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

The deprotonative functionalization of alpha,alpha-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 alpha,alpha-difluoro-beta-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 alpha,alpha-difluoro-beta-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.

Automated summary

The deprotonative functionalization of alpha,alpha-difluoromethyl ketones is achieved by using a catalytic organosuperbase and a silane additive, leading to the generation of difluoroenolates that can be trapped with aldehydes to produce alpha,alpha-difluoro-beta-hydroxy ketones. This strategy allows for the direct deprotonation of the difluoromethyl unit and is tolerant of various functional groups. The diastereoselective version of the reaction was also explored, with high diastereomeric ratios. Several transformations demonstrate the synthetic potential of these alpha,alpha-difluoro-beta-hydroxy ketones. Additionally, the method can be extended for the use of other electrophiles and nucleophiles, resulting in a diversity of difluoromethylene compounds.