Nickel-Catalyzed de novo Synthesis of C─N Atropisomeric Biaryls via Dual Chelation-Assisted Aza-Michael Addition.

Abstract

The asymmetric construction of C─N bonds using readily available C─H (arene) and N─H (amine) reagents constitutes a modular and flexible synthetic strategy. Nevertheless, de novo synthesis of axially chiral C─N scaffolds via direct C─H/N─H coupling remains a formidable challenge, and it has been previously restricted to organocatalysis using soft (more nucleophilic) NH indoles. Reported herein is a nickel-catalyzed oxidative coupling strategy that leverages the oxygen- or nitrogen-chelating group in the NH nucleophiles. The coupling system is applicable to three distinct classes of NH reagents, permitting asymmetric synthesis of diverse C─N atropisomers. Mechanistic studies reveal that the C─N formation is facilitated by a chelating group in the NH reagent through formation of a favored 5- and 7-membered ring-fused nickelacyclic transition state. This coupling system has addressed a series of challenges in intermolecular C─H/N─H cross-coupling by overcoming limited applicability of NH nucleophiles and the reliance on prefunctionalized electrophiles such as aryl halides and hypervalent iodines.