Pd‐Catalyzed Direct Access to 2‐Substituted (Aza)benzo[ <i>b</i> ]furans via Cascade Reactions Under “On‐Water” Conditions

The widespread occurrence of benzofuran frameworks in biologically active compounds has prompted the search for more efficient and sustainable synthetic methods to facilitate their preparation and reduce environmental impact. Here, we report a very efficient “on‐water” Pd‐catalyzed heteroannulation that rapidly constructs diverse 2‐aryl, 2‐alkenyl, and 2‐alkyl benzo[ b ]furans, plus furo[3,2‐ b ]pyridines, from simple o‐iodophenols or 2‐iodo‐3‐hydroxypyridines and alkynes. This protocol requires only very small amounts of Pd(OAc) 2 (0.005–0.05 mol%) along with inexpensive diphenylphosphine oxide. This ligand‐enabled, copper‐free protocol, promoted by Cs 2 CO 3 , transforms acyl‐masked o‐iodoaryl esters directly into benzofurans through a cascade hydrolysis–cyclization process. In this one‐pot transformation, benzofuran formation and in situ deprotection occur concurrently, eliminating the need for prior phenol protection and enabling orthogonal core modifications. In addition, the study features a greener synthetic pathway to Stemofuran A, products with palladium levels compatible with direct medicinal applications, and a mechanistic rationale supported by kinetic studies, poisoning tests, TEM analysis, and UPLC–ESI data.