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 a mechanochemical compression, application of 0.5 to 1.0 equivalent of piezoelectric materials enabled the solid-state formation of the key CF3 radical intermediate under mild and sustainable conditions. Catalytic amount of piezoelectric material proved to be just as efficient. The protocol showed a general efficiency and tolerance to multiple functional groups accessing trifluoromethylated enamides with up to 88% yield with a full stereoselectivity. The reaction conditions were applied to acrylamide substrates enabling trifluoromethylated oxindole derivatives synthesis through a radical cascade cyclization initiated from CF3 radical addition on electron-poor C-C double bonds. Radical quenching experiments highlighted a radical mechanism, and control experiments showcased the crucial need of piezoelectric materials/ball-milling system.