Nucleophilic trifluoromethylation with CF3H/LiHMDS: probing the nucleophilic reactivity of LiCF3 species

Abstract

The nucleophilic trifluoromethylation involving trifluoromethyllithium (LiCF₃) species has been an open question since Haszeldine attempted to prepare LiCF₃ in 1949. Indeed, LiCF₃ has been used for electrophilic difluoromethylene transfer processes (via elimination of fluoride ions) since 2010. Herein, we demonstrated that by using a polar solvent such as dimethylformamide (DMF) or hexamethylphosphoramide (HMPA) as the lithium chelator, the in situ deprotonation of fluoroform (HCF₃) with lithium hexamethyldisilazide (LiHMDS) could generate a tamed LiCF₃ species that is sufficiently persistent to undergo nucleophilic trifluoromethylation reaction. The nucleophilic reactivity of LiCF₃ species was probed with several electrophiles, including arylsulfonyl fluorides, diaryl ketones, and silyl chlorides. The synthetic utility of this method is demonstrated with the efficient synthesis of highly valuable triflones that are otherwise difficult to synthesize from HCF₃ using potassium or sodium bases. This work not only showcases a new protocol for the utilization of fluoroform (an industrial waste with high global warming potential) as the trifluoromethylation reagent, but also provides intriguing insights into the harnessing of nucleophilic reactivity of the transient LiCF₃ species.