated BnDT 19 and the
2,5-dibromo-3,4-difluorobenzo-2,1,3-thiadiazole 20 gave high yields of the difluorinated polymer PBnDTDTffBT (Fig. 712).39 The HOMO and LUMO energy levels of this polymer
(25.54 and 23.33 eV, respectively) are lower than that of the nonfluorinated analog (25.40
and 23.13 eV, respectively). The BHJ solar cells made of PBnDtDTffBT and [6,6]-phenyl
C61-butyric acid methyl ester, PC61BM, (PCBM), as the electron acceptor, performed superior
294
Organofluorine Chemistry
R
F
F
F
S
S
F
F
F
S
F
R
Thiophene
Benzodithiophene
(BnDT)
n-Bu
O
O
O
F
F
S
S
S
S
S
S
n
O
S
OR
n-Bu
R
F
OR
F
F
n
F
n-Bu
n-Bu
PTBF3
R
R′
P2FT
R′
R
O
O
F
S
n
F
S
S
F
N
N S
F
PDTBTBz-4F
FIGURE 7–11 Structures of fluorinated benzodithiophene, thiophene, and benzene-derived donor moieties in DA
polymers, used in the BHJ solar cells. BHJ, Bulk heterojunction; DA, donoracceptor.
to those of the corresponding nonfluorinated analog with a PCE of 7.2% (Voc 5 0.91 V) as
compared to 5.0% (Voc 5 0.87) for the nonfluorinated analog. The PCE of 7.2% achieved
using this polymer/P61BM BHJ device is in the top range of PCE reported for this type of fullerenepolymer-based BHJ solar cells.
A fluorinated polymer, PBnDTXTAZ (X 5 F; 24), consisting of BnDT moieties as
donor moieties and difluorinated TAZ moieties as acceptor moieties, when blended with
the PCBM electron acceptor, affords high photovoltaic conversion efficiency of 7.1%, as
compared to the corresponding nonfluorinated analog, 23, which affords a PCE of 4.3%
(Fig. 713).38 This polymer was synthesized through Stille-coupling polycondensation
polymerization of stannylated BnDT (21) and the brominated TAZ derivative (22) in
high yields.
Chapter 7 • Materials applications of organofluorine compounds
S
N
R
Pd 2(dba) 3
P(o-tolyl) 3 , o-xylene
microwave, 150 ˚C
20 min
N
S
Me 3 Sn
SnMe3
+
S
S
S
Br
19
Br
F
F
R
295
20
R
O
R
S
N S
N
S
S
R
F
CH3
O
S
F
n
PBnDT–DTffBT
PCBM
FIGURE 7–12 Synthesis of the DA polymer PBnDTDTffBT, used in the fullerene-based BHJ solar cells. BHJ, Bulk
heterojunction; DA, donoracceptor.
R1
R
N
N
Pd 2(dba) 3
P(o-tol) 3
o-Xylene
N
S
(H3 C)3 Sn
Sn(CH 3 ) 3
S
Br
R
R = 3-butylnonyl
S
S
X
X
Br
95%–96% yield
R 1 = 2-butyloctyl
21
X = H/F
22
R
R1
N N
N
S
S
S
R
X
X
R = 3-butylnonyl
R 1 = 2-butyloctyl
S
n
PBnDT–XTAZ; X = H (23); X = F (24)
FIGURE 7–13 Synthesis of the DA polymer PBnDTXTAZ, used in the BHJ solar cells. BHJ, Bulk heterojunction;
DA, donoracceptor.
296
Organofluorine Chemistry
7.4.4 π-Conjugated benzodithiophenequinoxaline copolymers
Fluorinated π-conjugated polymers serve as efficient semiconducting materials, and, in fact,
some of the best performing semiconducting materials used in solar cell applications are
fluorinated π-conjugated polymers.43 Polymer solar cells consisting of solution phase BHJ
structure currently are capable of yielding PCE of about 10%. These polymeric materials are
prepared through roll-to-roll solution coating, and in view of their ease of synthesis and high
PCE, there is ever-increasing interest in the structural modification of the polymeric backbone for enhancing their optoelectronic properties. In particular, the PCE of these solar cells
is directly correlated with the HOMO (donor)LUMO (acceptor) gap. Fluorination of the
polymeric backbones of the conjugated polymers, in general, increases this HOMOLUMO
gap, and thereby the fluorinated polymeric materials exhibit enhanced PCE. For example,
the nonfluorinated analog of the copolymer PBQ-4, consisting of benzo[1,2-b:4,5-b0 ]dithiophene (BDT) as donor moiety and 2,3-diaryl-5,8-di(thiophen-2-yl)quinoxaline (DTQ) as
acceptor unit exhibits an open-circuit voltage (Voc) of 0.64 V and a PCE of 5.63%. The corresponding fluorinated copolymer PBQ-4, on the other hand, exhibits a relatively higher Voc of
0.90 V and an improved PCE of 8.55%.44 The synthesis of the fluorinated polymer PBQ-4 was
achieved through Pd(0)-catalyzed Stille-coupling polycondensation of the difluoro-BDT (25)
and the difluoro-DTQ (26) (Fig. 714).
7.4.5 Fluorinated polymers in fullerene-free, all-polymer (organic) solar
cells
An all-polymer solar cell, consisting of a fluorinated acceptor polymer 27 (called
PFBDTIDTIC) and a fluorinated donor polymer 28 (called PM6) provides high PCE of
10.3% (Fig. 715).45 The exceptionally high PCE achieved using this polymer composite
was attributed to the favorable absorption property and high electron mobility of the polymer 27.
A fullerene-free, all-organic solar cell consisting of a donor polymer, PBDB-T-SF, and a small
molecule acceptor, IT-4F, with a 100200 nm thickness, exhibits a PCE of 13.1%. The electrondonor polymer PBDB-T-SF was synthesized through Pd(0)-catalyzed Stillecross coupling condensation polymerization of the distannylated thiazole derivative, BDT, and the brominated
thiazole derivative, BDD (Fig. 716A). The small molecule electron-acceptor molecule IT-4F
was synthesized through the aldol condensation reaction of the activated ketone EG-2F using
pyridine as a mild base (Fig. 716B).40 The fluorinated small molecule acceptor IT-4F, in comparison with its nonfluorinated version, exhibits slightly enhanced absorption coefficient in its
UVvis spectrum, and also its absorption maximum is red-shifted by 17 nm, indicating an
enhanced intramolecular charge transfer, and thereby increased harvesting of solar photons, by
this compound. Furthermore, the fluorinated versions of the donor and acceptor components
exhibit downshifted HOMO and LUMO energy levels as compared to the corresponding nonfluorinated compounds. The active layer of organic solar cell, consisting of blended components
of the donor polymer PBDB-T-SF and the acceptor small molecule IT-4F, shows more ordered
Chapter 7 • Materials applications of organofluorine compounds
297
R2 O
R1
S
OR 2
N
S
N
S
S
S
S
R1
n
PBQ-1; nonfluorinated version of PBQ-4
Open-circuit voltage (Voc) = 0.64 V
Power conversion efficiency (PCE) = 5.63%
R1
R2 O
F
S
OR 2
N
N
S
Me 3 Sn
SnMe 3
+
Br
S
S
F
F
S
F
Br
R1
26
25
R1
S
R2 O
F
S
OR 2
N
S
N
S
S
F
F
S
F
S
R1
n
D
A
PBQ-4
Open-circuit voltage (Voc) = 0.90 V
Power conversion efficiency (PCE) = 8.55%
FIGURE 7–14 Synthesis of fluorinated benzodithiophenequinoxaline copolymers (bottom) and the structure of
the corresponding nonfluorinated copolymer (top).
298
Organofluorine Chemistry
CN
NC
S
O
F
R
F
R
n
F
R
S
R
F
S
O
R1
S
S
O
S
S
S
NC
S
CN
S
S
S
R1
R1
R1
R 1 = 2-ethylhexyl
R = C 16H 33
R1
S
R1
O
n
R1 = 2-ethylhexyl
PFBDT–IDTIC
(27)
PM6
(28)
FIGURE 7–15 Structure of a fluorinated polymer composite of PFBDTIDTIC (27) and PM6 (28) for solar cell
applications.
intermolecular arrangements (i.e., increase in crystallinity), and the hole mobility (μh) of the
PBDB-T-SF and electron mobility (μe) of the IT-4F are slightly improved over that of the nonfluorinated version of the molecular blend.40
7.5 Fluorinated poly(aryl thioethers) in organic electronic
materials
Fluorinated poly(aryl ethers) and poly(aryl thioethers) are high-performance polymeric
materials with desirable characteristics, such as high thermal stability and enhanced chemical stabilities, and are hydrophobic materials. Polymer composites of these materials with
nonfluorinated aryl polymers would be expected to have enhanced thermal and chemical
stabilities and are useful for applications in a variety of applications, including in the area of
organic electronic materials.
Practical and convenient synthetic approaches for the polymeric materials consisting of
thiolated polyfluoroaryl copolymers are of substantial interest in the area of organic electronic materials.34,46 Toward that goal, synthesis of alternating thiophene and perfluoroarene
copolymers 30 and 31 was achieved through fluoride-activated copolymerization of silylated
thiophene derivatives (e.g., 29) with perfluorinated aromatics (Fig. 717). The volatile
byproduct trimethylsilyl fluoride (bp 16 C) could be easily removed from the polymeric
materials, and thus this synthetic route is amenable for the industrial scale synthesis of perfluoroarylthiophene copolymers.46
(A)
F
SR
S
R
R
S
O
+
S
Me3 Sn
SnMe 3
S
S
Br
S
Br
S
S
BDD
BDT
F
Pd(0)
O
SR
F
SR
S
R
S
R
O
S
O
S
S
S
S
S
n
F
SR
PBDB-T-SF (electron-donor polymer)
R
(B)
R
O
S
+
F
NC
S
F
Pyridine, CHCl3
O
S
CN
NC
F
CN
F
reflux
S
O
R
EG-2F
R
DTIDT–CHO
R
R
F
CN
O
S
CN
CN
F
F
NC
S
S
S
F
O
R
R
IT-4F (electron-acceptor compound)
FIGURE 7–16 Synthesis of the donor polymer PBDB-T-SF (A) and a small molecule electron-acceptor IT-4F (B), used
in an all-organic solar cell that gives a power conversion efficiency of 13.1%.
300
Organofluorine Chemistry
F
F F
F
F
F
F
F
F F
S
Bun -O
F
SiMe 3
O-Bu n
F
F F
O-Bu n
F
S
n
Bun -O
30
F
F
F
F
29
F
F
0.1 equiv CsF, 18-crown-6
toluene, heat
Me 3Si
F F
F
F
0.1 equiv CsF, 18-crown-6
toluene, heat
F
S
n
Bun -O
F
F
O-Bu n
31
FIGURE 7–17 Synthesis of polyfluoroarylthiophene copolymers through fluoride-initiated copolymerization.
A convenient synthesis of poly(fluoroaryl thioethers) involves reaction of the fluorinated
aromatics, such as perfluorobenzene and perfluorobiphenyl (34), with S,S-bis(trimethylsilyl)
dithiols (32) in the presence of mild organobases, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD), at room temperature (Fig. 718).30 This synthetic strategy could be used for the polymerization of a variety of polyfluorinated and other activated aromatics and is useful in the
processing and fabrication of fluorinated polymers, as there are no extra purification steps
for the removal of the volatile organocatalysts and trimethylsilyl fluoride byproducts. These
reactions proceed through aromatic nucleophilic substitution mechanism (SNAr), as substantiated by ab initio calculations.
7.6 Polymer electrolytes
A solid polymer electrolyte material, with propylene carbonate side chains, poly(vinylidene
fluoride-co-(2-oxo-1,3-dioxolan-4-yl)methyl 2-(trifluoromethacrylate) (39), was synthesized
by the copolymerization of the trifluoromethacrylate ester 38 and vinyldine fluoride
(Fig. 719).47 This random copolymer with added LiClO4 exhibits ionic conductivity values
as high as 2 3 1024 S/cm at room temperature and shows high lithium-ion transference
number and relatively large electrochemical window, from 1.4 to 4.9 V versus Li/Li1. Because
of the PVDF nano-domains, this polymer has high thermal and mechanical stability and thus is
a potentially next-generation solid polymer electrolyte for the solid-state lithium-ion batteries.
Polymer electrolytes, with ionic liquid moieties (such as imidazolium moiety) incorporated into the side chains, afford relatively high ionic conductivities. These solid polymer
Chapter 7 • Materials applications of organofluorine compounds
301
F
F
F
F
F
F
TBD, DMF
F
F
S
S
F
n
F
Me3 Si
S
S
33
SiMe 3
Aryl poly(thioether)
5
32
TBD, DMF
F
F
F
F
F
F
F
N
S
F
F
F
H
N
F
F
F
F
S
F
F
F
F
34
n
N
Aryl poly(thioether)
35
(TBD)
FIGURE 7–18 Synthesis of poly(fluoroaryl thioethers) through fluoride-initiated copolymerization of
perfluoroaromatics with silylated dithiols.
CF3
CF3
Cl
O
HO
O
+
O
37
36
O
F
Pyridine
O
O
O
O
O
38
F
TAPE
74°C, 24 h
CF3
F F
O
O
n
O
39
O
O
FIGURE 7–19 Synthesis of a PVDF copolymer with lithium-ion conducting propylene carbonate moieties as side
chains. PVDF, Poly(vinylidene fluoride); TAPE, tert-amyl peroxy-2-ethylhexanoate free-radical initiator.
302
Organofluorine Chemistry
electrolytes, also called poly(ionic liquids), are usually synthesized by controlled radical polymerization reactions (in the case of polyacrylates and polyvinyl polymers), or through ringopening metathesis polymerization as in the case of the polynorbornene polymers (e.g.,
44).48 A variety of these poly(ionic liquids) can be assembled using the corresponding
imidazolium, pyrrolidinium, and ammonium cations, associated with the relatively non2
2
2
nucleophilic counteranions, such as BF2
4 , PF6 , (CF3 SO 2 ) 2N , and CF3 SO3 . Poly(methyl
methacrylate)-based poly(ionic liquids) consisting of tetraalkylammonium (40), pyrrolidinium (41), and imidazolium cation (42) side chains along with bis(trifluoromethylsulfonyl)imide [TFSI; (CF3SO2)2N2)] anions, and other poly(ionic liquids) with a poly
(ethylene) backbone (43) typically have conductivities ranging from 10210 to 1025 S/cm,
depending on the alkyl substituents on the cationic nitrogen (Fig. 720). The counteranions play a significant role in modulating the ionic conductivities of these polymer electrolytes, and the strongly delocalized TFSI anion exhibits typically enhanced ionic
conductivity as compared to the other fluorinated counteranions, such as tetrafluoroborate, hexafluorophosphate, and trifluoromethanesulfinate anions. For example, poly(1-(2methacryloyloxy)ethyl)-3-butylimidazoluim salts (42) show the following conductivities
(S/cm) at 110 C as a function of the counteranion: 4.0 3 1024 (TFSI); 1.5 3 1025
26
26
48
(CF3 SO2
(BF2
(PF2
Similarly enhanced conductivities for the
3 ); 6.4 3 10
4 ); 3.8 3 10
6 ).
CH 3
n
O
CH3
CH3
O
n
O
n
O
O
N
O
CH3
H 3C
CH3
N
H3 C
N(SO2 CF3) 2
N
N(SO 2CF3 )2
41
40
H3 C
N
N CH
3
N(SO 2CF3 )2
N
CH 2CH3
N(SO 2CF3 )2
42
43
n
O
O
H3 C
N CH
3
N
N(SO 2CF3 )2
44
FIGURE 7–20 Structures of selected poly(ionic liquid) electrolytes for applications as solid polymer electrolytes in
lithium-ion batteries.
Chapter 7 • Materials applications of organofluorine compounds
303
TFSI counteranions were found in other polymer electrolytes, such as those derived from
the poly(norbornenes) (44).49
Gel polymer electrolytes, formed by mixing the polymer electrolyte with an ionic liquid, exhibit improved lithium-ion conductivities and other favorable electrochemical
properties, such as decreased operational temperature for the lithium-ion batteries. Yin
and coworkers have developed a new kind of polymer gel electrolyte that consists of a
composite of the dicationic ionic liquid 48 and an ionic liquid 49 (in Fig. 721) in the
presence of excess LiTFSI.50 The increased charge carriers in this polymeric gel electrolytes allowed assembly of Li/LiPO4 cells that afforded relatively high discharge capacities
(160 (A h)/g at 40 C). The synthesis of this dicationic polymer electrolyte, as shown in
Fig. 721, involves AIBN-catalyzed radical polymerization of N-vinylimidazole, followed
by N-alkylation using 2-bromo-(N,N,N-trimethyl)ethanamine and anion metathesis with
LiTFSI salt.
AIBN
N
n
N
N
Br
N
+
Br–
n
2 Br–
N
LiN(SO2CF3 )2
N
N
45
46
N+
47
CH 3
n
N
O
N
N
N +
CH 3
N(SO2CF3 )2
N
CH3
2 N(SO2CF3 )2
48
49
FIGURE 7–21 Synthesis of a dicationic polymer electrolyte and the structure of the coadditive ionic liquid
electrolyte 49.
A copolymer of VDF with polyethylene trifluoromethacrylate 52, with side-chain poly(ethylene oxide) (PEO) groups [poly(VDF-MAFTEG)] was synthesized through radical copolymerization (Fig. 722).51 This polymeric material with grafted PEO moieties could be used
as a gel polymer electrolyte, when mixed with an ionic liquid electrolyte, 1-propyl-1methylpyrrolidinium bis(fluorosulfanyl)imide and lithium bis(trifluoromethylsulfonyl)imide
(LiTFSI). This electrolyte material shows ambient conductivity in the range of 0.2 mS/cm,
and a relatively high electrochemical window of 1.54.1 V versus Li/Li1.
304
Organofluorine Chemistry
F
CF 3
CF 3
Cl
O
HO
+
O
O
O
n
51
F
O
n
(VDF)
Radical polymerization
52
50
CF 3
n
O
F F
O
O
n
Poly(VDF-co-MAFTEG)
53
FIGURE 7–22 Synthesis of poly(VDF-co-MAFTEG) gel polymer electrolyte.
7.7 Fluorinated ionomers as proton-exchange membranes in
fuel cells
Nafion-H is the state-of-the-art proton-exchange membrane (PEM) and is widely used in the
fuel cell applications.52 Nafion-H has a linear perfluoroalkyl moiety as the backbone with
flexible perfluoroalkylsulfonic acid moieties as side chains. Several variations of the Nafion-H
involve subtle differences in the side-chain sulfonic acid moieties. The structure of the widely
used Nafion 117 is shown in Fig. 723. In the direct methanol fuel cells (DMFCs), chemical
energy stored in methanol is converted into the electrical energy. In this electrochemical fuel
cell, methanol is oxidized at the anode and the resulting protons diffuse toward the cathode
through a PEM, such as Nafion-H, where they combine with electrons to generate electrical
energy and release water and CO2 as byproducts.
F
F
F
F
F
F
y
xF
O
F
F CF F
3 F
O
F
SO3H
n
F F
FIGURE 7–23 Structure of Nafion-H (Nafion 117).
Although, in theory, DMFCs provide substantially higher power densities as compared to
that of the state-of-the-art lithium-ion batteries, the currently attainable overall efficiencies
are in the order of only about 25%, limiting their practical applications. Among the most
important factors contributing to these limitations are the reaction kinetics at the anode and
the unwanted methanol crossover through the PEMs. Thus, there are numerous attempts of
improving the thermochemical, electrochemical, and chemical stability of the PEM ionomers.
Chapter 7 • Materials applications of organofluorine compounds
305
The success of the widely used Nafion-H membranes lies in their strongly hydrophobic polymer
backbone and the hydrophilic sulfonic acid side chains. Among various ionomers developed as
alternatives to the Nafion-H, the poly(ether sulfone) and poly(imide) materials with appropriately functionalized perfluoroalkylsulfonic acid side chains are widely used in the fuel cell
applications.5364 Illustrative examples of these ionomer membranes are outlined next.
A poly(ether sulfone) ionomer (56 in Fig. 724) with the perfluoroalkylsulfonic acid side
chain, 2 CF2CF2OCF2CF2SO3H, was synthesized through electrophilic bromination of the
poly(ether sulfone) 54, followed by Cu(0)-catalyzed coupling of the resulting aryl bromide 55
with the potassium 1,1,2,2-tetrafluoro-2-(1,1,2,2-tetrafluoro-2-iodoethoxy)ethanesulfonate
and subsequent neutralization with HCl. This poly(ether sulfone)-based ionomer (56) has relatively high proton conductivity of 0.12 S/cm at 80 C under 90% relative humidity and has relatively higher flexibility as compared to the nonfluorinated sulfonated poly(ether sulfone).53
O
O
Br2/DCM, 0°C to RT
Br
S O
O
S O
O
n
n
54
55
O
F
F
1. Cu/DMSO, 120 °C
F F F F
2. I
SO 3– K +
O
F F
F F
S O
O
O
F
F
F
F
F
F
n
SO3 H
DMSO, 120 °C
3. HCl
56
FIGURE 7–24 Synthesis of poly(ether sulfone)-based perfluoroalkylsulfonic acid for applications as proton-exchange
membrane in direct methanol fuel cells.
Zheng and coworkers have synthesized a poly(ether sulfone) ionomer (61) in a three-step
synthetic procedure involving step-growth condensation polymerization of 4,40 -bis(difluorophenyl)sulfone with the imide 57, followed by the BBr3-mediated deprotection of the methyl
ether and subsequent ring-opening perfluoroalkylation reaction using the perfluoroalkylsulfonic acid lactone 60 (Fig. 725).56 This ionomer has relatively high mechanical and thermal
stability and exhibited relatively low methanol permeability and conductivity of up to
0.083 S/cm, comparable to the state-of-the-art Nafion 117 membrane.
Saito and coworkers have synthesized a poly(imide) copolymer with pendant perfluoroalkylsulfonic acid moieties (65) in a one-step condensation copolymerization of 1,4,5,8naphthalenetetracarboxylic acid dianhydride (62), aryloxyperfluoroalkylsulfonic acid 63 and
306
Organofluorine Chemistry
O
S
OH
F
F
N
K2CO3 /DMSO, 140 ˚C
N
OCH 3
O
O
O
S
O
O
O
HO
O
57
n
OCH3
58
O
F
O
O S
O
O
S
O
CF3
O
BBr3 /DCM
(60)
N
n
O
F
F
DMSO, RT to 110 ˚C
OH
59
O
O
S
O
O
N
n
F F
O
O
SO 3H
F
CF3
61
FIGURE 7–25 Synthesis of a poly(ether sulfone) ionomer for applications as a proton-exchange membrane in fuel cells.
the triazole 64 (Fig. 726). This ionomer was soluble in polar organic solvents, was stable up
to about 180 C, and exhibited a relatively high proton conductivity of 6.6 3 1024 S/cm at
80 C, comparable with the proton conductivity of the conventional sulfonated poly(arylene
ether) ionomer membranes.55
A composite membrane, synthesized through radical polymerization of styrene and divinylbenzene (as a cross-linker), admixed with PVDF, (Fig. 727) proved to be superior to the
state-of-the-art Nafion-H membranes in terms of performance characteristics, such as
decreased methanol crossover and water management, inDMFCs.65
Chapter 7 • Materials applications of organofluorine compounds
NH2
O
O
H 2N
N
O
O
NH2
+
O
O
307
+ H2 N
OCF2 CF2SO 3H
62
m-Cresol, TEA, benzoic acid
N N
H
175°C to 195°C
64
63
O
N
O
O
N
O
O
N
N
O
O
N
O
F
F
O
HO3S
F
F
50
N N
H
50
65
FIGURE 7–26 Synthesis of the poly(imide)-based ionomers for applications as a proton-exchange membrane in the
fuel cells. TEA, Triethylamine.
F
F
F
1. Styrene/DVB/AIBN
n
PVDF matrix
2. ClSO3H/CHCl3
3. H2O, 60°C
F
n
HO3S
n
SO3 H
FIGURE 7–27 Synthesis of PVDFpolystyrenesulfonic acid composite material as proton-exchange membrane for
fuel cell applications. PVDF, Poly(vinylidene fluoride).
7.8 Fluorinated carbon nanoparticles and nonaqueous
electrolytes in lithium- and lithium-ion batteries
Fluorinated graphite (CFx)n (also called CFx) materials are used as positive electrodes in the
primary lithium batteries as they provide high specific charge densities compared to the conventionally used metal-oxide cathodes. The CFx electrodes exhibit relatively low electrical
conductivity with increase in the fluorine content, because the CF bonds are sp3-hybridized, and therefore optimal carbon-to-fluorine ratio is necessary for efficient performance of
the lithium batteries. The CFx electrodes can be used over a wide temperature range, from
260 C to 190 C, and exhibit theoretical discharge capacity of about 870 (A h)/kg.
308
Organofluorine Chemistry
Fluorinated carbon nanoparticles (F-CNPs) were shown to have improved discharge
capacities as compared to the state-of-the-art CFx cathodes that are widely used in primary
lithium batteries, although these materials are not commercialized to date.66 The F-CNPbased electrodes have intrinsic properties of the CFx and those of the nanoscopic materials.
The carbon nanoparticles are prepared by electrochemical reduction of the fused
Li2CO3Na2CO3K2CO3 at about 600 C, with nickel sheet as the working electrode and
graphite rods as counter-electrodes. Thus obtained carbon nanoparticles are fluorinated
using fluorine gas, as dilute solution in argon, to give the F-CNPs.
High thermal stabilities of the lithium-ion batteries are required for their use in electric
and hybrid electric vehicles. To enhance thermal stabilities, inorganic phosphates are used
as additives, although these additives lower the battery performance. Thermal stabilities of
the electrolytes could also be enhanced by using fluoroalkyl-derived dialkyl ethers (e.g., 66)
and carbonate-based solvents (e.g., 67). Organofluorine electrolyte solvents, including fluoroalkyl ethers [e.g., 3-(1,1,2,2-tetrafluoroethoxy)-1,1,2,2-tetrafluoropropane, 66], fluoroalkylsubstituted propylene oxide [e.g., 4-(2,2,3,3,3-pentafluoropropoxymethyl)-1,3-dioxolan-2one, 67], and fluorinated esters (e.g., methyl difluoroacetate), afford enhanced
thermochemical stabilities to the lithium-ion batteries.67 Fluorinated ionic liquid electrolytes
have potential advantages toward enhanced thermochemical and electrochemical stabilities,
although there remain challenges in improving their ionic conductivities and viscosity
effects. Fluoroalkyl-derived imidazolium-based ionic liquids (e.g., 68), due to their enhanced
thermal stability, ionic conductivity, and electrochemical stability, are potentially useful as
nonaqueous electrolytes in the lithium-ion and lithium batteries (Fig. 728).6870
O
F F
HF2C
O
O
O
CF2 H
F F
O
CF3
F
66
67
F
RF
N R
N
X–
X– = e.g., BF4–, (CF3 SO2 )2 N–
68
FIGURE 7–28 Structures of some fluorinated nonaqueous electrolytes.
7.9 Fluorinated hyperbranched dendrimers: synthesis and
applications
Wooley and coworkers have developed synthetic methods for the amphiphilic polyfluorianted hyperbranched homopolymers and copolymers through living radical polymerization.
Thus, the living atom transfer radical polymerization (ATRP) of pentafluorostyrene (69) and
4-[oxy(tri(ethylene glycol)bromoisobutyryl]-2,3,5,6-tetrafluorostyrene inimer (70) gave the
hyperbranched polymer 71.7173 The bifunctional monomer 70 is called inimer (initiator
Chapter 7 • Materials applications of organofluorine compounds
309
monomer) because it consists of dual polymerization-initiating functional groups, at either
end of the monomer: styrene and α-bromo ester moieties. The polymerization achieved by
such inimers is also called self-condensing vinyl copolymerization, as originally introduced
by Frechet and coworkers.74,75 This living radical polymerization was achieved using CuCl/
CuCl2 as the catalyst in the presence of 2,20 -bipyridine as the deactivating ligand (Fig. 729).
The homopolymers (72), synthesized from the inimer 70 alone (i.e., in the absence of
x
F
F
F
F
F
y
FF
F
FF
F F
F
F F
F
O
F
F
O
O
O
3
3
O
O
x
F
F
F
F
F
F F
F
F F
O
O
O
3
O
O
F
72
homopolymer
F
CuCl/CuCl2
N
(Bpy)
F
F
F
CuCl/CuCl2
N
F
F
71
copolymer
F
69
N
N
(Bpy)
F
O
O
F
F
O
3
F
3
O
Br
70
FIGURE 7–29 Synthesis of the fluorinated hyperbranched dendrimers 71 and 72, through the ATRP of the
bifunctional inimer 70.
310
Organofluorine Chemistry
monomer 69), as well as copolymer 71, have high thermal stabilities up to 175 C210 C
and were soluble in a broad range of organic solvents. The linker tri(ethylene glycol) moieties facilitate formation of the water-dispersible micelles of these hyperbranched polymers.
These hyperbranched fluoropolymers can be used as antibiofouling materials. The hyperbranched polymers 71 and 72 exhibit anti-icing characteristics and therefore would be
suitable as anti-icing coatings for applications in extreme environments.76 Furthermore,
these polymeric materials are amenable for structural modifications for applications in drug
delivery and in magnetic resonance imaging (MRI) (vide infra).
7.10 Fluorinated compounds in drug delivery and magnetic
resonance imaging
Fluorinated compounds are increasingly explored as MRI agents, because unlike other NMR
imaging approaches, 19F NMR is not affected by extraneous signals arising from the biological environments. 19F NMR has 100% natural abundance and is nearly as sensitive as 1H
NMR, and more importantly, there are no endogenous sources of fluorinated compounds in
the biological media. The fluorinated MRI agents can be designed such that they can be conjugated to the pharmaceutically active drug candidates and thereby can be used as the drug
delivery agents.
7.10.1 Fluorinated curcumin analogs as 19F MRI agents
Curcumin is an effective antioxidant and exhibits antitumor and antiamyloid effects. It can
permeate the bloodbrain barrier, and therefore curcumin and its derivatives are potential
therapeutic targets for Alzheimer’s disease (AD) and other neurological disorders. 19F NMR
of the 19F-labeled curcumin derivatives would be useful as probes to monitor the amyloid-β
plaques in the brain, as curcumin binds to Aβ plaques. Derivatives of curcumin with trifluoromethoxy moieties (Fig. 730) were synthesized and used as probes for monitoring Aβ formation in the mouse AD models.77 Through 19F MRI studies on amyloid-β overexpressing
Tg2576 mouse AD models, it was shown that a trifluoromethoxy derivative of curcumin is
effective in binding to the amyloid-β plaques.77
O
O
O
F3CO
OCF3
OH
HO
O
OCH3
H 3CO
O
OCH3
OH
HO
Curcumin
Trifluoromethyl analog of curcumin
FIGURE 7–30 Structures of curcumin and a trifluoromethyl analog for 19F MRI studies. MRI, Magnetic resonance
imaging.
Chapter 7 • Materials applications of organofluorine compounds
311
7.10.2 Polyfluorinated dendrimer amphiphiles as 19F MRI probes and
drug delivery agents
A polyfluorinated dendrimer amphiphile decorated with perfluoro-tert-butyloxy moieties,
with 81 fluorines for each of the dendrimer molecules (Fig. 731), was shown to be a potential 19F MRI probe in drug delivery applications. This dendritic amphiphile, when incorporated into liposome nanoparticles along with drug candidates of interest, such as
doxorubicin, could be used as a 19F MRI probe for tracing drug distribution.78 The pseudosymmetric environment of the fluorines in this compound results in a single 19F NMR signal
and thus affords high sensitivity of the MRI.
MeO
MeO
n
n
F3C CF3
OMe F C
CF3
F3C
3
CF3
n
O
O O
O
O
O
O
F3C
O
O
CF3
CF3
O
NH
HN
HN
O
F3C
F3C
F3C
F3C
O
O
CF3
CF3
O
H
N
O
N
H
O
F3 C
F 3C CF3
O
H
N
H
N
O
O
O n
O
O
O
O n
MeO n
OMe
O
OMe
n
O
O
NH
O
O
n OMe
HN
NH
MeO
OMe
n
O
HN
O
O
NH
O
F3 C O
F 3C CF O
3
CF3
CF3
O
CF3
CF3
CF3
CF3
FIGURE 7–31 Structure of a fluorinated dendrimer, with peripheral perfluoro-tertiary-butyl ether moieties.
A dendrimer decorated with 540 pseudosymmetrical fluorines was synthesized through a
convergent synthetic route involving sequential deoxybromination reactions and Williamson
ether synthesis (Fig. 732).79 The benzylic hydroxy moiety is relatively more acidic than the
primary hydroxy moiety due to the electron-withdrawing inductive effect of the adjacent
312
Organofluorine Chemistry
Me
HO
CF3
F 3C
F3C
Me
CF3
O
F 3C
F 3C
O Me
CF3
Me
CF3
O
F 3C
O
F3C
PBr3
OH
F 3C OH
CF3
CF 3
CF3
O
F 3C
OH
CF3
OH
CF 3
CF3
F 3C
O
CF 3
K2 CO3, acetone, 18-crown-6
reflux
Br
OH
O CF3
Me F 3C
O
F 3C
Me
DMF, 100 o C
F3C
OH
1. repeat the steps
H 3CO
OH
K2 CO3, acetone,
18-crown-6
2. Final step
CF 3
CF 3
OCH 3
CF3
CF 3
CF3 CF3
CF 3
CF3
CF3
CF3
H 3CO CF 3
CF 3 CF3
OCH 3
CF3OCH 3
F 3C
O
F 3C
CF 3
CF3
CF3
CF3
CF 3
O
CF3
CF 3
CF3 O
F 3C O
CF3
CF 3
OCH3
CF 3
CF 3
OCH 3
O
OCH 3
F 3C
CF3
CF3
CF 3
CF3
O
CF 3
O
CF3
CF 3
O
CF 3
O
CF3
F 3C
CF3
O
O
O
CF 3
CF3
CF3
O
O
CF 3
CF 3
CF3
OCH 3
CF 3
H 3CO CF3
CF3
O
F 3C
F3C
O
F 3C
CF3
H 3CO
F 3C
CF3
O
CF3
CF 3
CF3 O CF3
O CF3
CF3
O
CF 3
H 3CO
CF 3
CF 3
CF 3
O
CF 3
CF 3
CF3
F 3C O
CF3
CF 3
O
CF 3
CF3
CF 3
CF3
H3CO H CO CF3
3
CF 3
OCH 3
CF3
CF3
CF 3
H3CO
OCH 3
O
CF3
OCH3
CF 3
O
CF3
O
CF 3
CF3
CF 3
H 3CO
CF3
CF 3
CF 3
CF3
F3C O
CF 3
F 3C
O
F 3C
OCH3
CF 3
F3C O CF
3
CF 3
CF3 O
H 3CO CF3
CF 3
CF 3
OCH3
O
CF3
CF3
CF3
CF3
CF3 OCH 3
CF3
CF 3
CF3
CF 3
O
CF 3
3
CF 3
O
CF 3
CF3
CF3
H 3CO
CF 3
CF 3OCH
O
H 3CO
H 3CO
CF3
CF3 CF3
O
CF3
O
CF3
OH
CF 3
H 3CO
CF3 CF3
OCH 3
CF3
CF 3
H 3CO
HO
CF 3
H 3CO
CF3
OCH 3
H 3CO
CF3
H 3CO
H 3CO
CF3 CF 3
CF3
O
CF 3
CF 3
OCH 3
CF 3
CF 3
CF3
CF 3
CF 3
CF3
CF 3
OCH 3
F 3C
H3CO
OCH3
CF 3
OCH 3
CF 3
CF3
FIGURE 7–32 Polyfluorinated pseudosymmetric dendrimer decorated with surface trifluoromethyl groups.
Chapter 7 • Materials applications of organofluorine compounds
313
trifluoromethyl moieties, and therefore the Williamson reaction occurs exclusively at the
benzylic hydroxylic moiety under the reaction conditions.
Because of the pseudosymmetry of this dendrimer, it shows a single δ19F NMR signal for all
the trifluoromethyl groups and therefore exhibits relatively high sensitivity in the 19F MRI. This
fluorinated dendrimer shows relatively low spinlattice (T1) and spinspin relaxation times
(T2) of 366 and 122 ms, as compared to that of trifluoroethanol with a T1 and T2 of 2379 and
266 ms, respectively. Thus, the T1 and T2 values in the polyfluorinated dendrimer are dramatically reduced because of its large molecular size. The short relaxation times, combined with
high fluorine content, thus significantly contribute to the high MRI sensitivity of the fluorinated
dendrimers. Using the above dendrimer, 19F MRI could be performed at as low concentration
as 18.5 μM. The dendrimer-based fluorinated molecules thus would be potentially useful as
drug delivery agents as well as for monitoring the biodistribution of the drug candidates.
7.11 Organofluorine liquid crystal materials
Fluorinated molecules are widely used as LCDs, including everyday electronics and flat panel
TVs. Fluorine or fluoroalkyl groups, when used as terminal groups in place of the terminal
cyano groups of cyanobiphenyl- and related aryl cyanide-based liquid crystals (e.g., 73 and 74)
that were widely used prior to the 1990s, afford relatively high-voltage holding ratio (VHR) and
provide nematic liquid crystals suitable for applications in active matrix LCDs. A range of terminally substituted fluoroalkyl-, fluoroalkoxy-, and fluorosulfanyl-aromatics (e.g., 7583 in
Fig. 733) provide nematic liquid crystals with high VHR and strong dielectric anisotropy and
find numerous applications in LCDs and other optoelectronics (Fig. 733).80,81
7.11.1 Fluorinated dendrimer-based liquid crystals
Carbosilane dendrimers, with terminal perfluoroalkylthio groups, were synthesized by freeradical addition of the perfluoroalkyl mercaptan to the allyl-terminated carbosilane dendrimer,
in the presence of AIBN as the initiator (Fig. 734). The first-generation dendrimer (G1) formed
a mesophase at 215 C to 239 C, whereas the second- and third-generation dendrimers (G2
and G3) exhibited hexagonally ordered array of columns.82 Other carbosilane dendrimers, functionalized with terminal perfluoroalkyl groups, also exhibit liquid crystalline properties.83
The PAMAM [poly(amidoamine)] dendrimers (Fig. 735), as well as the [poly(propyleneimine)] dendrimers, when functionalized as ammonium carboxylates using perfluorononanoic
acid or 2H,2H,3H,3H-perfluoroundecanoic acid, exhibit liquid crystalline behavior.83
7.12 Organofluorine compounds in high-energy materials
There is an emerging interest in developing fluorinated compounds as high-energy materials.
Pentafluorosulfanyl (SF5) compounds and gem-difluoramine (NF2) compounds exhibit high
energy densities with relatively low shock sensitivity and thus find applications in highenergy materials.84
314
Organofluorine Chemistry
N
R
N
RO
74
73
F
C 3H 7
O
CHF 2
C 3H 7
75
76
O
CF 3
C 3H 7
CF3
C 3H 7
78
77
O
CF 2 CF3
C 3H 7
SF 5
C 3H 7
80
79
F
F
F
C 3H 7
F
81
C3 H 7
F
82
F
F
F
F
O
83
F
F
F
C 2H 5
F
F
F
FIGURE 7–33 Structures of illustrative cyanoaryl- and fluoro-, fluoroalkyl-, and pentafluorosulfanyl-based liquid
crystals.
7.12.1 N,N-Difluoramine (NF2) compounds
NF2-containing compounds, because of their relatively high energy densities and low shock
sensitivities, are potentially useful as high energy materials, or can be used as additives to
the conventionally used high-energy compounds, such as RDX (1,3,5-trinitroperhydro-1,3,5triazine), HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), and TNT (2,4,6-trinitrotoluene). The N,N-difluoramine analogs of HMX are also of potential use as defensive agents
against biological weapons. 3,3,7,7-Tetrakis(difluoramino)octahydro-1,5-dinitro-1,5-diazocine
(HNFX), a NF2 analog of the HMX (Fig. 7-36) is therefore of interest both as a high-energy
compound as well as in the decontamination of the bacterial spores; the detonation products
of HNFX—HF and fluorine gas—destroy anthrax Bacillus spores with an exposure time of
Chapter 7 • Materials applications of organofluorine compounds
315
Si
Si
Si
Si
Si
Si
HS(CH2)2C6F13
Si
Si
Si
Si
Si
Si
FS
SRR
F
AIBN, 70°C
RF S
Si
Si
RFS
Si
Si
SR F
SR F
SR F
Si
RFS
RFS
Si
Si
Si
SR F
SRF
RF S
SRF
Si
R FS
Si
R FS
Si
RFS
RFS
R FS
SR F
SR F
Si
Si
Si
Si
Si
Si
SRF
Si
RFS
SRF
Si
RF S
SR F
SRF
R FS
Si
RFS
RFS
Si
Si
SR F
SR F SR F
SR F
SR F
SRF
SRF
RF = e.g., –CH2CH2C6F13
FIGURE 7–34 Synthesis of a G2terminally fluoroalkyl-substituted dendrimer (36 terminal perfluoroalkyl moieties)
through the AIBN-catalyzed hydro-thiolation reaction. AIBN, Azobis(isobutyronitrile).
about 0.4 h.85 HNFX has a density of 1.807 g/cm3, which is comparable to that of HMX
(1.91 g/cm3) and relatively higher than that of TNT (1.65 g/cm3). The higher densities of the
materials translate into their higher detonation pressures and detonation speeds.86
7.12.1.1 Synthesis of HNFX
Chapman and coworkers synthesized HNFX in a multistep process. The key steps of the
conversion include conversion of the carbonyl moiety of the diazocine-diketone 84 to the
gem-difluoramine derivative (85), and desulfonative-N-nitration of compound 85
(Fig. 736).8691 The diketone 84 was reacted with a mixture of difluoramine (HNF2) and
concentrated sulfuric acid in a low-boiling CFCl3 solvent (bp 23.7 C) to give the gem-difluoramine derivative 85 in moderate yields. The N,N-difluorosulfamic acid (NF2SO3H), formed
in situ, formed through the reaction of HNF2 with H2SO4, is the de facto gem-difluoramination reagent in this reaction. The use of the low-boiling CFCl3 solvent prevents the possible
detonations that would otherwise result from the shock-sensitive difluoramine compounds.
The N-nitration of the sulfonamide derivative 85 was accomplished using a mixture of nitric
acid in triflic acid (CF3SO3H) to give HNFX in a moderate yield of 65%.
316
Organofluorine Chemistry
RFCO2–
RFCO2–
NH3 +
+
+H
3N
–
2
N
RFCO
O
HN
3N
H3 N
–
RFCO2
N
O
O
NH3+
N
N
NH 3+
HN
N
NH
O
NH3 +
N
NH
HN
N
RFCO2–
O
O
NH
O
H
N
N
NH3 +
O
RFCO2–
RFCO2–
NH3 +
NH3+
RFCO2–
RFCO2–
O
H
N
N
NH
3N
HN
O
O
RFCO
+H
NH
N
N
+H N
3
–
2
RFCO2–
N
RFCO2–
+
NH3 +
N
O
HN
+H
RFCO2–
H3 N
RFCO2–
N
+
H 3N
RFCO2–
NH 3+
RFCO2–
RF = e.g., CF3(CF2)7–
FIGURE 7–35 Structure of a PAMAM dendrimer, terminally derivatized as the perfluoroalkylammonium salt to
render liquid crystal characteristics. PAMAM, [Poly(amidoamine)].
7.12.1.2 Synthesis of RNFX
RNFX is a gem-difluoramine analog of the RDX, as the gem-difluoramine moiety is
isosteric and isoelectronic with respect to the N-nitro moiety. Chapman and coworkers
synthesized RNFX using a procedure analogous to that of the synthesis of HNFX, involving
gem-difluoramination of the ketone 86 as a key step. The gem-difluoramination was achieved
through the reaction of compound 86 with the in situ formed NF2SO3H (from the reaction of
HNF2 with concentrated H2SO4), in a low-boiling CFCl3 solvent, to prevent detonation of the
product. The final N-nitration of 87 with concomitant deprotection of the sulfonamide moiety, using nitric acid, affords the RNFX (Fig. 737).92,93
7.12.1.3 Synthetic methods for the gem-difluoramination
Difluoramine (HNF2) is a low-boiling liquid, with a bp of 223 C and is an extremely shocksensitive compound, similar to that of nitroglycerin.9497 Operationally convenient reagents
for the gem-difluoramination therefore are being sought in this area. The trityldifluoramine
(Ph3CNF2) is a stable solid and forms HNF2, in situ, in reaction with H2SO4. Reaction of
Chapter 7 • Materials applications of organofluorine compounds
NO2
N
NO2
N
O2 N
N
N
O 2N N
CH3
O2 N
NO2
N NO2
N
NO2
NO2
RDX
317
NO2
HMX
TNT
O
O
S N
O
O2 N
O
N
HNF2 + H2 SO4 /CFCl3
NO2
S
O
–15 °C to 0 °C; 15 days
O
84
O
S N
O 2N
F2N
NF2
F2N
O
F2 N
O
N S
O
NF2
NO2
HNO3 /CF3SO 3H
55 °C, 40 h
NF2
O2 N N
N NO2
F2 N
NF2
HNFX (density = 1.806 g cm–3)
85
60%
65%
FIGURE 7–36 Structures of RDX, HMX, and TNT, and synthesis of HNFX.
O
HNO3
HNF2 /H2 SO4 /CFCl3
Nos
N
N
86
F2 N NF2
F2 N NF2
Nos
–15 °C
Nos
N
N
O2 N
Nos
87
SO 3H
N
N
NO 2
RNFX
O2 N
FIGURE 7–37 Synthesis of RNFX, a gem-difluoramine analog of RDX; Nos 5 4-nitrobenzenesulfonyl.
trityldifluoramine with carbonyl compounds in 30% oleum gives high yields of the corresponding gem-difluoramine derivatives (Fig. 738).98
A relatively more convenient synthetic method for the gem-difluoramination is provided
by Prakash and coworkers using the reaction of sodium salt of N,N-difluorosulfamic
acid (NF2SO3Na; 90) with the carbonyl compounds. The latter reaction affords the
318
Organofluorine Chemistry
O
Ph3 C–NF2
R
R
R
F2 N NF2
30% oleum/CH 2Cl2
R
88
80%–90%
O
Na
O
H
S N
H
O
+ –O
1. 2F2/H2O; 0 °C
Na +
O
F
O S N
F
O
–
2. –H2O/HF
R
R
H 2SO 4 /oleum
R
100% by NMR
94%
O
Ph3 C–NF2
F2 N NF2
R
R
30% oleum/CH2Cl2
R
88
90
89
R
F2N NF2
R
88
80%–90%
O
Na +
–
O
H
O S N
H
O
89
1. 2F2/H2O; 0 °C
Na +
2. –H2O/HF
–
O
F
O S N
F
O
R
R
H 2SO 4 /oleum
90
94%
F2N NF2
R
R
88
100% by NMR
FIGURE 7–38 Convenient synthetic methods for gem-difluoramination of carbonyl compounds.
gem-difluoramine products in quantitative yields, under mild conditions (Fig. 738). The
NF2SO3Na reagent can be synthesized through direct fluorination of sodium sulfamate (89),
using elemental fluorine gas in aqueous solutions.99
7.12.2 Pentafluorosulfanyl (SF5) compounds
SF5-containing organic compounds are of potential interest as oxidizers and high-energy materials, as they exhibit relatively higher densities, higher thermal and chemical stabilities, and relatively lower impact sensitivities.100102 For example, pentafluorosufanylnitramide salts
2
(NF1
4 SF5 NNO2 ) exhibit comparable oxidizer capacity with that of ammonium dinitramide
2
1
[NH4 NðNO2 Þ2 ], a nonchlorine-containing oxidizer.103 The oxidation products of SFs compounds,
COS and HF, are environmentally benign, unlike those derived from the perchlorate explosive
compounds. High-energy compounds, with high nitrogen content, such as triazoles, furazans,
and tetrazoles, when derivatized with fluorinated substituents, such as SF5, significantly enhances
their performance. For example, SF5-substituted furazans possess higher density and detonation
properties (calculated values), as compared to the unsubstituted furazans.102 However, the SF5containing compounds have not found practical applications as high-energy materials to date.
Chapter 7 • Materials applications of organofluorine compounds
319
Shreeve and coworkers synthesized the pentafluorosulfanyl 1,2,3-triazoles through Cu(I)catalyzed cycloaddition reactions of the (pentafluorosulfanyl)acetylene with various azides
and showed that these compounds have relatively higher densities than the corresponding
trifluoromethyl compounds, which, in turn, have relatively higher densities than the nonfluorinated analogs (Fig. 739).104 The higher densities are translated into the higher
H3 C
N3
N
H3 C
F5 S
H
H 3C
CuI (10 mol%), 2,6-lutidine
6 h, RT
91
CH3
N
N
N
N
(70%)
SF5
92 d = 1.61 g cm–3
N3
N3
N3
N3
F5 S
N N
H
F5 S
CuI (10 mol%), 2,6-lutidine
6 h, RT
N
N
N NN
F5 S
N
N N
N
SF5
N
(73%)
93
SF5
94 Tm = 292 ˚C
F5 S
OH
N3
N3
H
CuI (10 mol%), 2,6-lutidine
6 h, RT
F 5S
N N
N
96
d = 1.90 g cm–3
N
N3
F5 S
H
N3
N3
CuI (10 mol%), 2,6-lutidine
6 h, RT
F5 S
N
N N
N N
N
F5S
97
SF5
(55%)
95
N
N N
N
OH
N
N N
SF5
( 67%)
98 Tm = 169.3 ˚C
FIGURE 7–39 Synthesis of SF5-triazoles through Cu(I)-catalyzed azidealkyne click reactions.
320
Organofluorine Chemistry
O
O
1. SF5 Cl, Et3B, –45 ˚C
CH3
2. MeOH, 50 ˚C
99
HO
OMe
F5 S
OMe
F5 S
Ph
F5S
OH
O
O
101
93%
71%
O
Cl
OH
Ph
Cl
F5S
O
O
103
102
42%
88%
H 2N
NH2
N
N
O
O
H 2N
(104)
pyridine/THF
Cl
F5 S
HN
SF5
NH
N
O
N
SF5 –furazan
N
N
N
O
H 2N
(105)
103
OMe
F5 S
100
H
OH
O
MeOH
O
H 2 O/NaOH
then HCl
O
S
O
F5 S
pyridine/THF
HN
N
N
N
N
H
SF5 –tetrazole
Cl
Cl
N
N
Cl
CH 2N 2
N
N
CHN2
N
N
Cl
Cl
106
107
NaN 3
N3
CHN2
N
N
N
N3
108
N NH
F5 S
H
N3
N
N
N
SF5
N3
SF5 –pyrazole
FIGURE 7–40 Synthesis of SF5-containing high-energy materials, furazan, tetrazole, and pyrazole derivatives.
Chapter 7 • Materials applications of organofluorine compounds
321
detonation properties for these high-energy materials. The thermal melting temperatures
(Tm) of these SF5-derived triazoles ranged from 120 C to 312 C and are insensitive to
impact. The CF3- and SF5-substituted triazoles, in general, exhibited higher densities, and
both series of compounds are of potential interest as high-energy materials. The SF5-triazole
92, for example, has a density of 1.61 g/cm3, which is substantially higher than that for nitrobenzene (1.2 g/cm3) or trifluorotoluene (1.19 g/cm3). The dimeric SF5-triazole 96 has even
higher density of 1.90 g/cm3.
Various derivatives of SF5-containing heterocyclic compounds, such as furazans,102 tetrazoles,102 and pyrazoless,105 were synthesized for their potential applications as high-energy
materials (Fig. 740). These materials exhibit substantially higher densities than that of the
analogous organic compounds, in the range of 1.802.08 g/cm3, and may find applications as
alternatives to the conventionally used high-energy materials, such as RDX, HMX, and TNT.
Dolbier and coworkers have developed synthetic methods for the free-radical pentafluorosulfanylation of alkenes, using pentafluorosulfanyl chloride (SF5Cl) and triethylborane
(Et3B), the latter serving as a free-radical initiator.102,106 Thus, the reaction of vinyl acetate
(99) with SF5Cl and Et3B, followed by methanolysis, gives the (pentafluorosulfanyl)ethanal
dimethyl acetal (100). The acetal 100 could be transformed, in a series of reactions, to the
(pentafluorosulfanyl)acetyl chloride 103 and (pentafluorosulfanyl)acetic acid (102). Either
the acid chloride 103 or the carboxylic acid 102 can be used in the acylation of furazans
(e.g., 104) or tetrazoles (105) to afford the corresponding SF5-containing high-energy compounds. SF5-derived pyrazoles are also thermally stable, high energy compounds. Shreeve
and coworkers have synthesized a high-energy SF5-pyrazole compound, through the reaction
of the (pentafluorosulfanyl)acetylene with 2-(diazomethyl)-4,6-diazidotriazole, 108. The latter
compound has relatively higher density (1.85 g/cm3) and thereby enhanced detonation performance (detonation pressure 5 20 GPa; detonation velocity 5 7464 m s21), which is
comparable to that of TNT.105
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Index
Note: Page numbers followed by “f” refer to figures.
A
Abemaciclib, 172, 173f
Accufluor, 44
Acquired immune deficiency syndrome (AIDS)
disease, 163
Acyl fluorides, 8
Afatinib, 167, 169f
Ag(I)-catalyzed decarboxylative fluorination, 123,
124f
Ag(II)-catalyzed oxidative ring-opening
fluorination of cyclic amines, 121 123,
122f, 123f
Aliphatic aldehydes, 111
Alkyl azides with 18F-labeled triarylphosphine
esters, 238f
Alkyltrifluoroborates, 54
Allylsilanes and enolsilyl ethers, 50 51, 51f
α,α-difluoromethylated phosphonate esters,
46 47
α-fluorinated amino acids, synthesis of, 53 54,
53f, 54f, 55f
α-fluorination of aldehydes, 48 49, 49f
α-fluorination of amide, 50, 50f
α-fluorination of ketones and 1,3-dicarbonyl
compounds, 51 52
α-fluorophosphonate esters, 47, 48f
α7 nicotinic acetylcholine receptor (nAChR)
agonist, 136 137, 137f
α-tocopherol, 105
Alzheimer disease (AD), 152 155, 152f, 157 158,
218, 257f, 296
Amantadine, 247
Amcinonide (Cyclocort), 201
Amidinate salt, 18
Amino-trifluoromethylation of styrenes, 92f
Amitriptyline, 26 27
Amyloid beta (Aβ) plaques, 153 155, 221,
260 261
Amyloid plaques, 152 153, 218 219
Amyloid precursor protein (APP), 153 154
Angiogenesis, 267 268
Angiotensin-converting enzyme (ACE) inhibitor,
223 225, 225f
Anti-Alzheimer pharmaceuticals, 152 163, 154f
BACE-1 inhibitors, 153 159, 155f, 156f
γ-secretase inhibitors and modulators, 159 163
Antibacterial pharmaceuticals, 141 146
erythromycin, 141 142, 142f
fluoroquinolone, 142 145, 143f
flurithromycin, 141 142, 142f
tetracyclines, 145 146, 146f
Anticancer pharmaceuticals, 167 185
abemaciclib, 172, 173f
BRAF and mitogen-activated protein kinase
kinase enzyme inhibitors, 183 185
cobimetinib, 171 172, 172f
dacomitinib, 167 169, 168f
enasidenib, 178 181, 180f
fulvestrant, 177 178, 178f
lorlatinib, 169 171, 171f
nonsteroidal antiandrogens, 181 183
PARP inhibitors, 172, 173f
taxoid anticancer agents, 173 177
Antidepressant, 202 204
Antidiabetic pharmaceuticals, 146 152
canagliflozin, 151 152, 151f
carmegliptin, 150 151, 150f
sitagliptin, 146 149, 147f, 148f
Anti-HIV pharmaceuticals, 163 165, 164f
bictegravir, 163 165, 164f
doravirine, 165, 166f
Antiinflammatory pharmaceuticals
celecoxib, 200, 200f, 201f
corticosteroids, 200 202, 202f, 203f
nonsteroidal antiinflammatory agents, 199
Antimalarial pharmaceuticals, 165 167
329
330
Index
Antimalarial pharmaceuticals (Continued)
mefloquine, 166 167, 168f
tafenoquine, 165 166, 167f
Anti-Markovnikov hydro-trifluoromethylation of
alkenes, 86, 87f
Antiplatelet drugs
cangrelor, 138 139
riociguat, 198, 199f
Antiviral pharmaceuticals, 185 195
antiplatelet drugs, 189 190
glecaprevir, 190 194, 192f
ledipasvir, 189 190
letermovir, 194 195, 195f
pibrentasvir, 190 194, 192f
sofosbuvir, 187 188, 188f, 189f
tecovirimat, 185 187, 185f
voxilaprevir, 194, 194f
Aortic dissections, 142 144
Apalutamide (Erleada), 181 182, 182f
Aromatic trifluoromethylation, 84 86, 85f
Artemether, 167f
Artemisinin, 165, 167f
Artesunate, 167f
Aryl(alkyl)sulfenyl chlorides, 31
Arylboronic acids and esters, fluoroalkylation of,
125 126
copper-mediated trifluoromethylation, 125, 125f
Cu(I)-catalyzed trifluoromethylation of
arylboronate esters, 126, 126f
Pd(0)-catalyzed difluoroalkylation of
arylboronic acids, 126, 127f
Aryl difluoromethylation, 118 121, 120f, 121f
Aryl fluorination, 106 108, 107f
Aryl thiocyanates, 31
Aspirin, 199
Asymmetric trifluoromethylthiolation,
64 65, 65f
Atabecestat, 154 155, 156f
Atorvastatin (Lipitor), 104, 104f, 135 136, 135f,
136f, 195 196, 196f
Au(I)-catalyzed hydrofluorination of alkenes and
alkynes, 114 115, 114f, 115f, 116f, 117f
Au(I)-catalyzed photoredox reactions, 113, 113f
Au(III) catalysis for [18F]trifluoromethyl
compounds synthesis, 248, 251f
Avagacestat, 159, 161f
Aza-dibenzocyclooctyne (ADIBO) amide
derivatives, 231 232
Azetidines, 121
Azido-fluoroalkylation of alkenes, 88 90, 89f, 90f,
91f
B
BACE-1 inhibitors, 153 159, 155f, 156f
atabecestat, structure of, 156f
Aβ oligomers and Aβ aggregates, formation of,
155f
CNP520, 156 157, 158f
lanabecestat, structure of, 156f
verubecestat, 157 159
structure of, 156f, 159f
X-ray structure of, 159, 160f
Baeyer Villiger reaction, 240
Baloxavir marboxil (Xofluza), 140, 141f
Balz Schiemann reaction, 105
Benzophenone, 23 25
Benzylic fluorination, 108 111
Mn(III)-catalyzed benzylic fluorination, 108,
109f
Pd(II)-catalyzed benzylic fluorination, 108 111,
110f
Benzylic hydrogens, 108
β-amino-fluoroalkylation of alkenes, 80 82
Cu(I)-catalyzed amino-fluoroalkylation, 80 81,
81f
Fe(II)-catalyzed azido- and aminotrifluoromethylation, 81, 82f
Ru(II)-catalyzed amino-fluoroalkylation, 81 82,
83f
β-(azido)fluoroalkylation of alkenes, 90f
β-(azido)sulfones, 90f
β-(azido)trifluoromethyl compounds, 88 90
β-carbonyl esters, 52
β-naphthols, 66 67, 69f
β-secretase-I (BACE-1) inhibitor, 75 77
β-(trifluoromethyl)amines, 88 89, 89f
Bicalutamide (Casodex), 181 182, 182f
Bictegravir, 163 165, 164f
Billard’s reagents, 63, 65 66, 66f
synthesis of, 65, 67f
Index
trifluoromethylthiolation of alkynes and
Grignard reagents, 65 66, 68f
Binimetinib, 183, 184f
Biotin, 174 176, 259, 259f
Bis-cinchona alkaloids, 50 51
Blood brain barrier (BBB) permeability,
136 137, 138f, 220 221
BMS-932481, 161, 161f
Borazine-mediated gem-difluroalkylation, 23 25,
26f
Borazine-mediated trifluoromethylation, 23 25,
25f
BPN-15606, 161 162, 161f
BRAF and mitogen-activated protein kinase
kinase enzyme inhibitors, 183 185
Bristol Myers Squibb, 161, 163, 164f
Bronsted acids, 115
Buclizine (antihistamine), 118 121
Butyl ciprofibrate, 106 108
C
Canagliflozin (Invokana), 151 152, 151f
Cangrelor, 138 139, 198f
Carbapenems, 145
Carbotegravir, 163 165, 164f
Carmegliptin, 150 151, 150f
structure of, 150f
synthesis of, 151, 151f
X-ray crystal structure of, 150, 150f
Celecoxib, 108, 162, 199 200, 200f, 201f, 245
Celestolide, 108
Cell-cycle hypothesis, 153
Cephalosporins, 145
Ceritinib, 169 170
Cerivastatin, 135 136, 135f
Chemoorthogonal scavenger-assisted purification,
232
Chichibabin reaction, 9 10
Chiral imidazolidinone catalyst, 48 49
Chiral N-acyl oxazolidinones, 96
Chlorodiphenhydramine, 118 121
Chloroquine, 165, 167f
Chlorotetracycline, 145
Cholinesterase inhibitors, 154f
Chronic obstructive pulmonary disorders, 45 46
331
Cinchona alkaloids, 51
Cinchonidine catalyst, 14 15
Ciprofloxacin (Cipro), 104, 104f, 142 144, 143f
Cisplatin, 229
Citalopram, 202 204, 203f
Claritin, 248
Click chemistry, 227 228, 230f
strain-promoted, 231 234, 233f, 235f
Clofibrate, 118 121
Clomipramine, 118 121
Clopidogrel (Plavix), 198
Coadditive ionic liquid electrolyte, 303f
Cobimetinib, 171 172, 172f
Copper/iridium catalysis, 77f, 78
Copper-mediated trifluoromethylation, 125, 125f
Corticosteroids, 45 46, 200 202, 202f, 203f
Crizotinib, 169 170
Cu(I)-catalyzed α-trifluoromethylation of
hydrazones, 114f
Cu(I)-catalyzed amino-fluoroalkylation, 80 81, 81f
Cu(I)-catalyzed fluoroalkylation of aryl halides,
126 127, 128f
Cu(I)-catalyzed radiofluorinations, 252, 254, 255f
Cu(I)-catalyzed trifluoromethylation of
arylboronate esters, 126, 126f
Cu(I)-catalyzed trifluoromethylation of vinyl (or
aryl) trifluoroborates, 89f
Cu(I)-mediated dediazoniative
difluoromethylation, 124, 125f
Cu(II)-catalyzed trifluoromethylation of
arylboronic acids, 125
Cyanuric fluoride, 2 3
Cyclic RGDYK (arginine-glycine-aspartic acidtyrosine-lysine) dimer-derived positron
emission tomography tracers, 267 273
[18F]FAl-NOTA-PRGD2 (18F-alfatide), 268 271,
270f
18
F-fluciclovine (Axumin), 273, 273f
folate-NOTA-Al18F, 271 272, 272f
FPPRGD2 (dimeric cyclic RGDYK peptide),
267 268, 269f
[68Ga]-NOTA-PRGD2, 268 271, 270f
NOTA-conjugated linear peptides 18F-AlFNOTA-IF7 and 18F-Al-NOTAMATBBN, 271,
272f
332
Index
CYP450 enzymes, 139 140
Cystic fibrosis drugs, 139 140
Cystic fibrosis transmembrane conductance
regulator (CFTR) protein, 139 140
D
Dacomitinib, 104, 104f, 167 169, 168f
Dapagliflozin, 151 152, 151f
Decarboxylative fluoroalkylation
decarboxylate difluoromethylation,
78 79, 80f
decarboxylative trifluoromethylation, 78
Deconstructive ring-opening fluorination of Nacyl cyclic amines, 123f
Delafloxacin (Baxdela), 144, 144f
δ-tocopherol, 108
Deoxo-Fluor [bis(2-methoxyethyl)aminosulfur
trifluoride], 2 4, 6 8, 10
Desoximetasone (Topisolone), 201
Dexamethasone, 200
Diastereoselective trifluoromethylation of Nsulfinylimines, 24f
Dicationic polymer electrolyte, 303f
Diethylaminosulfur trifluoride (DAST), 2 4, 6 8,
10, 65
DAST mediated trifluoromethylthiolation of
silylenol ethers, 66 67, 69f
Difluoramines, 280
Difluoroalkylation of hydrazones, 111 113, 112f
Difluoroenolates, 19
Difluoromethylation, 44
of pyrazole aldehyde, 13f
Difluoromethylthiolation, 68 70, 69f, 70f
Dimethylformamide (DMF), 12 13
5,5-dimethyl-1-pyrroline N-oxide (DMPO), 91 93
Dipeptidyl peptidase-4 (DPP-4), 75 77
Direct methanol fuel cells (DMFCs), 304 305
Diversinates, 82 84
DNA aptamer drug conjugates, 177
Docetaxel, 175f
Dolutegravir, 163 165, 164f
Donepezil, 153, 154f
Dopamine, 108, 245
Doravirine, 165, 166f
Doxycycline, 145
E
Efavirenz, 15, 16f, 54 55, 163, 164f, 165
Electrochemical oxy-trifluoromethylation, 92f
Electrophilic difluoromethylation, 57 60, 60f
Electrophilic fluorinations
α-fluorinated amino acids, synthesis of, 53 54,
53f, 54f, 55f
enantioselective, 48 52
allylsilanes and enolsilyl ethers, 50 51, 51f
α-fluorination of aldehydes, 48 49, 49f
α-fluorination of amide, 50, 50f
α-fluorination of ketones and 1,3-dicarbonyl
compounds, 51 52
β-carbonyl esters, 52
of tetralones, 52f
reagents for, 44 47, 45f
fluorinated bioisosteres of phosphate esters,
46 47, 48f
NFPy reagent, 44
Selectfluor, 44 46, 46f
stereoselective electrophilic fluorination of
β-diketone, 52f
Electrophilic fluoroalkylation, 54 60
electrophilic difluoromethylation, 57 60, 60f
NHC-catalyzed electrophilic
trifluoromethylation, 57, 59f
reagents for, 55 56
trifluoromethylated pharmaceuticals and
herbicide, structure of, 56f
Electrophilic O-difluoromethylation of alcohols,
60f
Electrophilic radiotrifluoromethylation, 227, 228f
Electrophilic trifluoromethoxylation, 60f, 61 62,
61f, 62f
electrophilic O-difluoromethylation of alcohols,
60f
O-trifluoromethylation, synthetic methods for,
61 62, 62f, 63f
SCF3-containing pharmaceuticals and
veterinary medicines, 61f
Electrophilic trifluoromethylation
electrophilic difluoromethylation, 57 60, 60f
NHC-catalyzed electrophilic
trifluoromethylation, 57, 59f
reagents for, 55 56
Index
trifluoromethylated pharmaceuticals and
herbicide, structure of, 56f
Electrophilic trifluoromethylthiolation, 60f, 61 62,
61f, 62f
electrophilic O-difluoromethylation of alcohols,
60f
O-trifluoromethylation, synthetic methods for,
61 62, 62f, 63f
reagents, 127
SCF3-containing pharmaceuticals and
veterinary medicines, 61f
Elvitegravir, 163 165, 164f
Empagliflozin (treatment of type II diabetes),
118 121
Emtricitabine, 163, 164f
Enalaprilat, 108, 245
Enantiomeric fluorination of β-amido esters, 53f
Enantioselective fluorinations, 48 52
allylsilanes and enolsilyl ethers, 50 51, 51f
α-fluorination of aldehydes, 48 49, 49f
α-fluorination of amide, 50, 50f
α-fluorination of ketones and 1,3-dicarbonyl
compounds, 51 52
β-carbonyl esters, 52
of tetralones, 52f
Enantioselective trifluoromethylation, 14 15, 15f,
16f
Enasidenib, 178 181, 180f
synthesis of, 181f
Encorafenib (Braftovi), 183, 184f
Enolsilyl ethers of tetralones, 66 67
Environmentally benign perfluorosurfactants, 285
Enzalutamide (Xtandi), 182 183, 182f, 183f, 184f
Epi-androsterone, 4
Eravacycline (Xerava), 145 146, 146f, 147f
Erythromycin, 141 142, 142f
Escitalopram, 202 204, 203f
Estradiol, structures of, 178f
Estrone, 105, 128, 248
Ethyl bromodifluoroacetate, 112f
EVP-0015962, 162 163
Ezetimibe, 116 117, 196, 197f, 242 243, 247 248
F
18
Fdifluoromethylarenes, 248
333
Fe(II)-catalyzed azido- and aminotrifluoromethylation, 81, 82f
Fenbufen, 78
Fenofibrate, 118 121, 248
[18F]Florbetaben, 261
[18F]flortaucipir, 261
18
F-fluciclovine (Axumin), 273, 273f
[18F]fluoroarylsulfonamido-maleimide, 239f
[18F]fluorodopamine, 253 254, 254f
[18F]fluoxetine, 252, 252f
[18F]flutamide, 252, 252f
18
F-labeled aliphatic trifluoromethyl compounds,
synthesis of, 251f
18
F-labeled aza-dibenzocyclooctyne (ADIBO)
amide derivatives, 231 232
18
F-labeled captopril, 223 225, 225f
18
F-labeled compounds, 2, 219f, 222f
enzymatic fluorination reactions for [18F]labeled PET tracers, 258 259
[18F]5ʹ-deoxy-5ʹ-fluoroadenosinebiotin
conjugate, 259, 259f
5ʹFluoro-5ʹ-deoxyadenosine and 5fluororibose, 258, 258f
5ʹ-Fluoro-5ʹ-deoxyadenosine-RGD conjugate
in cancer detection, 259, 260f
[18F]FIBT, 221 222, 223f
18
F-labeled PET imaging agents, 218
18
F-labeled reagents, synthesis of, 223 227,
226f, 227f
florbetapir, 221
PET tracers in Alzheimer’s disease,
260 265
2-(4-Aminoaryl)quinoline-based 18F-labeled
PET tracers (THK series), 263 265, 264f,
265f
flortaucipir-18F, 261 263, 262f, 263f
tropomyosin receptor kinase, 265, 266f
PET tracers in cancer diagnosis, 266 273
cyclic RGDYK dimer-derived PET tracers,
267 273
[18F]-(R)-lorlatinib, 266 267, 267f
radiofluorination, synthetic methods for,
222 227, 224f
radiofluorination via aromatic nucleophilic
substitution, 237 244, 239f
334
18
Index
F-labeled compounds (Continued)
L-3,4-Dihydroxy-6-[18F]fluorophenylalanine
(6-[18F]L-DOPA), 240, 240f
[18F]fluoro-(1)-biotin, 238 239, 239f
γ-Aminobutyric acid transporter positron
emission tomography tracers, 240 241
phenolic compounds, 241 244, 242f, 243f,
244f
radiofluorination via diaryliodonium salts,
252 257, 253f, 254f
Cu(I)-catalyzed radiofluorination, 254, 255f
iodonium ylides, 255 257, 256f, 257f
Sharpless click reactions for PET tracers,
227 234, 228f, 229f
18
F-octreotate PET tracers for tumor imaging,
230, 231f, 232f
protein and oligonucleotide triazole, 229,
230f
Staudinger ligation reactions for, 234 237
strain-promoted click chemistry, 231 234,
233f, 235f
Staudinger ligation reactions for PET tracers,
234 237, 236f, 237f
alkyl azides with 18F-labeled triarylphosphine
esters, 238f
18
F-labeled GABAA receptor antagonist, 237f
18
F-labeled peptide analogs, synthesis of,
237f
traceless Staudinger ligation reaction, 236f
transition metal-mediated radiofluorination,
245 252
Au(III) catalysis for [18F]trifluoromethyl
compounds synthesis, 248, 251f
Cu(I)-catalyzed radiofluorinations, 252
Mn(III)-catalyzed radiofluorinations,
245 247, 245f, 246f, 247f
Ni(II)-catalyzed radiofluorinations, 249 251
Pd-catalyzed radiofluorinations, 248, 249f,
250f
18
F-labeled RNA oligonucleotides, 230f
18
F-labeled trifluoromethylthiolation of aromatics,
31f
Flomoxef, 68
Florbetaben (Neuraceq), 218 219, 260 261
Florbetapir (Amyvid), 218 219, 221, 260 261
[18F]-(R)-lorlatinib, 266 267, 267f
Flortaucipir-18F, 261 263, 262f, 263f
Flucarbazone, 33, 61
Fluciclovine (Axumin), 218
Flunisolide (AeroBid), 201
FluoLead (4-tert-butyl-2,2-dimethylphenylsulfur
trifluoride), 2 3, 12
Fluorinated acceptor polymer, 296, 298f
Fluorinated bioisosteres of phosphate esters,
46 47, 48f
Fluorinated carbon nanoparticles (F-CNPs),
307 308, 308f
Fluorinated compounds in drug delivery and
magnetic resonance imaging, 310 313
curcumin analogs, 310, 310f
polyfluorinated dendrimer amphiphiles,
311 313, 311f, 312f
Fluorinated dendrimer-based liquid crystals, 313,
315f
Fluorinated donor acceptor polymers, synthesis
of
for fullerene polymer solar cells, 293 295,
295f
Fluorinated donor polymer, 296, 298f
Fluorinated graphite (CFx)n, 307
Fluorinated hyperbranched dendrimers, 308 310,
309f
Fluorinated ionic liquid electrolytes, 308
Fluorinated ionomers as proton-exchange
membranes in fuel cells, 304 306, 304f,
305f, 306f, 307f
Fluorinated π-conjugated polymeric materials in
photovoltaic devices, 289 298
fluorinated polymers in fullerene-free, allpolymer (organic) solar cells, 296 298,
299f
π-conjugated benzodithiophene quinoxaline
copolymers, 296, 297f
π-conjugated polymers, 289 293, 291f, 292f,
294f
π π stacking interactions in
polyfluoroaromatics, 289, 290f
synthesis of fluorinated donor acceptor
polymers for fullerene polymer solar cells,
293 295, 295f
Index
Fluorinated pharmaceuticals for cardiovascular
diseases, 195 198
ezetimibe, 196, 197f
nebivolol, 196 197, 197f
statin drugs, 195 196, 196f
Fluorinated poly(arylene ethynylene) copolymers,
291f
Fluorinated poly(aryl ethers), 298
Fluorinated poly(aryl thioethers) in organic
electronic materials, 298 300, 300f, 301f
Fluorinated polymers in fullerene-free, allpolymer (organic) solar cells, 296 298,
299f
Fluorinated poly(thienothiophene-cobenzothophene)s, 292f
Fluorinated surfactants, 280 285, 282f
environmentally benign perfluorosurfactants,
285
fluorous catalysis, 285, 285f
Oxygent, 281
perfluoroalkyl-derived surfactants, 282f
perfluorocarbon nanomaterials, 282 285
perfluorooctyl bromide, 283f
Fluorinated taxoids, tumor-targeted drug delivery
of, 174 176, 176f
Fluorine, 134 138, 145, 192, 291 293
Fluoroacetone hydrates for nucleophilic
fluoroalkylations, 18 19, 19f
Fluoroalkene peptide bioisosteres, 114, 114f
Fluoroalkyl(aryl) moieties, 134 135
Fluoroalkylations, 12 30
of arylsilanes, 116 117, 118f, 119f
fluoroacetone hydrates for nucleophilic
fluoroalkylations, 18 19, 19f
of hydrazones, 111 113
tetrakis(dimethylamino)ethylene-mediated
fluoroalkylations, 28 30, 28f
Fluoroalkyl-derived copolymers, 286 287
Fluoroalkyl-derived imidazolium-based ionic
liquids, 308
Fluoroalkyl radicals, 81f
Fluorocyclines, 145
Fluoroform (CHF3), 19 25, 20f, 22f, 23f, 24f, 127
Fluorohydrin, 121 122
Fluorometholone, 201
335
Fluoropolymers, 280, 286 289, 287f
fluoroalkyl-derived copolymers, 286 287
photoresist material, synthesis of, 287f
poly(tetrafluoroethylene), 287, 288f
poly(vinylidene fluoride), 287 289, 288f
2-fluoropropanoyl-labeled PEGylated dimeric
cyclic RGDYK peptide (FPRGD2),
267 268, 269f
Fluoroquinolones, 142 145, 143f, 165
delafloxacin, 144, 144f
FDA-approved, 143f
levofloxacin, 144
mechanism of action, 145, 145f
5-fluorouracil, 177
Fluorouracil-phosphoramidite module, 177, 177f
Fluorous catalysis, 285, 285f
Fluorous Pd(I) catalysis, 285f
Fluosol, 281
Fluoxetine, 104, 202 204, 248
Flurbiprofen, 49, 49f, 104, 104f, 162 163, 200f
Flurithromycin, 141 142, 142f
Flurprimidol, 33, 61
Flutamide (Eulexin), 181 182, 182f, 247
Flutemetamol (Vizamyl), 218 219, 260 261
Fluticasone, 43 46, 200
Fluticasone furoate, 45 46
Fluticasone propionate (Flonase), 46, 124f, 201
Fluvastatin (Lescol), 135 136, 135f, 195, 196f
Fluvoxamine (Luvox), 202 204, 203f
18
F-octreotate PET tracers for tumor imaging, 230,
231f, 232f
Fosnetupitant, 142f
Fostamatinib (Tavalisse), 140, 141f
[18F]phenylalanine, 257
Free-radical reactions
β-amino-fluoroalkylation of alkenes, 80 82
Cu(I)-catalyzed amino-fluoroalkylation,
80 81, 81f
Fe(II)-catalyzed azido- and aminotrifluoromethylation, 81, 82f
Ru(II)-catalyzed amino-fluoroalkylation,
81 82, 83f
CF3/CF2H substituents, pharmaceuticals
containing, 76f
decarboxylative fluoroalkylation
336
Index
Free-radical reactions (Continued)
decarboxylate difluoromethylation, 78 79,
80f
decarboxylative trifluoromethylation, 78
fluoroalkylation, sodium triflinate, 82 94
aromatic trifluoromethylation, 84 86, 85f
azido-fluoroalkylation of alkenes, 88 90, 89f,
90f, 91f
functional group transformations, 84f
hydro-trifluoromethylation of alkenes, 86
trifluoromethylation of arylboronic acids,
86 88, 88f, 89f
trifluoromethylation of proteins, 93 94, 93f,
94f
free-radical trifluoromethylation, reagents for,
77 78, 77f
photoredox-catalyzed S-fluoroalkylation and
arylation, 94 95, 95f
radical fluoroalkylation of enolates, 96 97, 96f,
97f
Togni’s and Umemoto’s reagents, structures of,
77f
Free-radical S-fluoroalkylation, 95f
Free-radical trifluoromethylation, reagents for,
77 78, 77f
Friedel Crafts reactions, 56, 254
Friedel Crafts trifluoromethylation of aromatics,
56
Fulvestrant (Faslodex), 177 178, 178f
structures of, 178f
synthesis of, 178, 179f
Furazans, 320f, 321
G
Galantamine, 4, 153, 154f
γ-Aminobutyric acid (GABA) transporter positron
emission tomography tracers, 240 241
γ-Aminobutyric acid (GABA) transporter type 1
(GAT-1) imaging agents, 240 241, 241f
γ-secretase inhibitors (GSIs), 153, 159 163
γ-secretase modulators (GSMs), 153, 159 163
BMS-932481, 161 162
BPN-15606, 161 162
nonsteroidal antiinflammatory drugs, 162 163,
162f
GDC-0994 and its analog, 185f
Gefitinib, 169f
Gel polymer electrolytes, 303
gem-difluoramination, synthetic methods for,
316 318, 318f
gem-difluorination of carbonyl compounds, 12f,
13f
gem-difluoromethylation, 2 3, 3f, 77 78
gem-difluoromethylene phosphonate derivative,
47
gem-(difluoromethyl)thioethers, synthesis of, 30,
30f, 31f
Gemifloxacin (Factive), 142 144, 143f
Glecaprevir, 75 77, 190 194, 192f
Glucocorticosterone drugs, 45 46
Grignard reactions of ethyl trifluoroacetate,
16 17, 17f
Grignard reagents, 65 66
H
Haas’s reagent, 63
Hepatitis C virus (HCV), 187
Hexafluoroacetone, 18, 19f
HIV, 163
Homophenylalanine, 108
Human neuronal nitric oxide synthase (hnNOS)
inhibitor, 138f
Human type II topoisomerases, 145
Hydrazones, fluoroalkylation of
difluoroalkylation of hydrazones, 111 113, 112f
trifluoromethylation of hydrazones, 113
Hydrofluoric acid, 18f
Hydro-trifluoromethylation of alkenes, 86
Hypercholesterolemia, 195
Hypervalent iodonium ylide reagent, 63
I
Ibuprofen, 8, 108, 162, 245
Imidazole, 190
Imipramine, 65
Indoxacarb, 33, 61
Inimer (initiator monomer), 308 310
Integrin, 267 268
Interferon, 190 192
Iodosobenzene, 108
Index
Ionazolac, 78
Iridium photoredox catalysis, 86
[Ir(III)] photoredox catalyzed difluoroalkylation
of hydrazones, 112f
Ishikawa’s reagent, 2 3
Isocitrate dehydrogenase-2 (IDH2) enzyme,
135 136
Isoxepac, 78
Itanapraced, 162f
Ivacaftor, 139 140
Ivosidenib (Tibsovo), 171, 171f
K
Ketoprofen, 8
L
Lamivudine, 165
Lanabecestat, 154 155, 156f
Langlois reagent, 23 25, 25f, 63, 77 78, 82 84
aromatic trifluoromethylation, 84 86, 85f
azido-fluoroalkylation of alkenes, 88 90, 89f,
90f, 91f
functional group transformations, 84f
hydro-trifluoromethylation of alkenes, 86
selective trifluoromethylation of proteins,
93 94, 93f, 94f
trifluoromethylation of arylboronic acids,
86 88, 88f, 89f
Larotrectinib (Vitrakvi), 171, 171f, 265f
Ledipasvir, 189 190
structure of, 189f
synthesis of, 190, 191f
Letermovir (prevymis), 194 195, 195f
Levofloxacin (Levaquin), 142 144, 143f
Lewis acids, 91 93, 115
Lithium- and lithium-ion batteries
fluorinated carbon nanoparticles and
nonaqueous electrolytes in, 307 308
Lithium hexamethyldisilazide (LiHMDS), 64 66
Loratadine, 118 121
Lorlatinib, 167, 169 171, 171f, 257
Lovastatin (Mevacor), 195
177
Lu DOTA-TATE (Lutathera), 218, 230
Lumacaftor, 139 140, 140f
Lung cancer, diagnosis of, 220, 221f
Lyrica (anticonvulsant), 247
337
M
Malaria, 165
Maraviroc, 104
Mavyret, 190
Mefloquine, 166 167, 167f, 168f
Meisenheimer complex, 108, 242 243
Meldrum’s acid, 255 257
Memantine, 153
Mericitabine, 188f
9-Mesitylacridinium salt, 86
Methicillin-resistant Staphylococcus aureus, 68,
144
Microfluidic-based continuous flow reactor
techniques, 43 44
Mild cognitive impairment (MCI), 261
Mitogen-activated protein kinase (MAPK),
171 172
Mn(III)-catalyzed benzylic fluorination, 108, 109f
Mn(III)-catalyzed radiofluorinations, 245 247,
245f, 246f, 247f
Mn(salen)-catalyzed radiofluorination of aliphatic
C H bonds, 245f
Monepantel, 44, 61
Monotrifluoromethylation, 17 18
Morphine, 4
Morpho-DAST (morpholinosulfur trifluoride),
2 3
Morpholino hydrazones, 111
Moxifloxacin (Avelox), 142 145, 143f, 145f
Munavalli’s reagent, 63 64, 64f, 68 70
N
Nafion-H, 304 306, 304f
Naftifine, 26 27
Nanoparticulate perfluorooctyl bromide, 284
Naproxen, 8, 162
N-benzoylazacycloalkanes, 121
N-3,5-Bis(trifluoromethyl)benzylcarboxamides,
140 141
N-(difluoromethyl)phthalimide, 70f
Nebivolol, 196 197, 197f
Neuroendocrine neoplasms (NENs), 230
N-fluoroalkyl phthalimide reagents, 44
N-fluoroalkyl sulfenamide reagents, 44
N-fluorobenzenesulfonimide (NFSI), 43 45,
50 51, 108, 225 226
338
Index
N-fluoropyridinium salts, 43 44
N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate (NFPy), 44
N-Heterocyclic carbenes (NHC)-catalyzed
electrophilic trifluoromethylation, 57, 59f
Ni(0)-catalyzed difluoromethylation of aryl
chlorides, 121f
Ni(0)-catalyzed difluoromethylation of
chloroarenes, 120f
Ni-catalyzed fluoroalkylation of aromatics,
116 121
aryl difluoromethylation, 118 121, 120f
121f
fluoroalkylation of arylsilanes, 116 117, 118f,
119f
Ni(II)-catalyzed radiofluorinations, 249 251
Ni-catalyzed trifluoromethylthiolation, 127 128
Ni-catalyzed trifluorothiomethylation of aryl
triflates, 129f
Nicotinic acetylcholine receptors (nAChRs), 220
Nimesulide, 254
NMDA receptor antagonist memantine, 154f
N,N-difluoramines (NF2 compounds), 314 318
Nonaqueous electrolytes, in lithium- and lithiumion batteries, 307 308
Nonmetastatic castration-resistant prostate cancer
(CRPC) (NM-CRPC), 181 182
Nonsmall-cell lung carcinoma (NSCLC), 167,
169 170, 220
Nonsteroidal antiandrogens, 181 183
Nonsteroidal antiinflammatory drug (NSAID), 49,
161 162, 199
Nonstructural protein 5A (NS5A) inhibitor,
190 192
Norfloxacin, 143f
Novartis, 75 77, 156
N-protected α-fluoro-β-bromo glycine ester,
synthesis of, 54f
N-tosyl-p-chlorobenzene-sulfonimidoyl fluoride
(SulfoxFluor), 6, 7f
N-trifluoromethylation of amines, 26 28, 27f
Nucleophilic deoxyfluorination, 3 8, 4f, 5f, 7f, 8f,
9f
Nucleophilic difluoromethylation of aldehydes,
12 13, 13f
Nucleophilic fluorination of pyridines and
diazines, 8 10, 10f
Nucleophilic fluoroalkylations, 2
Nucleophilic gem-difluorination of carbonyl
compounds, 10 12, 11f, 12f, 13f
Nucleophilic radiofluorination strategy, 248
Nucleophilic reactions, 2
deoxyfluorination, 3 8, 4f, 5f, 7f, 8f, 9f
fluorination of pyridines and diazines, 8 10,
10f
fluoroalkylations, 12 30
borazine-mediated gem-difluroalkylation,
23 25, 26f
borazine-mediated trifluoromethylation,
23 25, 25f
difluoromethylation of aldehydes, 12 13, 13f
fluoroacetone hydrates for nucleophilic
fluoroalkylations, 18 19, 19f
fluoroform (CHF3), 19 25, 20f, 22f, 23f, 24f
N-trifluoromethylation of amines, 26 28, 27f
Ruppert Prakash reagent (CF3SiMe3) for,
13 18, 14f
tetrakis(dimethylamino)ethylene-mediated
fluoroalkylations, 28 30, 28f
gem-difluorination of carbonyl compounds,
10 12, 11f, 12f, 13f
reagents for, 2 3, 3f
trifluoromethoxylations, 31 35, 33f
trifluoromethylthiolation, 31, 32f
Nucleophilic trifluoromethoxide anion, 35f
O
Ofloxacin, 142 144, 143f
Olah’s reagent, 2, 53 54
Olaparib (Lynparza), 172, 173f
Organoarsenicals, 141
Organofluorine compounds in high-energy
materials, 313 321
N,N-difluoramines (NF2 compounds), 314 318
pentafluorosulfanyl (SF5) compounds, 318 321,
319f, 320f
Organofluorine liquid crystal materials, 313, 314f
fluorinated dendrimer-based liquid crystals,
313, 315f
Organometallic approach, 128
Index
Organotransition metal catalysis, 105
Ag(I)-catalyzed decarboxylative fluorination,
123, 124f
Ag(II)-catalyzed oxidative ring-opening
fluorination of cyclic amines, 121 123,
122f, 123f
Au(I)-catalyzed hydrofluorination of alkenes
and alkynes, 114 115, 114f, 115f, 116f, 117f
Cu(I)-catalyzed fluoroalkylation of aryl halides,
126 127, 128f
Cu(I)-mediated dediazoniative
difluoromethylation, 124, 125f
fluoroalkylation of arylboronic acids and esters,
125 126
copper-mediated trifluoromethylation, 125,
125f
Cu(I)-catalyzed trifluoromethylation of
arylboronate esters, 126, 126f
Pd(0)-catalyzed difluoroalkylation of
arylboronic acids, 126, 127f
Ni-catalyzed fluoroalkylation of aromatics,
116 121
aryl difluoromethylation, 118 121, 120f, 121f
fluoroalkylation of arylsilanes, 116 117, 118f,
119f
Ni-catalyzed trifluoromethylthiolation, 127 128
Pd-catalyzed fluorination of aryl halides and
triflates, 105, 106f
Pd(II)-catalyzed (amino)trifluoromethoxylation,
129 130, 130f
transition metal catalyzed C H fluorination,
106 113
aryl fluorination, 106 108, 107f
benzylic fluorination, 108 111
fluoroalkylation of hydrazones, 111 113
Orkambi, 139 140
O-trifluoromethylation, synthetic methods for,
61 62, 62f, 63f
Oxidative radiofluorination of Ar Ni(II)
complexes, 251f
Oxygent, 281, 283f
P
Paclitaxel (Taxol), 173 174, 175f
Palbociclib, 172
339
PAMAM [poly(amidoamine)] dendrimers, 313,
316f
Pantoprazole, 104
Parallel artificial membrane permeability for BBB
(PAMPA-BBB) assay, 137
Parkinson’s disease, 104, 140, 218 219, 261
Paroxetine, 202 204, 203f
PARP inhibitors, 172, 173f
Pd-catalyzed electrophilic aromatic C H
fluorination, 107f
Pd-catalyzed fluorination of aryl halides and
triflates, 105, 106f
Pd-catalyzed radiofluorinations, 248, 249f, 250f
Pd(II)-catalyzed (amino)trifluoromethoxylation,
129 130, 130f
Pd(II)-catalyzed benzylic fluorination, 108 111,
110f
Pd(II)-catalyzed enantioselective benzylic C H
fluorination 2-alkylbenzaldehydes,
108 109
Pd(0)-catalyzed difluoroalkylation of arylboronic
acids, 126, 127f
Pd(0)-catalyzed ipso-fluorination of aryl
bromides/triflates, 105
Pd(0)-catalyzed Suzuki reactions, 126
Penicillins, 141, 145
Pentafluoroethylation of aryl halides, 128f
Pentafluoroethylation of aryl iodides, 126 127
Pentafluorosulfanyl (SF5) compounds, 280,
318 321, 319f, 320f
Perfluorinated hydrocarbon-based nanomaterials,
280
Perfluorinated nanoparticles, 284
Perfluoroalkylated surfactants, 280 281
Perfluoroalkyl-derived surfactants, 282f
Perfluoroalkylsulfonyl chloride, 81f
Perfluorocarbon-based nanoparticles, 284
Perfluorocarbon nanomaterials, 282 285
Perfluorooctanesulfonic acid (PFOS), 281, 285,
286f
Perfluorooctanoic acid (PFOA), 281, 285, 286f
Perfluorooctyl bromide, 283f
Perfluorotributylamine forms spherical
nanoparticles, 284
Petrov reagent, 2 3
340
Index
Pfizer’s neurokinin-receptor antagonist, 14 15
Pharmaceutical applications of organofluorine
compounds
anti-Alzheimer pharmaceuticals, 152 163, 154f
BACE-1 inhibitors, 153 159, 155f, 156f
γ-secretase inhibitors and modulators,
159 163
antibacterial pharmaceuticals, 141 146
erythromycin, 141 142, 142f
fluoroquinolone, 142 145, 143f
flurithromycin, 141 142, 142f
tetracyclines, 145 146, 146f
anticancer pharmaceuticals, 167 185
abemaciclib, 172, 173f
BRAF and mitogen-activated protein kinase
kinase enzyme inhibitors, 183 185
cobimetinib, 171 172, 172f
dacomitinib, 167 169, 168f
enasidenib, 178 181, 180f
fulvestrant, 177 178, 178f
lorlatinib, 169 171, 171f
nonsteroidal antiandrogens, 181 183
PARP inhibitors, 172, 173f
taxoid anticancer agents, 173 177
antidepressant, 202 204
antidiabetic pharmaceuticals, 146 152
canagliflozin, 151 152, 151f
carmegliptin, 150 151, 150f
sitagliptin, 146 149, 147f, 148f
anti-HIV pharmaceuticals, 163 165, 164f
bictegravir, 163 165, 164f
doravirine, 165, 166f
antiinflammatory pharmaceuticals
celecoxib, 200, 200f, 201f
corticosteroids, 200 202, 202f, 203f
nonsteroidal antiinflammatory agents, 199
antimalarial pharmaceuticals, 165 167
mefloquine, 166 167, 168f
tafenoquine, 165 166, 167f
antiviral pharmaceuticals, 185 195
antiplatelet drugs, 189 190
glecaprevir, 190 194, 192f
ledipasvir, 189 190
letermovir, 194 195, 195f
pibrentasvir, 190 194, 192f
sofosbuvir, 187 188, 188f, 189f
tecovirimat, 185 187, 185f
voxilaprevir, 194, 194f
blood brain barrier (BBB) permeability,
136 137, 138f
fluorinated pharmaceuticals for cardiovascular
diseases, 195 198
ezetimibe, 196, 197f
nebivolol, 196 197, 197f
statin drugs, 195 196, 196f
metabolic stability and bioavailability, 137 140
π π stacking interactions, 140 141, 142f
PhenoFluor [1,3-bis(2,6-diisoproylphenyl)-2,2difluoro-4-imidazoline], 2 4
PhenoFluorMix, 241
Phenols, 4, 4f
Phosphazene superbase (P4-tBu), 23, 24f
Photodynamic therapy (PDT), 280, 282 283, 283f
Photoredox catalysis, 55f, 77 78, 79f, 94, 111
Photoredox-catalyzed fluoroalkylation of
dehydroalanine, 54
Photoredox-catalyzed S-fluoroalkylation and
arylation, 94 95, 95f
Phthalimido-Au(I) complex, 115
Phthalimido esters of carboxylic acids, 78 79
π-conjugated benzodithiophene quinoxaline
copolymers, 296, 297f
π-conjugated polymers, 289 293, 291f, 292f, 294f
Pibrentasvir, 190 194, 192f, 193f
Piperidines, 121
π π stacking interactions, 140 141, 142f
in polyfluoroaromatics, 289, 290f
Pitavastatin (Livalo), 195
Poly(chlorotrifluoroethylene) (PCTFE), 286
Poly(chlorotrifluoroethylene-co-ethylene), 286
Poly(ether sulfone) ionomer, 305, 305f, 306f
Polyfluorinated compounds, 2
Polyfluoroaromatics, 289
Poly(fluoroaryl thioethers), synthesis of, 301f
Polyfluoroaryl thiophene copolymers, 300f
Poly(imide)-based ionomers, 307f
Poly(imide) copolymer with pendant
perfluoroalkylsulfonic acid moieties,
305 306
Poly(ionic liquids), 300 303, 302f
Index
Polymer electrolytes, 300 303, 301f, 302f, 303f,
304f
gel polymer electrolytes, 303
poly(ionic liquid) electrolytes, 302f
poly(VDF-co-MAFTEG) gel polymer electrolyte,
304f
Polynorbornene polymer, 289
Poly(tetrafluoroethylene) (PTFE), 280, 286 287,
288f
Poly(tetrafluoroethylene-co-ethylene), 286
Poly(VDF-co-MAFTEG) gel polymer electrolyte,
304f
Poly(vinyl fluoride), 286
Poly(vinylidene fluoride) (PVDF), 280, 286 289,
288f, 301f, 306, 307f
Positron emission tomography (PET) tracers
in Alzheimer’s disease, 260 265
2-(4-Aminoaryl)quinoline-based 18F-labeled
positron emission tomography tracers
(THK series), 263 265, 264f, 265f
flortaucipir-18F, 261 263, 262f, 263f
tropomyosin receptor kinase, 265, 266f
in cancer diagnosis, 266 273
cyclic RGDYK dimer-derived positron
emission tomography tracers, 267 273
[18F]-(R)-lorlatinib, 266 267, 267f
Sharpless click reactions for, 227 234, 228f,
229f
18
F-octreotate PET tracers for tumor imaging,
230, 231f, 232f
protein and oligonucleotide triazole, 229,
230f
Staudinger ligation reactions for, 234 237
strain-promoted click chemistry, 231 234,
233f, 235f
Staudinger ligation reactions for, 234 237, 236f,
237f
alkyl azides with 18F-labeled triarylphosphine
esters, 238f
18
F-labeled GABAA receptor antagonist, 237f
18
F-labeled peptide analogs, synthesis of,
237f
traceless Staudinger ligation reaction, 236f
Pravastatin (Pravachol), 195
Primaquine, 165 166, 167f
341
Procymidone, 106 108
Protein and oligonucleotide triazole, 229, 230f
Pyrazole, 320f, 321
2-pyridinesulfonyl fluoride (PyFluor), 2 3, 5f, 6,
7f, 225, 226f
Pyriprole, 68
Pyrroles, 121
Q
Quinine, 166 167
Quinoline-based drugs, 165
Quinolone, 142 145
Quinuclidine, 136
R
Radical fluoroalkylation of enolates, 96 97, 96f,
97f
Radiofluorination
via aromatic nucleophilic substitution,
237 244, 239f
[18F]fluoro-(1)-biotin, 238 239, 239f
γ-Aminobutyric acid transporter positron
emission tomography tracers, 240 241
L-3,4-Dihydroxy-6-[18F]fluorophenylalanine
(6-[18F]L-DOPA), 240, 240f
phenolic compounds, radiofluorination of,
241 244, 242f, 243f, 244f
via diaryliodonium salts, 252 257, 253f, 254f
Cu(I)-catalyzed radiofluorination, 254, 255f
iodonium ylides, radiofluorination, 255 257,
256f, 257f
synthetic methods for, 222 227, 224f
Radiofluorination of enolsilanes and arylstannes,
45f
Raltegravir, 163 165, 164f
Rasagiline, 108, 245
Ribavirin, 190 192
Ribociclib, 172
Rifluzole, 33
Riluzole, 61
Riociguat, 198, 199f
Rivastigmine, 153, 154f
RNFX, synthesis of, 316, 317f
Rofecoxib, 162, 199 200
Roflumilast, 75 77, 104, 200f
342
Index
Rosuvastatin (Crestor), 104, 104f, 135 136, 135f,
195, 196f
Rucaparib (Rubraca), 172, 173f, 174f
Ru(II)-catalyzed amino-fluoroalkylation, 81 82,
83f
Ru(II)-catalyzed redox reactions, 97f
Ru(II)-mediated solid-phase synthesis (SPSS),
244f
Ruppert Prakash reagent, 13 18, 14f, 28 29,
77 78
enantioselective trifluoromethylation, 14 15,
15f, 16f
trifluoromethylation of imines, 18
trifluoromethyl ketones, synthesis of, 16 18,
17f
S
Safinamide (Xadago), 104, 104f, 140, 141f
Sandmeyer-type of dediazoniative
difluoromethylation of arylamines, 124,
125f
SCF3-containing pharmaceuticals and veterinary
medicines, 61f
S-(difluoromethyl)diarylsulfonium
tetrafluoroborate, 57 58
Selectfluor (1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis
(tetrafluoroborate)), 43 46, 45f, 46f, 47f,
48 49, 52f, 54, 108, 121 123, 129 130,
130f, 225 226, 266 267
Selective serotonin reuptake inhibitors (SSRIs),
202 204, 203f
Self-condensing vinyl copolymerization, 308 310
Semagacestat, 159
S-(fluoromethyl)diarylsulfonium tetrafluoroborate,
57 58
Shen’s reagent, 63
Silylenol ethers, 50 51, 66 67, 69f
Simvastatin (Zocor), 195 196
Sitagliptin (Januvia), 75 77, 137 139, 139f,
146 149, 147f, 148f
GLP-1, 146 148
structure of, 147f
synthesis of, 148 149, 149f
X-ray crystal structure, 148, 148f
Sodium glucose cotransporter 2 (SGLT-2)
inhibitors, 151 152, 151f
Sodium triflinate, fluoroalkylation using, 82 94
aromatic trifluoromethylation, 84 86, 85f
azido-fluoroalkylation of alkenes, 88 90, 89f,
90f, 91f
functional group transformations, 84f
hydro-trifluoromethylation of alkenes, 86
trifluoromethylation of arylboronic acids,
86 88, 88f, 89f
trifluoromethylation of proteins, 93 94, 93f, 94f
Sofosbuvir, 187 188, 188f, 189f, 190 192, 194
Sonidegib, 33, 61
Sparfloxacin, 142 144
S-perfluoroalkylation, 94
Spleen tyrosine kinase (SYK) inhibitor, 52, 53f
Squamous- and basal-cell skin cancers, 159
Statins, 135 136, 135f, 195 196, 196f
Staudinger ligation reactions for positron
emission tomography tracers, 234 237,
236f, 237f
alkyl azides with 18F-labeled triarylphosphine
esters, 238f
18
F-labeled GABAA receptor antagonist, 237f
18
F-labeled peptide analogs, synthesis of, 237f
traceless Staudinger ligation reaction, 236f
Stereoselective electrophilic fluorination of
β-diketone, 52f
Stille-coupling condensation polymerization,
293 294
Strain-promoted alkyne azide cycloaddition
(SPAAC), 231
Strain-promoted click chemistry, 231 234, 233f,
235f
Streptomycin, 141
S-trifluoromethylated cysteine, 31, 32f
S-trifluoromethylation, 94
Sulfa drugs, 141
Sulfonamide reagent, 65 66
Sulfuryl fluoride (SO2F2), 6, 7f, 12, 12f
Suzuki Miyaura reaction, 190
T
Tafenoquine (Krintafel), 165 166, 167f
Tafluprost, 104
Index
TAK-637, 140 141, 142f
Talazoparib (Talzenna), 171, 171f
Tarenflurbil, 161 162, 162f
Taxoid anticancer agents, 173 177
drug delivery through aptamer, drug
conjugates, 177, 177f
paclitaxel (Taxol), 173 174, 175f
tumor-targeted drug delivery of the fluorinated
taxoids, 174 176, 176f
Tebufenpyrad, 12 13
Tecovirimat, 185 187, 185f
structure of, 185f
synthesis of, 186 187, 186f
Tenofovir alafenamide fumarate, 163, 164f
Tenofovir disoproxil fumarate, 165
Testosterone, 4
Tetracaine, 26 27
Tetracyclines, 145 146, 146f
Tetraethylammonium bicarbonate, 255 257
3,3,7,7-Tetrakis(difluoramino)octahydro-1,5dinitro-1,5-diazocine (HNFX), 314 315,
317f
Tetrakis(dimethylamino)ethylene (TDAE), 28 30
Tetrakis(dimethylamino)ethylene (TDAE)mediated nucleophilic fluoroalkylation
method, 28 30, 28f
gem-(difluoromethyl)thioethers, synthesis of,
30, 30f, 31f
TMSCF3 reagent, 28 29
trifluoromethylation of acyl chlorides, 29, 29f
Tetralones, 52f
Tetramethylammonium fluoride (TBAF), 6, 7f, 12,
15, 17 18
Tetrazole, 320f, 321
Tezacaftor, 139 140, 140f
Thrope Ingold effect, 129
Ticagrelor (Brillinta), 198, 198f
Tiflorex (anorectic), 44, 61
Togni’s reagents, 23 25, 25f, 44, 55 57, 61,
77 78, 80 81, 113
Cu(I)-catalyzed α-trifluoromethylation of
hydrazones, 114f
Cu(I)-catalyzed asymmetric aminotrifluoromethylation reactions, 81f
electrophilic trifluoromethylations, 58f
343
Fe(II)-catalyzed vicinal azidotrifluoromethylation of alkenes, 82f
structures of, 56f, 77f
Toltrazuril, 44, 61
Tolvaptan, 118 121
Transition metal-mediated radiofluorination,
245 252
Au(III) catalysis for [18F]trifluoromethyl
compounds synthesis, 248, 251f
Cu(I)-catalyzed radiofluorinations, 252
Mn(III)-catalyzed radiofluorinations, 245 247,
245f, 246f, 247f
Ni(II)-catalyzed radiofluorinations, 249 251
Pd-catalyzed radiofluorinations, 248, 249f, 250f
Triamcinolone (Kenalog), 201
Triflumuron, 33, 61
Trifluoroacetaldehyde hydrate, 19
Trifluoroethanol (TFE), 86
Trifluoromethanol, 285
Trifluoromethoxylations, 31 35, 33f, 35f
flucarbazone, 33
flurprimidol, 33
of glycosyl halides, 63f
indoxacarb, 33
rifluzole, 33
sonidegib, 33
triflumuron, 33
trifluoromethyl benzenesulfonate mediated
vicinal (bromo) trifluoromethoxylation, 33,
34f
trifluoromethyl benzoate mediated
trifluoromethoxylation, 34 35, 35f
Trifluoromethyl anion, 21, 22f, 23 25, 23f
Trifluoromethylation, 2, 12 30, 44
of acyl chlorides, 29, 29f
of arylboronic acids, 86 88, 88f, 89f
borazine-mediated gem-difluroalkylation,
23 25, 26f
borazine-mediated trifluoromethylation, 23 25,
25f
diaryldisulfides, 30
fluoroacetone hydrates for nucleophilic
fluoroalkylations, 18 19, 19f
fluoroform (CHF3), 19 25, 20f, 22f, 23f, 24f
of hydrazones, 113
344
Index
Trifluoromethylation (Continued)
of imines, 18
N-trifluoromethylation of amines, 26 28, 27f
of proteins, 93 94, 93f, 94f
Ruppert Prakash reagent for, 13 18, 14f
Trifluoromethyl benzenesulfonate (TFMS), 33 35,
34f
Trifluoromethyl benzoate, 34 35, 35f
Trifluoromethyl ketones, synthesis of, 16 18, 17f
Trifluoromethyl phenylsulfonate (TFMS), 34f
Trifluoromethyl radicals, 82f
Trifluoromethylthiolation, 31, 32f
of carbonyl compounds, amines, alkynes and
arylboronic acids, 64f
diethylaminosulfur trifluoride mediated
trifluoromethylthiolation of silylenol ethers
and β-naphthols, 66 67, 69f
difluoromethylthiolation, 68 70, 69f, 70f
reagents for, 63 65, 63f
asymmetric trifluoromethylthiolation, 64 65,
65f
Billard’s reagents, 65 66, 66f
Munavalli’s reagent, 64, 64f, 68 70
trifluoromethylthiolating reagents,
commercially available, 63, 63f
Trifluoromethyltrimethylsilane (CF3TMS), 3,
13 14, 17 18, 17f, 20f, 23 25, 25f
Trimethylsilyl azide (TMSN3), 81 82
1,3,5-trinitroperhydro-1,3,5-triazine (RDX),
314 316, 317f
2,4,6-trinitrotoluene (TNT), 314 315, 317f
Tris(dimethylamino) sulfonium
difluorotrimethylsilicate (TASF), 13 14
Tropomyosin receptor kinase, 265, 266f
Type 2 diabetes, 146 148, 151 152, 195 196
U
Umemoto’s reagents, 44, 55 56, 61, 77 78,
81 82, 227
electrophilic trifluoromethylations, 57f
structures of, 56f, 77f
V
Vancomycin, 144
Velpatasvir (Vosevi), 194
Vemurafenib, 171 172, 172f
Verubecestat, structure of, 156f
Vicinal (bromo)trifluoromethoxylation, 33, 34f
Vitamin E, 105
Vorapaxar (Zontivity), 197 198, 198f
Voxilaprevir, 75 77, 194, 194f
W
Weinreb amides, 17 18, 17f
X
Xenon difluoride (XeF2), 43 44, 61
XtalFluor reagents, 8f
XtalFluor-E [(diethylamino)difluorosulfinium
tetrafluorobrate], 2 4, 6 8, 10
XtalFluor-M (morpholinodifluorosulfinium
tetrafluoroborate), 2 4, 6 8, 10