Skeletal Metalation of Lactams through Carbonyl-to-Nickel Exchange Logic

Classical metalation reactions such as the metal-halogen exchange are powerful tools to construct chemical bonds between two molecules. An analogous metal-carbon exchange strategy would provide a new entry into the direct structural remodeling of core carbon frameworks, yet its development has remained highly challenging. Here we introduce a skeletal metalation strategy that enables lactams, a highly prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained CN bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel exchange process. The underlying principles of this unique reactivity was rationalized by organometallic and computational studies. The skeletal metalation was further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the synthetic potential of metal-carbon exchange logic for skeletal modifications of complex molecules.