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 degrees, 2 degrees, and 1 degrees 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 n(N) -> pi(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.

Automated summary

We report the Pd-catalyzed Suzuki-Miyaura cross-coupling of aliphatic amides. The selective N-C(O) cleavage to form C-C bonds from aliphatic amides has been a major challenge in Pd catalysis. This study addresses this longstanding problem by using N,N-pym/Boc amides as reagents for cross-coupling and steric tuning of Pd(II)-NHC catalysts. The method is effective for various degrees of aliphatic amide derivatives and the catalyst system is user-friendly. Mechanistic studies support the twist of amide bond and external n(N) -> pi(C=O/Ar)* delocalization as a unified enabling feature of N,N-pym/Boc amides in selective N-C(O) bond activation. This method provides a rare example of Pd-NHC-catalyzed cross-coupling of aliphatic acyl amide electrophiles.