Palladium-NHC (NHC = N‑heterocyclic Carbene)-Catalyzed Suzuki–Miyaura Cross-Coupling of Alkyl Amides

We
report the Pd-catalyzed Suzuki–Miyaura cross-coupling
of aliphatic amides. Although tremendous advances have been made in
the cross-coupling of aromatic amides, C–C
bond formation from aliphatic amides by selective
N–C­(O) cleavage has remained a major challenge. This longstanding
problem in Pd catalysis has been addressed herein by a combination
of (1) the discovery of N,N-pym/Boc amides as a class of readily accessible
amide-based reagents for cross-coupling and (2) steric tuning of well-defined
Pd­(II)-NHC catalysts for cross-coupling. The methodology is effective
for the cross-coupling of an array of 3°, 2°, and 1°
aliphatic amide derivatives. The catalyst system is user-friendly,
since the catalysts are readily available and are air- and bench-stable.
Mechanistic studies strongly support an amide bond twist and external
nN → π*CO/Ar delocalization
as a unified enabling feature of N,N-pym/Boc amides in selective N–C­(O)
bond activation. The method provides a rare example of Pd-NHC-catalyzed
cross-coupling of aliphatic acyl amide electrophiles.