Ball-milling and piezoelectric materials enabled radical trifluoromethylation of enamides and acrylamides†

Abstract

A mechanochemical radical direct C(sp²)–H trifluoromethylation of enamide derivatives was developed using Togni II reagent. Under mechanochemical compression, the use of 0.5 to 1.0 equivalents of piezoelectric materials enabled the solid-state formation of the key CF₃ radical intermediate in mild and sustainable conditions. The use of 0.5 equivalents of piezoelectric materials proved to be just as efficient. The protocol showed a general efficiency and tolerance to multiple functional groups, accessing trifluoromethylated enamides with yields of up to 88% and full stereoselectivity. The reaction conditions were applied to acrylamide substrates, enabling synthesis of trifluoromethylated oxindole derivatives through a radical cascade cyclization initiated from addition of CF₃ radical onto electron-poor C–C double bonds. Radical quenching experiments highlighted a radical mechanism, and control experiments showcased the crucial need to use of piezoelectric materials/ball-milling system.