Development and Mechanistic Investigations of a Base-Free Suzuki-Miyaura Cross-Coupling of α,α-Difluoroacetamides via C-N Bond Cleavage

This study describes the development and understanding of a palladium-catalyzed cross-coupling of fluoroacetamides with boronic acids, under base-free conditions, to selectively give valuable alpha,alpha-difluoroketone derivatives. Detailed mechanistic studies were conducted to assess the feasibility of each elementary step, that is, C(acyl)-N bond oxidative addition, followed by base free transmetallation and reductive elimination. These investigations allowed the structural characterization of palladium(II)-fluoroacyl intermediates derived from C-N bond oxidative addition of an amide electrophile. They also revealed the high reactivity of these intermediates for transmetallation with boronic acids without exogenous base. The mechanistic studies also provided a platform to design a practical catalytic protocol for the synthesis of a diversity of alpha,alpha-difluoroketones, including CF2H-ketones. Finally, the synthetic potential of this fluoroacylation methodology is highlighted in sequential, orthogonal C-Br and C-N bond functionalization of an alpha-bromo-alpha,alpha-difluoroacetamide with a focus on compounds of potential biological relevance.