Difluoromethylation and trifluoromethylation reagents derived from tetrafluoroethane β-sultone: Synthesis, reactivity and applications

Abstract

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.