Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

Difluoromethylated arenes are one of the privileged structural motifs that are important for fine tuning the biological properties of drug molecules. No general catalytic method exists for the formation of difluoromethylarenes. Previous methods for the preparation of difluoromethylarenes typically required harsh conditions, multiple steps or stoichiometric amount of catalysts. Here we report a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides under mild conditions. We develop the system by initial preparation of the putative intermediates in the dual-catalytic cycles, followed by studying the elemental steps to demonstrate the viability of the proposed cooperative catalytic cycle. The reaction is compatible with a variety of functional groups such as ester, amide, protected phenoxide, protected ketone, cyclopropyl, bromide and heteroaryl subunits such as pyrrole, benzothiazole, carbazole or pyridine.