Direct Deprotonative Functionalization of α, α‐Difluoromethyl Ketones using a Catalytic Organosuperbase. (31st January 2023)

• Record Type: Journal Article
• Authors: Messara, Amélia; Panossian, Armen; Mikami, Koichi; Hanquet, Gilles; Leroux, Frédéric R.
• Is Part Of: Angewandte Chemie. Volume 135:Number 10(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-31
• Subjects: Aldol Reaction -- Deprotonation -- Difluoromethyl -- Difluoromethylene -- Fluorine; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202215899
• Languages: English
• ISSNs: 0044-8249

Abstract

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. Abstract : The deprotonation of α, α‐difluoromethyl ketones is underinvestigated due to the instability of the generated carbanion that can evolve into a fluorocarbene. A method for the deprotonative functionalization of these compounds is described herein under an organocatalytic system using various electrophiles, and is also applied to a related α, α‐difluoromethyl sulfoxide. This strategy gives access to highly valuable difluoromethylene scaffolds.