Organofluorine Chemistry: Synthesis and Applications

Teachers

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 task-specific 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 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 FDA-approved 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 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 FDA-approved 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 ¹⁸F-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 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 oxygen-enriched 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 ever-increasing 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

Abstract

Nucleophilic fluorinations and fluoroalkylations are widely used for the synthesis of organofluorine compounds. Efficient nucleophilic deoxyfluorination of alcohols and gem-difluorination of carbonyl compounds can be achieved using the commercially available nucleophilic fluorination reagents, such as diethylaminosulfur trifluoride, Deoxo-Fluor, XtalFluor, and FluoLead. Fluoroalkylation reactions, including difluoromethylations and trifluoromethylations, are of unique importance in the design of pharmaceuticals. Enantioselective nucleophilic fluorinations and trifluoromethylations can be achieved using chiral auxiliaries or cinchonidine-based alkaloids as the chiral catalysts. Nucleophilic trifluoromethylations are also used in the efficient synthesis of the pharmaceutically significant trifluoromethoxylated and trifluoromethylthiolated compounds. This chapter outlines modern nucleophilic fluorinations and fluoroalkylation reactions that have broad scope in the design of pharmaceuticals and materials.

Keywords

Nucleophilic reactions; deoxyfluorination; gem-difluorination; enantioselective trifluoromethylation; fluoroalkylations; trifuoromethylations; trifluoromethylthiolation; trifluoromethoxylation; DAST; Deoxo-Fluor; PhenoFluor; PyFluor; gem-(difluoromethyl)thioethers

Chapter Outline

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 Ruppert–Prakash 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 benzenesulfonate–mediated vicinal (bromo)trifluoromethoxylation 33

1.8.2 Trifluoromethyl benzoate–mediated trifluoromethoxylation 34

References 35

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. ¹⁸F-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, ¹⁹F-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],⁵–⁷ XtalFluor-E [(diethylamino)difluorosulfinium tetrafluorobrate],⁸ XtalFluor-M (morpholinodifluorosulfinium tetrafluoroborate),⁸ FluoLead ((4-tert-butyl-2,6-dimethylphenyl)sulfur 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. 1–1).¹²,¹³

Figure 1–1 Selected commercially available reagents for the transformation of the carbonyl compounds to the gem-difluoromethyl and -methylene compounds.

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; Ruppert–Prakash 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. 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 reagent–mediated 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. 1–2).

Figure 1–2 PhenoFluor-mediated deoxyfluorination of phenols.

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. 1–3). PhenoFluor provides access to the late-stage fluorination of pharmaceuticals and is suitable for the preparation of ¹⁸F-labeled compounds for the PET.

Figure 1–3 PhenoFluor-mediated deoxyfluorination of alcohols.

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 1,8-diazabicyclo-[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 ¹⁸F-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. 1–4A).¹¹ The reaction proceeds through the intermediate formation of the 2-pyridylsulfonate ester (1), through SN2 reaction pathway, with the in situ generated DBU–HF providing the nucleophilic fluoride anion. Elimination reactions are minimized using the DBU or MTBD reagents, as compared to the other amine-based reagents.

Figure 1–4 Deoxyfluorination reactions mediated by PyFluor(A), and SulfoxFluor (B).

Among other related nucleophilic reagents for the deoxyfluorination, N-tosyl-p-chlorobenzene-sulfonimidoyl fluoride (SulfoxFluor) has dramatically high reactivity (10­–30 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. 1–4B).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. 1–5).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 [2′-methoxyphenyl-(N-2′-pyridinyl)-p-fluorobenzamide-ethylpiperazine], a serotonin 1A receptor ligand.

Figure 1–5 Deoxyfluorination of phenols using SO2F2 and Me4NF.

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.²⁴–²⁶ 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 BF3–Et2O. XtalFluor, in the presence of Et3N–3HF, transforms carboxylic acids into the corresponding acid fluorides in high yields (Fig. 1–6).²⁶

Figure 1–6 Deoxyfluorination of carboxylic acids using XtalFluor