Direct Deprotonative Functionalization of α,α-Difluoromethyl Ketones using a Catalytic Organosuperbase

Abstract

The deprotonative functionalization of α,α-difluoromethyl ketones is described herein. Using a catalytic organosuperbase and a silane additive, the corresponding difluoroenolate could be generated and trapped with aldehydes to deliver various α,α-difluoro-β-hydroxy ketones in high yields. This new strategy tolerates numerous functional groups and represents the access to the difluoroenolate by direct deprotonation of the difluoromethyl unit. The diastereoselective version of the reaction was also investigated with d.r. up to 93 : 7. Several transformations were performed to demonstrate the synthetic potential of these α,α-difluoro-β-hydroxy ketones. In addition, this method has been extended to the use of other electrophiles such as imines and chalcogen derivatives, and a difluoromethyl sulfoxide as nucleophile, thus leading to a diversity of difluoromethylene compounds.

Keywords: Aldol Reaction; Deprotonation; Difluoromethyl; Difluoromethylene; Fluorine.