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 α,α-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 α,α-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
α-bromo-α,α-difluoroacetamide with a focus on compounds
of potential biological relevance.