Selective Synthesis of [6-6-7]/[6-6-6] Core Polycyclic Heterocycles Via Lewis Acid-Mediated Cascade Annulation of 1,6-Enynols with Aminonitriles

Polycyclic heterocycles are prevalent in medicines, functional materials and natural products, making their synthesis a significant focus in modern organic chemistry. Herein, we present a Lewis acid-mediated cascade annulation of 1,6-enynols with o-aminobenzonitriles for the chemoselective synthesis of oxepino[3,4,5-de][1,6]naphthyridine and chromeno[2,3,4-de][1,6]naphthyridine derivatives. This reaction design enables selective control over the carbon-heteroatom and carbon-carbon bond formation in an efficient, atom-economical manner, allowing the one-step synthesis of rare [6-6-7] and [6-6-6] core polycyclic heterocycles containing three heteroatoms. Density functional theory (DFT) calculations and control experiments reveal that the reaction’s high selectivity is achieved by modulating the reactivity of electron-rich alkenyl groups in the enynols, which selectively directs the intramolecular dehydroaromatization and cyclization processes.