Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp(3)–sp(2) Carbon–Carbon Bonds

[Image: see text] Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp(3))–C(sp(2)) bonds following preactivation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl(3), and GaCl(3). Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl(3) supports the decarbonylation event, thereby improving reaction selectivity.