Trifluoromethylation Reactions Research Articles

A Universal Procedure for the [18F]Trifluoromethylation of Aryl Iodides and Aryl Boronic Acids with Highly Improved Specific Activity

Herein, we describe a valuable method for the introduction of the [(18)F]CF3 group into arenes with highly improved specific activity by the reaction of [(18)F]trifluoromethane with aryl iodides or aryl boronic acids. This [(18)F]trifluoromethylation reaction is the first to be described in which the [(18)F]CF3 products are generated in actual trace amounts and can therefore effectively be used as PET tracers. The method shows broad scope with respect to possible aryl iodide and aryl boronic acid substrates, as well as good to excellent conversion. In particular, the [(18)F]trifluoromethylation of boronic acids was found to outperform [(18)F]trifluoromethylation reactions of halogenated aryl precursors with regard to conversion, reaction conditions, and kinetics.

Long‐Lived Trifluoromethanide Anion: A Key Intermediate in Nucleophilic Trifluoromethylations

AbstractThe trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. However, for more than six decades, the trifluoromethanide anion was widely believed to exist only as a short‐lived transient species in the condensed phase. It has now been prepared in bulk for the first time in THF solution. The trifluoromethanide anion with the [K(18‐crown‐6)]+ cation was unequivocally characterized by low‐temperature 19F and 13C NMR spectroscopy. Its intermediacy in nucleophilic trifluoromethylation reactions was directly evident by its reaction chemistry with various electrophilic substrates. Variable‐temperature NMR spectroscopy, along with quantum mechanical calculations, support the persistence of the trifluoromethanide anion.

Long-lived trifluoromethanide anion: a key intermediate in nucleophilic trifluoromethylations.

The trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. However, for more than six decades, the trifluoromethanide anion was widely believed to exist only as a short-lived transient species in the condensed phase. It has now been prepared in bulk for the first time in THF solution. The trifluoromethanide anion with the [K(18-crown-6)](+) cation was unequivocally characterized by low-temperature (19)F and (13)C NMR spectroscopy. Its intermediacy in nucleophilic trifluoromethylation reactions was directly evident by its reaction chemistry with various electrophilic substrates. Variable-temperature NMR spectroscopy, along with quantum mechanical calculations, support the persistence of the trifluoromethanide anion.

ChemInform Abstract: Recent Progress in Asymmetric Fluorination and Trifluoromethylation Reactions

AbstractReview: 230 refs.

Application of Langlois’ Reagent in Trifluoromethylation Reactions

AbstractThe incorporation of a trifluoromethyl (CF3) group into organic compounds is of great importance in pharmaceutical, agricultural, and materials science. Trifluoromethylation based on radical intermediates, as a valuable alternative transformation using the inexpensive and stable solid sodium trifluoromethanesulfinate (CF3SO2Na; Langlois’ reagent), has attracted much attention and has become a hot research field. This review examines recent advances in radical trifluoromethylation reactions with CF3SO2Na as CF3 source.magnified image

Sandmeyer Trifluoromethylation

A range of benzotrifluorides are conveniently accessible in high yields from widely available (hetero)aromatic amines and the inexpensive trifluoromethylating agent TMSCF₃ through a copper-mediated Sandmeyer trifluoromethylation reaction. Two practical procedures are presented. In the first, the diazonium salts are preformed in an extra reaction step, in the second approach the diazotization and the trifluoromethylation are combined into a one-pot procedure.

Computational study of singlet and triplet sulfonylnitrenes insertion into the C―C or C―H bonds of ethylene

Formation of N-sulfonylaziridines, N-ethylidenesulfonamides, N-vinylsulfonamides and 4,5-dihydro-1,2,3-oxathiazole 2-oxides by the reaction of singlet and triplet trifluoromethyl-, methyl- and tosylnitrenes with ethylene is studied computationally at the B3LYP/6-311++G(d,p) level of theory in both gas phase and in solution. Singlet sulfonylnitrenes react with ethylene via [1 + 2]-cycloaddition exothermically to give N-sulfonylaziridines. Triplet sulfonylnitrenes are formed from the singlet ones by the intersystem crossing with the energy barrier not exceeding 2.5 kcal/mol and react in a stepwise fashion by C-addition or H-abstraction. The C-addition gives rise to the formation of N-sulfonylaziridines or N-ethylidenesulfonamides depending on the S―N―Csp3―Csp2 dihedral angle, with the barrier to rotation about the N―Csp3 bond not exceeding 2.5 kcal/mol. The H-abstraction results in N-vinylsulfonamides. Transformation of N-sulfonylaziridines to N-ethylidenesulfonamides requires to overcome the barrier of 57–60 kcal/mol, N-ethylidenesulfonamides to 4,5-dihydro-1,2,3-oxathiazole 2-oxides—74–80 kcal/mol and N-vinylsulfonamides to N-ethylidenesulfonamides—about 64 kcal/mol. The use of the polarizable continuum model does not lead to a change of the course of the reaction of trifluoromethanesulfonylnitrene with ethylene and only slightly affects the relative energies of the products, intermediates and transition states. Copyright © 2014 John Wiley & Sons, Ltd.

ChemInform Abstract: Oxidative Trifluoromethylation and Trifluoromethylthiolation Reactions Using (Trifluoromethyl)trimethylsilane as a Nucleophilic CF3 Source

AbstractReview: 88 refs.

ChemInform Abstract: Controlled Trifluoromethylation Reactions of Alkynes Through Visible‐Light Photoredox Catalysis.

AbstractThree different CF3‐substituted compounds ‐ trifluoromethylated alkenyl iodides, alkenes, and alkynes ‐ can be selectively generated from terminal alkynes and CF3I by appropriate choice of catalyst, base, and solvent.

ChemInform Abstract: Nucleophilic Non‐metal‐assisted Trifluoromethylation and Perfluoroalkylation Reactions of Organic Substrates

AbstractReview: 38 refs.

Self-induced stereoselective in situ trifluoromethylation: preparation of spiro[indoline-3,3'-quinoline] via palladium-catalyzed cascade reaction.

An efficient method to prepare 1'H-spiro[indoline-3,3'-quinoline]-2',4'-diones and their trifluoromethylated products was developed via a palladium-catalyzed Sonogashira coupling/Wacker-type oxypalladation/cyclization cascade reaction. The amount of water in the reaction system played an important role in the in situ trifluoromethylation reaction, and the trifluoromethylation exhibited excellent molecular self-induced stereoselectivity.

Recent Advances in Radical Trifluoromethylation Reactions

In recent years,research on trifluoromethylation reactions have been developed rapidly. Since the special chemical and physical properties of the trifluoromethyl group,it plays an increasingly important role in the fields of medicine,pesticides and materials. As the result,a new recognition of radical trifluoromethylation has been achieved along with the development of organofluorine chemistry. This article delivered an overview of the recent progress of radical trifluoromethylation from the perspective of various radical trifluoromethylative precursors as well as reaction mechanisms.

Catalytic Cycle for Palladium-Catalyzed Decarbonylative Trifluoromethylation using Trifluoroacetic Esters as the CF3 Source

This paper demonstrates a catalytic cycle for Pd-catalyzed decarbonylative trifluoromethylation using trifluoroacetic esters as CF3 sources. The proposed cycle consists of four elementary steps: (1) oxidative addition of a trifluoroacetic ester to Pd0, (2) CO deinsertion from the resulting trifluoroacyl PdII complex, (3) transmetalation of a zinc aryl to PdII, and (4) aryl–CF3 bond-forming reductive elimination. The use of RuPhos as the supporting ligand enables each of these steps to proceed under mild conditions (<100 °C). These studies set the stage for the development of catalytic arene trifluoromethylation and perfluoroalkylation reactions using inexpensive trifluoroacetic acid derived CF3 sources.

Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl)trimethylsilane as a nucleophilic CF3 source.

The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF3 group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon-CF3 bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF3 anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF3 cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants. In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF3SiMe3 in the presence of oxidants. We have focused most of our efforts on constructing carbon-CF3 bonds via direct trifluoromethylation of various C-H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C-H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C-H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or -catalyzed cross-coupling reactions with CF3SiMe3. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P-CF3 bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C-H bonds, and P-H bonds as novel nucleophiles in transition-metal-mediated or -catalyzed cross-coupling reactions with CF3SiMe3, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon-SCF3 bonds by using CF3SiMe3 and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF3- and CF3S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF3 and SCF3 moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields.

Recent Progress in Asymmetric Fluorination and Trifluoromethylation Reactions

All domains of society are impacted by fluorine chemistry. In particular, fluorine plays a key role in medicinal, pharmaceutical and agrochemical sciences in which the synthesis and evaluation of molecules featuring one or more fluorine atoms is nowadays routine in every new discovery and development program. Since the beginning of this century, enantiopure fluorinated molecules are at the forefront of innovation of the tremendous achievements in fluorine chemistry. This review introduces the reader to the recent progress in asymmetric installation of one fluorine and a trifluoromethyl group via nucleophilic, electrophilic and radical diastereo- and enantioselective reactions.

O‐Trifluoromethylation of N,N‐Disubstituted Hydroxylamines with Hypervalent Iodine Reagents

AbstractA mild trifluoromethylation reaction of N,N‐disubstituted hydroxylamines that is tolerant towards a variety of functional groups, including nitriles, alcohols, ketones, esters, amides, imides, and nitrogen heterocycles, is reported. The key feature of this reaction is the activation of the CF3 reagent with either trimethylsilyl triflate or LiClO4 and partial or full deprotonation of the substrate with tetramethylguanidine or lithium diisopropylamide. Products were obtained in up to 80 % yield. Preliminary mechanistic studies suggested that the reaction follows a radical pathway in which the deprotonated hydroxylamine and a Lewis or Brønsted acid activated CF3 reagent engages in a single‐electron‐transfer step to generate a pair of radicals that recombine to afford the desired product. The trifluoromethylation procedure was successfully used in the modification of secondary nitrogen groups of pharmaceutically relevant targets (Fluoxetine and Mefloquine), which afforded new derivatives containing a novel N‐trifluoromethoxy moiety.

Metal-catalyzed synthesis of heterocycles bearing a trifluoromethyl group

AbstractThe trifluoromethyl group has unique functional properties and is widely used not only in organic chemistry, but also in pharmaceutical and agrochemical science. Here we describe trifluoromethylation reactions of indoles and alkenes using Togni’s reagent. These reactions provide useful trifluoromethylated organic compounds, including heterocycles, with high efficiency.

Copper‐Catalyzed Trifluoromethylation of Internal Olefinic CH Bonds: Efficient Routes to Trifluoromethylated Tetrasubstituted Olefins and N‐Heterocycles

The functionalization of internal olefins has been a challenging task in organic synthesis. Efficient CuII-catalyzed trifluoromethylation of internal olefins, that is, α-oxoketene dithioacetals, has been achieved by using Cu(OH)2 as a catalyst and TMSCF3 as a trifluoromethylating reagent. The push-pull effect from the polarized olefin substrates facilitates the internal olefinic C-H trifluoromethylation. Cyclic and acyclic dithioalkyl α-oxoketene acetals were used as the substrates and various substituents were tolerated. The internal olefinic C-H bond cleavage was not involved in the rate-determining step, and a mechanism that involves radicals is proposed based on a TEMPO-quenching experiment of the trifluoromethylation reaction. Further derivatization of the resultant CF3 olefins led to multifunctionalized tetrasubstituted CF3 olefins and trifluoromethylated N-heterocycles.

Nucleophilic trifluoromethylation of carbonyl compounds and derivatives

This review highlights the main methods for the nucleophilic trifluoromethylation of aldehydes, ketones, esters, imines and their analogous compounds published in the literature in the last six years. The focus is on synthetically useful procedures and the work is organized according to the type of carbonyl compound subjected to the trifluoromethylation reaction.

Recent Advances in Copper-Promoted Trifluoromethylation Reactions

Abstract Drug molecules that contain trifluoromethyl group can effectively improve their lipophilicity, absorbability and metabolic stability. Thus, considerable attention has been paid to the introduce of trifluoromethyl group into organic molecules. Recently, transition metal-catalyzed trifluoromethylation has been well developed. The cheap and high activity copper catalyst has also been used to access a variety of trifluoromethylation reactions. In this review, we focus the conversion of a number of substrates including halogenated hydrocarbons, boron reagents, C—H compounds, amines and carboxylic acids into the corresponding trifluoromethyl-containing compounds.