Ball-Milling Assisted Iron-Catalyzed Difluoromethylation for the Synthesis of Difluoromethylated Oxindoles

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 was then developed for the synthesis of valuable difluoromethylated oxindoles. Under a mechanochemical compression, the use of readily accessible PhI(OCOCF2H) 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 demonstrated a 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 was 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 Fe-catalyst and mechanochemical compression.