Stereoselective Nucleophilic Di‐ and Monofluoro(sulfoximidoyl)Methylation of C═C Bonds: Remote Neighboring Group Participation Enables Facile Access to Chiral γ‐Fluorinated Amines

Abstract

Abstract There remains an ongoing challenge to develop facile methods for the preparation of chiral γ,γ‐difluorinated amines, which are commonly considered a privileged motif in bioactive compounds. In this context, we report a straightforward protocol for the stereoselective nucleophilic difluoro(sulfoximidoyl)methylation of C═C bonds (considered to be more challenging than the reported C═O bonds), which exhibits high stereoselectivity and broad substrate scope. The key features of this chemistry include 1) stereoselective addition of the difluoro(sulfoximidoyl)methyl anion to C═C bonds, although it was considered to be highly unfavorable from the view of hard–soft acid–base (HSAB) theory; 2) intriguing neighboring group participation of the oxygen from the nitro group that was found to play a crucial role in controlling the stereoselectivity and efficiency of the transformation and was supported by mechanistic experiments and DFT calculations. This method has been applied to the late‐stage modification of several complex molecules and the preparation of enantioenriched bioactive γ‐fluorinated amines, such as a phytopathogenic fungi inhibitor, TRPC6 and CDK11 inhibitors, and even monofluorinated lorcaserin, which further demonstrated the significance and potential of this approach.