Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C-C Bond Cleavage (vol 3, pg 2233, 2021)

Medium-sized nitrogen heterocycles are prevalent motifs in many kinds of bioactive molecules and natural products. Owing to the unfavorable enthalpic and entropic barriers during the transition states, access to medium-sized rings is challenging. Herein, a general and practical electrochemical ring-expansion protocol has been developed from com-mercially available benzocyclic ketones and amides. In this regard, a series of highly functionalized eight-to eleven-membered lactams could be successfully accessed in high yields and efficiencies. Notably, this transformation features excellent tolerance toward different electronic substituents of benzocyclic ke-tone and aniline moieties. Furthermore, satisfactory yields for gram-scale and direct one-pot synthesis, as well as the esterification of inert benzylic C-H bond, are additional advantages. Mechanistic studies indi-cate that this electrochemical dehydrogenative ring expansion proceeds through a unique remote amidyl radical migration-induced C-C bond cleavage and subsequent single-electron oxidation.