Mechanism-Inspired Ligand Design for Efficient Copper-Catalyzed C–N Coupling of Aryl and Heteroaryl Chlorides

Cross-coupling reactions to form C-N bonds catalyzed by copper are becoming sustainable and cost-effective alternatives to those catalyzed by palladium. An array of ligand classes has been reported over the past two decades to create copper catalysts that couple aryl iodides and bromides. However, these systems typically require higher catalyst loadings than are required for palladium, and the couplings of aryl chlorides catalyzed by copper complexes require particularly high loadings, high temperatures, or both. We report a catalytic system designed to destabilize the bis-ligated copper(II) oxalamide complexes that are the major species in reactions of aryl bromides catalyzed by complexes of oxalamide ligands. A sterically hindered oxalamide ligand in combination with Cu(I) or Cu(II) leads to the coupling of aryl and heteroaryl chlorides with a set of primary amines, as well as aqueous ammonia, under mild conditions at low catalyst loadings (0.03-1 mol %) with turnover numbers up to 2300. Mechanistic studies reveal that increased steric bulk on the amide causes a monoligated copper species with a Cu(I) oxidation state to be the major copper complex in the reactions of aryl chlorides. Both Cu(I) and Cu(II) amine complexes containing this oxalamide have been isolated, structurally characterized, and observed in the catalytic systems by EPR and NMR spectroscopy. Initial kinetic studies indicate that oxidative addition to the amine complex is rate limiting, and the identity of the halide on the aryl halide (Cl vs Br) changes the oxidation state of the major copper species in solution.