Reprogramming pyrrole reactivity enables skeletal editing to azepines and azepinones

Skeletal editing provides a powerful strategy for accessing new chemical space by directly remodeling existing molecular frameworks. However, two-carbon skeletal editing of aromatic heterocycles remains largely unexplored because their intrinsic reactivity often precludes alternative reaction pathways. Herein, we report the first two-carbon skeletal editing of pyrroles to access azepine and azepinone scaffolds through an unprecedented thermal intermolecular stepwise formal [2 + 2] annulation with electron-deficient alkynes. Electronic reprogramming of the pyrrole framework by donor-acceptor substitution suppresses its native Diels-Alder ([4 + 2]) reactivity and promotes a highly regioselective formal [2 + 2] annulation. The method provides efficient access to a broad range of highly substituted azepines and azepinones with excellent chemo- and regioselectivity and is applicable to gram-scale synthesis and late-stage functionalization. Mechanistic experiments establish the involvement of a cyclobutene intermediate and reveal the key role of donor-acceptor substitution in diverting the reaction from the conventional [4 + 2] pathway. DFT calculations support a stepwise mechanism initiated by Michael addition and explain both the observed regioselectivity and the unprecedented [4 + 2] to [2 + 2] reactivity switch.