Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction

An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1-2 mol % of Vaska's complex (IrCl(CO)(PPh(3))(2)), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF(2)R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N-aryl- and N-heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.