Distinguishing Competing Mechanistic Manifolds for C(acyl)–N Functionalization by a Ni/N-Heterocyclic Carbene Catalyst System

[Image: see text] Carboxylic acid derivatives are appealing alternatives to organohalides as cross-coupling electrophiles for fine chemical synthesis due to their prevalence in biomass and bioactive small molecules as well as their ease of preparation and handling. Within this family, carboxamides comprise a versatile electrophile class for nickel-catalyzed coupling with carbon and heteroatom nucleophiles. However, even state-of-the-art C(acyl)–N functionalization and cross-coupling reactions typically require high catalyst loadings and specific substitution patterns. These challenges have proven difficult to overcome, in large part due to limited experimental mechanistic insight. In this work, we describe a detailed mechanistic case study of acylative coupling reactions catalyzed by the commonly employed Ni/SIPr catalyst system (SIPr = 1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidine). Stoichiometric organometallic studies, in situ spectroscopic measurements, and crossover experiments demonstrate the accessibility of Ni(0), Ni(I), and Ni(II) resting states. Although in situ precatalyst activation limits reaction efficiency, the low concentrations of active, SIPr-supported Ni(0) select for electrophile-first (closed-shell) over competing nucleophile-first (open-shell) mechanistic manifolds. We anticipate that the experimental insights into the nature and controlling features of these distinct pathways will accelerate rational improvements to cross-coupling methodologies involving pervasive carboxamide substrate motifs.