The Bifunctional Silyl Reagent Me₂(CH₂Cl)SiCF₃ Enables Highly Enantioselective Ketone Trifluoromethylation and Related Tandem Processes

We report the development of bifunctional trifluoromethylsilyl reagents for selective trifluoromethylation. The newly developed reagent, Me₂(CH₂Cl)SiCF₃, allows highly enantioselective trifluoromethylations of ketones with broad scope. Notably, by taking advantage of the chloromethyl group, a tandem synthesis of chiral trifluoromethylated oxasilacyclopentanes is developed, paving way to α-CF₃ tertiary alcohols with vicinal tertiary or quaternary stereocenters. Theoretical studies revealed the important role of nonclassical C−H⋅⋅⋅F−C interactions in stabilizing the transition state, and that the presence of the chlorine atom enhances such interactions for better enantiofacial control.