Solvent‐Driven Mechanistic Insights into Cu‐Catalyzed Asymmetric C─H Amidation via Nitrene Transfer

Abstract Copper‐catalyzed asymmetric C─H amidation via nitrene transfer (NT) is a powerful strategy for synthesizing nitrogen heterocycles and amines that are found as key structural components in many pharmaceuticals and agrochemicals. While asymmetric Cu‐catalyzed aziridinations are well‐known, enantioselective methods for the intramolecular insertion of a nitrene into a C(sp 3 )─H bond are surprisingly underdeveloped for reasons that are poorly understood. In this study, we investigate the role of solvent, particularly acetonitrile (MeCN) and dichloromethane (DCM), and the ligand in tuning the reactivity and enantioselectivity of a series of copper‐bisoxazoline (Cu‐BOX) catalysts for asymmetric benzylic C─H bond amidation. Mechanistic studies reveal that while MeCN promotes high yields, it compromises enantioselectivity through the proposed formation of a monoligated Cu species. In contrast, DCM enhances enantioselectivity through the desired bis‐ligated Cu species, but the potential for product inhibition to induce a second, less enantioselective catalytic cycle should be considered. Cyclic voltammetry and kinetic analyses support the likelihood of distinct catalytic mechanisms in MeCN and DCM, highlighting the role solvent plays in determining the equilibrium between active Cu species. These results provide valuable insights into the future design of improved catalysts for achieving high levels of enantioselectivity in Cu‐catalyzed C─H functionalizations.