The Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds

Amines and carboxylic acids are abundant building blocks for synthesis that classically are united to form an amide bond. To access new pockets of chemical space we are interested in the development of complementary amine–acid coupling reactions. 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(sp3)–C(sp2) bonds following pre-activation 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. High-throughput experimentation was essential to the development of the reaction, and to the discovery of performance-enhancing additives such as cyclic imides, RuCl3 and GaCl3. Preliminary mechanistic investigations suggest that RuCl3 supports the decarbonylation event, increasing reaction selectivity. Numerous amine or acid containing pharmaceuticals are successfully diversified under the optimized conditions.