Pd(II)-NHC (NHC = N-Heterocyclic Carbene)-Catalyzed Alkylation of Primary Amides by Site-Selective N─C(O) Activation

Although over the past decade, there have been tremendous advances in amide bond cross-coupling, one of the major remaining challenges is selective alkylation of ubiquitous primary amides. Herein, a highly efficient method for Pd(II)-NHC (NHC = N-heterocyclic carbene)-catalyzed alkylation of primary amides using alkyl organozinc reagents is reported. The method is distinguished by the use of practical, bench-stable Pd(II)-NHC precatalysts, where the sterically-hindered and readily accessible IPr^* is found to be privileged for facilitating this highly challenging alkylation. All substrates used are common primary amides that are ubiquitous through all facets of chemical science. Comparative studies, application to the synthesis of pharmaceutical intermediates, scope of diverse acyl precursors and one-pot activation/cross-coupling are described. Considering the importance of primary amides in all fields of chemistry and the practical access to Pd(II)-NHC complexes, this C(O)─N alkylation approach offers a broadly applicable avenue for amide bond interconversion pathways.