Mechanistic Organometallic Studies Drive Reagent Selection and Catalyst Design for the Palladium-Catalyzed Trifluoromethylthiolation of Aryl Electrophiles

Abstract

This article describes a detailed investigation of the palladium-catalyzed coupling of aryl (pseudo)halides (ArX) with MSCF₃ to form aryl trifluoromethylthioethers (ArSCF₃). Mechanistic organometallic studies are used to interrogate two key elementary steps of the catalytic cycle: (1) transmetalation of Pd^II(Ar)(X) complexes with MSCF₃ and (2) Ar–SCF₃ bond-forming reductive elimination. These studies reveal that tetramethylammonium trifluoromethylthiolate, NMe₄SCF₃, exhibits a combination of fast kinetics and high chemoselectivity for transmetalation. Furthermore, Ar–SCF₃ reductive elimination is fastest and highest yielding with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), di-tert-butylphosphinoferrocene (D^tBuPF), and tri-tert-butylphosphine (P^tBu₃) as ligands. These results are leveraged to develop a palladium-catalyzed method for coupling aryl iodides, -bromides, and -triflates with NMe₄SCF₃ using catalytic Pd(dba)₂ and D^tBuPF. This transformation exhibits a broad substrate scope and offers several advantages over state-of-the-art Pd-catalyzed methods for aryl–SCF₃ coupling.