Iron(III)-Catalyzed Arylation of Spiro-Epoxyoxindoles with Phenols/Naphthols towards the Synthesis of Spirocyclic Oxindoles.

An efficient and highly regioselective iron(III)-catalyzed Friedel-Crafts-type arylation of spiro-epoxyoxindoles with phenols was developed for rapid access to 3-(3-indolyl)-oxindole-3-methanols, which could be further elaborated into benzofuranyl-spirooxindoles under Mitsunobu conditions. When spiro-epoxyoxindoles were reacted with naphthols in the presence of a catalytic amount of FeCl3 ⋅6 H2 O in dichloromethane, they underwent a tandem Friedel-Crafts-type arylation and O-cyclization to yield novel naphthofuranyl-spirooxindoles in excellent yields. This method is applied to enable the efficient and highly regioselective synthesis of a small-molecule inhibitor of the sodium channel Nav 1.7 (±)-XEN402, which is currently in a phase IIb clinical trial for the treatment of pain.