Modular and Diverse Synthesis of Oxaheterocycles via Pd-Catalyzed Migratory 1,n-Cycloannulation of Alkenes

Here, we report a general and modular strategy for the diverse synthesis of oxaheterocycles via a Pd-catalyzed migratory 1,n-cycloannulation reaction (MCAR, n > 2) of alkenes. Employing readily availa-ble (homo)allylphenols and 2-iodophenols as start-ing materials, this method enables the efficient con-struction of a broad range of 5- to 8-membered oxa-heterocycles with good functional group tolerance. The key to achieving high reactivity and controlled ring-closure is the kinetically favored formation of a para-quinone methide (p-QM) intermediate rather than an ortho-quinone methide (o-QM) intermedi-ate during the migration process, which facilitates selective single-site cyclization at the less steric hindrance site and suppresses competing pathways. The synthetic utility of this strategy is further demonstrated by the efficient preparation of several bioactive oxaheterocyclic compounds including cy-totoxic flavan and MRGPRX4 inhibitor, highlighting its potential in both synthetic and medicinal chem-istry.