Difluoromethylation of Carboxylic Acids via the Addition of Difluorinated Phosphorus Ylide to Acyl Chlorides

Abstract

A one-step protocol for the difluoromethylation of carboxylic acids is described. The reaction involves the interaction of intermediate acyl chlorides with in situ generated difluorinated phosphorus ylide PhP═CF. Aromatic acids can be selectively transformed within one step either to bis-difluoromethylated alcohols or to difluorinated ketones depending on the particular reaction conditions. For bulky α-branched carboxylic acids, only ketones are produced.

Methods for the Synthesis of α,α‐Difluoroketones

“…Perhaps more synthetically useful is Dilman's addition of Me 3 SiCF 2 Br to acid chlorides mediated by triphenylphosphine and DMPU (Scheme ) . DMPU promotes the decomposition of Me 3 SiCF 2 Br to difluorocarbene, which reacts with PPh 3 to make a difluoroylide 63 .…”

Trapping of Difluorocarbene by Frustrated Lewis Pairs

“…[9] Due to facile decomposition of 1 back to the phosphine and carbene, this ylide has not yet been characterized spectroscopically, but it can be successfully coupled with carbonyl compounds and other electrophiles. [10][11][12] Herein we report on the interception of difluorocarbene with a phosphine/borane FLP to generate zwitterionic phosphonium borate species. This process is expected to proceed via primary nucleophilic attack of the Lewis basic phosphorus at difluorocarbene followed by rapid trapping of the intermediate ylide nucleophile by Lewis acidic boron.…”

“…The reaction likely proceeds via heterolytic cleavage of the CÀB bond with the formation of the difluorinated ylide followed by interaction with the aldehyde. [15] Basic hydrolysis of 7 gave expected difluoro-methyl alcohol ArCH(OH)CHF 2 via cleavage of the C,P bond, which is typical for gem-difluorinated phosphonium salts [12] (see Supporting Information for details).…”

A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF2Br

“…TMSCF 2 Br, a difluorocarbene precursor developed by us,‐ is now commercially available and is one of the most versatile difluorocarbene reagents . It has been applied in the difluoromethylation of (thio)phenols, alcohols, thiols, and amines, as well as the cyclopropanation or cyclopropenation of alkenes and alkynes, among other applications –. In continuation of our effort to develop TMSCF 2 Br as a versatile and robust difluorocarbene reagent, we report herein our recent success in the difluoromethylation of carbon acids with TMSCF 2 Br (Scheme c).…”