Photoredox‐Catalyzed Radical Relay for C─N Cleavage and Ring Expansion: Accessing Medium‐Sized Lactams From Unstrained Cyclic Amines

Abstract The synthesis of medium‐ring lactams constitutes a formidable yet pivotal frontier in modern chemical research. Persistent endeavors in this field are essential for overcoming the prevailing obstacles, particularly in the realm of ring expansion strategies for unstrained cyclic amines. In this study, we introduce a groundbreaking photoredox‐catalyzed radical relay process that accomplishes direct C─N bond cleavage in unstrained cyclic amines, thereby enabling the efficient construction of highly functionalized 9–11‐membered lactams adorned with a Z‐olefin moiety. Remarkably, our methodology exhibits exceptional compatibility with a broad spectrum of acids, encompassing α‐amino acids, peptides, and carboxylic acids, thus facilitating the ring expansion of readily accessible propiolamides. Control experiments and computational investigations provide compelling evidence that the ring expansion mechanism is initiated via a reductive radical‐polar‐crossover‐induced C─N bond cleavage, offering profound insights into the underlying reaction dynamics. This advancement not only broadens the synthetic methodology for medium‐ring lactam construction but also paves the way for future explorations in complex molecule synthesis and drug discovery.