Theoretical Study on an Excited-State Copper-Catalyzed [4 + 1] Cyclization Reaction for the Construction of α,β-Unsaturated-γ-Lactams via an Oxidative Radical-Polar Crossover Mechanism

The reaction mechanism of the excited-state copper-catalyzed cascade synthesis of α,β-unsaturated-γ-lactams from aroyl chlorides, acrylamides, and <i>n</i>-hexanol has been systematically investigated using density functional theory (DFT) calculations. The reaction consists of four elementary steps: initiation of aroyl radical formation from aroyl chlorides by the excited-state Cu-Complex; subsequent radical relay between the aroyl radical and acrylamides leading to C-C bond formation; coupling of the C-N bond through the activation of N-H bond/coordination site migration facilitated by a Cu-Complex resulting in the formation of a five-membered ring scaffold; and then the functionalization of the γ-C of lactam to introduce alkoxy or hydride groups is achieved through electrophilic substitution. The single-carbon atom insertion is realized by the radical relay and copper-catalyzed radical polar cross-coupling strategy. The findings presented herein provide a detailed and well-supported reaction mechanism for the cascade reaction leading to α,β-unsaturated-γ-lactam synthesis.