Modular and diverse synthesis of oxaheterocycles via Pd-catalyzed migratory 1,n-cycloannulation of alkenes

Abstract

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 available (homo)allylphenols and 2-iodophenols as starting materials, this method enables the efficient construction of a broad range of 5- to 8-membered oxaheterocycles with good functional group tolerance. The key to achieving high reactivity and controlling ring-closure is the kinetically favored formation of a para-quinone methide (p-QM) intermediate rather than an ortho-quinone methide (o-QM) intermediate during the migration process, which facilitates selective single-site cyclization at the less sterically hindered site and suppresses competing pathways. The synthetic utility of this strategy is further demonstrated by the efficient preparation of several bioactive oxaheterocyclic compounds including a cytotoxic flavan and an MRGPRX4 inhibitor, highlighting its potential in both synthetic and medicinal chemistry.