This review summarizes the recent advances in the catalytic syntheses of CF3S-containing organic molecules using various nucleophilic or electrophilic trifluoromethylthiolating reagents. C–halogen and CH bonds in various molecules have been transformed to CSCF3 bonds by transition-metal-catalyzed reactions, such as cross-coupling of aryl halides. Enantioselective reactions controlled by chiral metal complexes or chiral organocatalysts have afforded many trifluoromethylthiolated chiral architectures, such as β-ketoesters and oxindoles. Very recently, visible-light-induced photoredox trifluoromethylthiolations have been developed, providing versatile CF3S-containing structures efficiently.The trifluoromethylthio group (CF3S) with high lipophilicity and strong electron-withdrawing properties plays an exceedingly important part in biological and medicinal chemistry. The review summarizes the recent developments in direct trifluoromethylthiolation using three catalytic methods, namely, transition-metal catalysis, chiral organocatalysis, and photocatalysis.Download high-res image (122KB)Download full-size image

Cu-promoted reactions of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) with dialkyl phosphonates produced dialkyl (2,2,2-trifluoroethyl)phosphonates efficiently under mild conditions by successively activating the two inert C–Cl bonds in HCFC-123. These reactions can be efficiently carried out on a >30 g scale with moderate to good yields.

•A hydrochlorofluorocarbon (HCFC) is used to synthesize 2,2,2-trifluoroethyl diynes.•The C–C bond formation is promoted by copper and ethanolamine.•Two examples of converting the diynes to heterocycles are demonstrated.Copper-mediated reaction of terminal 1,3-diynes with 1,1-dichloro-2,2,2-trifluoroethane (CF3CHCl2) using ethanolamine as ligand gave trifluoroethylated unsymmetrical 1,3-diynes in moderate to good yields. The reaction were carried out under mild conditions, and were easy to operate. Aryl groups with weak electron-withdrawing group or electron-donating group, and alkyl substitutents at terminal 1,3-diynes were tolerated. Synthesis of a trifluoroethylated conjugated triyne by using this method was demonstrated. Further transformation of the trifluoroethylated unsymmetrical 1,3-diyne to provide trifluoroethyl-substituted 1,2,3-triazole and isoxazole as application examples were successfully realized.

A mild, operationally simple, visible light-induced photoredox method for constructing novel trifluoromethylated quaternary carbon centers from trifluoromethylated tertiary bromides has been developed. Using this method, a wide range of alkenes were successfully bifunctionalized to γ-butyrolactams. As for electron-rich alkenes, reactions catalyzed by Ir(dF(CF3)ppy)2(dtbbpy)(PF6) were kinetic processes with high yields and short times. For styrenes, reactions catalyzed by Ir(ppy)2(dtbbpy)(PF6) were thermodynamic processes with moderate yields and prolonged reaction times. For aliphatic alkenes, the reactions were neither thermodynamic nor kinetic and fac-Ir(ppy)3 was used as catalyst. Thus, reactions were not as efficient as electron-rich alkenes. The atom-transfer radical addition reactions of trifluoromethylated tertiary bromides with alkynes were also achieved. The configuration of products we separated was E type only. Some of the products exhibited bactericidal activity.

The visible-light-induced photoredox difunctionalization reactions of styrenes with 1,1,1-trifluoro-2-iodoethane under an oxygen atmosphere in the presence of water give γ-trifluoromethyl alcohols. In this radical reaction, the oxygen atom in the product originates from molecular oxygen, and water is shown to be important to promote the reaction.

•This review covers compounds with a CF bond, CF2 or CF3.•Various organic compounds are synthesized through CF bond activation.•Aliphatic fluorides could be activated by Lewis acid, Brønsted superacids or hydrogen bonding.•The cleavage of CF bond could be mediated by transition-metal or rare earth metal.•Dehydrofluorination by a base or SN2′ displacement by a nucleophile could be a method for leaving of a fluoride.CF bond activation of aliphatic fluorides provides new methodologies for synthesis of new fluorinated building blocks as well as versatile non-fluorinated products. This review covers the recent CF bond cleavage examples and further transformation of compounds bearing with an aliphatic fluoride, difluoromethylene group or trifluoromethyl groups. The methods to activate a CF bond include activation by Lewis acid, Brønsted superacids and hydrogen bonding, and mediation by transition-metals and rare earth metals. Partial reduction of trifluoromethyl group through a single electron transfer (SET) process can provide the compounds with less fluorine. Bases are often used for the elimination of hydrofluoride. SN2′ displacement is also an important method for transformation of monofluorinated, difluorinated and trifluorinated olefins to various synthetically interesting molecules.

•Trifluoromethylated ketene aminoacetals were prepared.•Pd-catalyzed allylation was carried out.•Asymmetric reaction was researched.•Quaternary carbon centers were built.A new development in the palladium-catalyzed allylation reaction of trifluoromethylated ketene aminoacetals was reported. These nucleophilic reagents were prepared by adding aminoalcohols to methyl 3,3,3-trifluoro-2-trifluoromethylpropanoate. The asymmetric version of the allylation reaction was investigated using chiral oxazolidine-based starting materials or chiral palladium catalysts. Asymmetric allylic alkylation was carried out with up to 74% ee using a chiral catalyst. However, no improvement was observed using double stereodifferentiation. These results provided a novel access for trifluoromethylated all-carbon quaternary carbon centers.

•Hundreds of fluorinating reagents are derived from tetrafluoroethane β-sultone.•They are versatile difluoromethylation and/or trifluoromethylation reagents.•They have been widely used in design of drug candidates and synthesis of materials.•HCF2SO2R and FSO2CF2CO2H generate difluorocarbene under acidic conditions.•FSO2CF2CF2OCF2CO2Me/CuI can trifluoromethylate unactivated aryl chlorides.Tetrafluoroethane β-sultone (TFES) has hundreds of useful fluorinating derivatives as reagents. The reactions of TFES with nucleophiles provide a variety of interesting fluoroalkylsulfonic acids and their derivatives, as well as ω-halo-perfluoropentanesulfonyl fluorides. Fluorosulfonyldifluoroacetic acid derivatives such as FSO2CF2COOH, FSO2CF2COOMe, FSO2CF2COOTMS, HCF2SO2R (R = F, OH, OCF2H, OC6H5), ICF2SO2F, and RCF2OCF2CF2SO2F (R = CF2I, CO2Me, CO2Na) are versatile difluoromethylation and/or trifluoromethylation reagents. FSO2CF2COOH, FSO2CF2COOMe, FSO2CF2COOTMS, HCF2SO2R, and ICF2SO2F can effectively incorporate a CF2 group into OH, NH, SH, CC, and CC bonds. HCF2SO2R (R = OH, OCF2H, OC6F5) and FSO2CF2CO2H generate difluorocarbene under acidic conditions, which significantly expanded the scope of the carbene-based difluoromethylation reactions. FSO2CF2CO2Me, FSO2CF2I, and RCF2OCF2CF2SO2F (R = CF2I, CO2Me, CO2Na) are powerful trifluoromethylation reagents, with FSO2CF2CO2Me being world-renowned and widely used in the design of drug candidates and synthesis of novel functional materials. FSO2CF2CO2Me, FSO2CF2I, and RCF2OCF2CF2SO2F are generally produced by nucleophilic substitution, thermal decomposition, or single-electron transfer mechanism in trifluoromethylation reactions under mild conditions. FSO2CF2CF2OCF2CO2Me can successfully trifluoromethylate unactivated aryl chlorides with CuI, and FSO2CF2CF2OCF2CO2K/CuI can smoothly transform aryl halides at very low temperature. For more than half a century's development, the chemistry of TFES and its derivatives has been extensively studied. This review recounts the recent progress of TFES and reports on TFES-derived difluoromethylation and trifluoromethylation reagents. The syntheses and reactivities of these interesting reagents, as well as their applications in medicinal chemistry and materials science, are briefly summarized.

•Synthesis of α-trifluoromethyl ketones is reported.•Visible light photoredox trifluoromethylation of alkenes is performed.•An electrophilic trifluoromethylating reagent (Togni's reagent) was used.•The reaction involves a trifluoromethyl radical.α-Trifluoromethyl ketones are important fluorinated intermediates and products in chemical synthesis and medicinal development. Herein, visible light-catalyzed photoredox trifluoromethylation of 1-aryl-2-alkyl substituted alkenes using an electrophilic trifluoromethylating reagent to produce α-trifluoromethyl ketones is reported. Two possible pathways involving either a trifluoromethyl radical or a styrene radical cation are proposed and discussed.

Significant synthetic challenges remain for the asymmetric synthesis of tertiary α-fluoro ketones, which are potentially useful molecules for the development of drugs, agrochemicals, and functional materials. Herein, we describe the development of a method for the catalytic enantioselective synthesis of tertiary α-fluoro ketones via the Tsuji–Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched acyclic α-cabonyl tertiary fluorides can be produced with the aid of a palladium/phosphinooxazoline catalyst.

A method has been developed for the synthesis of α-trifluoromethyl ketones via the Cu-catalyzed trifluoromethylation of silyl enol ethers with an electrophilic trifluoromethylating agent, which produces a trifluoromethyl radical.

Allylic C–H alkylation of allylarenes with dimethyl 2-trifluoromethylmalonate was successfully developed. The reactions were carried out at room temperature in the presence of a catalytic amount of Pd(OAc)2/Ph3P and a stoichiometric amount of 2,6-dimethylbenzoquinone. The reactions avoided defluorination successfully, providing a new method to construct a CF3-containing all-carbon quaternary center.

CF3-containing esters smoothly reacted with electron-deficient alkenes in the presence of a phosphine (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) organocatalyst at room temperature in an aerobic atmosphere. These Michael reactions efficiently provided products with a CF3 quaternary carbon center.

The sulfinatodehalogenation reaction represents one of the most important methodologies to incorporate fluorine into organic molecules. Using inexpensive sulfur-containing reactants such as Na2S2O4 under mild conditions, per- and polyfluoroalkyl halides (RFX, X = Br, I, CCl3) can be transformed smoothly into the corresponding sulfinate salts. This method is also used for the perfluoroalkylation of alkenes, dienes, alkynes and aromatics. Notably, after 1998, the sulfinatodehalogenation of perfluoroalkyl chlorides (RFCl) has been realized by using dimethylsulfoxide (DMSO) as a solvent instead of CH3CN/H2O in the Na2S2O4/NaHCO3 initiation system. Perfluoroalkyl chlorides, ethyl chlorofluoroacetates and chlorodifluoroacetates, and even nonfluorinated compounds, such as ethyl chloro- or dichloroacetates and chloroform, were either converted into the corresponding sulfinate salts or alkylated alkenes, alkynes and aromatics (including porphyrins). The sulfinatodehalogenation reaction has remarkable advantages. With the increasing demands to utilize the unique properties of fluorine and fluorinated functional groups in medicinal, agricultural and material sciences, we believe that there will continue to be useful developments in sulfinatodehalogenation chemistry and it will be applied more widely in the future.

The Henry (nitroaldol) reaction of fluorinated nitro compounds with various aromatic aldehydes and a fluorinated aliphatic aldehyde to give β-fluoro-β-nitroalcohols which bearing a fluorinated quaternary carbon center was reported. The relative configuration of the major diastereoisomer of 2-fluoro-2-nitro-1-(4-nitrophenyl)-3-phenylpropanol (5bf) was determined by X-ray single crystal analysis.Graphical abstractHenry reaction of α-fluoro nitro compounds with various aldehydes gave fluorinated nitroalcohols in moderate to good yields.Highlights► An organocatalytic Henry reaction of fluoro nitro compounds was described. ► β-Fluoro-β-nitroalcohols bearing a fluorinated quaternary carbon center were obtained. ► The relative configurations of products were determined using X-ray and NMR analysis.

The sulfinatodehalogenation reaction represents one of the most important methodologies to incorporate fluorine into organic molecules. Using inexpensive sulfur-containing reactants such as Na2S2O4 under mild conditions, per- and polyfluoroalkyl halides (RFX, X = Br, I, CCl3) can be transformed smoothly into the corresponding sulfinate salts. This method is also used for the perfluoroalkylation of alkenes, dienes, alkynes and aromatics. Notably, after 1998, the sulfinatodehalogenation of perfluoroalkyl chlorides (RFCl) has been realized by using dimethylsulfoxide (DMSO) as a solvent instead of CH3CN/H2O in the Na2S2O4/NaHCO3 initiation system. Perfluoroalkyl chlorides, ethyl chlorofluoroacetates and chlorodifluoroacetates, and even nonfluorinated compounds, such as ethyl chloro- or dichloroacetates and chloroform, were either converted into the corresponding sulfinate salts or alkylated alkenes, alkynes and aromatics (including porphyrins). The sulfinatodehalogenation reaction has remarkable advantages. With the increasing demands to utilize the unique properties of fluorine and fluorinated functional groups in medicinal, agricultural and material sciences, we believe that there will continue to be useful developments in sulfinatodehalogenation chemistry and it will be applied more widely in the future.

Allylic C–H alkylation of allylarenes with dimethyl 2-trifluoromethylmalonate was successfully developed. The reactions were carried out at room temperature in the presence of a catalytic amount of Pd(OAc)2/Ph3P and a stoichiometric amount of 2,6-dimethylbenzoquinone. The reactions avoided defluorination successfully, providing a new method to construct a CF3-containing all-carbon quaternary center.