Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts

Abstract

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential C–F bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C–F bond scission. A chemoselectivity-controllable two-stage process enables sequential generation of difluoro- and monofluoroalkyl radicals, which are selectively functionalized with different radical traps to afford diverse fluorinated products. The reaction mechanism and the origin of chemoselectivity were established by experimental and computational approaches.

C-F bond activation under transition-metal-free conditions

“…Very recently, Wang's group [63] published their research on the sequential C-F functionalizations of trifluoroacetamides and acetates (Scheme 21). This breakthrough provides a straightforward manner for the selective formation of mono-and difluoroalkyl from readily accessible trifluoroacetic acid derivatives.…”

“…In the presence of thiocarboxylic acids or thiols, the CF 2 cations underwent sulfanylation. They provided the products, which could be transformed to fluorodihydrothiophene (without H + ) or difluorinated tetrahydrothiophenes (with H + ) under alkaline conditions via 5-endotrig cyclization.In an inspiring contribution, Wang and co-workers[63] recently reported the chemoselectivity-controllable C-F functionalizations via sequential generation of difluoro-and monofluoroalkyl radicals (vide supra). The coupling of trifluoroacetamides with alkenes could be step by step (stage A or stage B) toward the synthesize of difluorinated or monofluorinated molecules (Scheme 42).…”

Selective C–F Bond Allylation of Trifluoromethylalkenes

“…[3] Nevertheless, the fact that -CF 2 -unit finds a wide occurrence in pharmaceutically and agrochemically relevant molecules [4] evokes considerable interest from the synthetic community regarding selective C À F bond functionalization of CF 3 group. [5] In this area, the past several years have witnessed significant progress with respect to aryl-CF 3 [6][7][8][9][10] and carbonyl-CF 3 , [11] however, the alkenyl counterparts remain comparatively far less explored. Due to the competing interference of highly activated alkenyl moiety, the vast majority of reported protocols only led to g-selective defluorinative functionalization for gem-difluoroalkene synthesis.…”

Selective C–F Bond Allylation of Trifluoromethylalkenes

“…[3] Nevertheless, the fact that -CF 2 -unit finds a wide occurrence in pharmaceutically and agrochemically relevant molecules [4] evokes considerable interest from the synthetic community regarding selective C À F bond functionalization of CF 3 group. [5] In this area, the past several years have witnessed significant progress with respect to aryl-CF 3 [6][7][8][9][10] and carbonyl-CF 3 , [11] however, the alkenyl counterparts remain comparatively far less explored. Due to the competing interference of highly activated alkenyl moiety, the vast majority of reported protocols only led to g-selective defluorinative functionalization for gem-difluoroalkene synthesis.…”