Abstract

The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF₃ group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon–CF₃ bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF₃ anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF₃ cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants.

In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF₃SiMe₃ in the presence of oxidants. We have focused most of our efforts on constructing carbon–CF₃ bonds via direct trifluoromethylation of various C–H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C–H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C–H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or -catalyzed cross-coupling reactions with CF₃SiMe₃. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P–CF₃ bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C–H bonds, and P–H bonds as novel nucleophiles in transition-metal-mediated or -catalyzed cross-coupling reactions with CF₃SiMe₃, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon–SCF₃ bonds by using CF₃SiMe₃ and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF₃- and CF₃S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF₃ and SCF₃ moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields.