Silver-Catalyzed Difluorocarbene Activation Enables Multicomponent Synthesis of δ,γ-Unsaturated β-Hydroxynitriles.

Herein, we report an efficient and general one-pot multicomponent strategy, innovatively developed for the construction of δ,γ-unsaturated β-hydroxy nitrile scaffolds. Using readily available aldehydes and ketones as starting materials and TMSCFBr as a difluorocarbene precursor, the transformation proceeds via tandem Aldol condensation, a difluorocarbene electrophilic reaction, and hydrolysis. Mechanistic studies revealed that the difluorocarbene activates the oxygen atom of the α,β-unsaturated carbonyl group through electrophilic orientation, significantly enhancing the electrophilicity of the carbonyl carbon, thereby driving the reaction to proceed with high selectivity via a 1,2-addition pathway. This method not only provides a new synthetic route to δ,γ-unsaturated β-hydroxy nitrile compounds but also offers a reference approach for designing difluorocarbene-mediated multicomponent reactions.