Highly ortho-selective trifluoromethylthiolation reactions using a ligand exchange strategy

The trifluoromethylthio group (-SCF₃) is a highly privileged modifier for drug molecules. Direct C-H trifluoromethylthiolation reactions are highly valuable synthetic tools for the late-stage modification of drug candidates, which have so far been underexplored. We report a palladium-catalyzed ortho-selective mono-trifluoromethylthiolation reaction of arenes. The reaction proceeds through a key ligand exchange pathway using readily available silver trifluoromethylthiolate (AgSCF₃). Acetic acid was found to be crucial to minimize oxidative dimerization of the starting materials and to facilitate the "SCF₃^-" transfer. We expect this strategy to have broad applications in C-H functionalization reactions using a stand-alone oxidant and various anions.