Ball-Milling Assisted Iron-Catalyzed Difluoromethylation Toward the Synthesis of Valuable Oxindoles.

Abstract

SEM analyses revealed that the ball-milling and piezoelectric-mediated radical difluoromethylation might be, in fact, catalyzed by iron contamination of BaTiO₃ due to abrasion of the stainless steel milling assembly (jar and balls). A ball-milling mediated, Fe-catalyzed radical difluoromethylation is subsequently developed for the synthesis of valuable difluoromethylated oxindoles. Under a mechanochemical compression, the use of readily accessible PhI(OCOCF₂H)₂ in the presence of 25 mol% of Fe(OAc)₂ enabled the unprecedented solid-state formation of the CF₂H radical, prone to add onto an acrylamide substrate to initiate a radical cascade process affording the desired difluormethylated oxindoles. The practical protocol demonstrates broad substrate scope and functional group tolerance, including N-substitution and substitution on the CC double bond or the aromatic ring of the acrylamide substrates. Furthermore, the protocol is extended to the introduction of CF₂Me, CF₂Bn, and CF₂Ph motifs, delivering the corresponding products in moderate to good yields. Radical trapping experiments supported a radical-based mechanism, while control experiments confirmed the essential role of both the Fe-catalyst and mechanochemical compression.