Internally Reuse Waste: Catalytic Asymmetric One-Pot Strecker Reaction of Fluoroalkyl Ketones, Anilines and TMSCN by Sequential Catalysis

We report a highly enantioselective one-pot facile synthesis of fluorinated C-alpha-tetrasubstituted amino nitriles from alpha-fluoroalkyl alpha-aryl ketones, anilines, and TMSCN through a sequential p-TsOH catalyzed ketimine formation and chiral bifunctional tertiary amine mediated asymmetric Strecker reaction. This one-pot approach has two important advantages. First, it greatly improves the overall yield of the synthesis of chiral C-alpha-tetrasubstituted fluorinated aminonitriles from ketones, because the purification of alpha-fluorinated ketimines by column chromatography suffers from great yield loss. Second, it represents the first example of asymmetric tandem reactions that can simultaneously reuse the by-product and catalyst from the upstream step as a promoter and an additive to improve the reactivity and enantioselectivity of the subsequent catalytic enantioselective reaction, respectively. It could utilize the by-product H2O generated in-situ from the ketimine formation step to activate TMSCN to form HCN, and concurrently reuse the remaining p-TsOH acid as an additive to improve enantioselectivity.