Ball-Milling-Promoted Copper-Catalyzed Solid-State Radical C–H Difluoroalkylation Reactions

Abstract

A mechanochemical strategy for promoting copper-catalyzed solid-state radical C–H difluoroalkylation reactions has been devised. Compared to traditional solution-based methods, this mechanoredox approach offers enhanced ease of handling, greater cleanliness, and improved sustainability for the synthesis of difluoroalkylated indoles, which constitute crucial structural motifs in contemporary drug discovery. The underlying reaction mechanism is investigated through meticulous step-by-step control experiments that highlighted the substantial influence of the mechanochemical conditions. The versatility of this protocol is demonstrated by its applications to complex natural products and drug derivatives.