Borane-Catalyzed Chemo- and Regioselective Ring Opening of 2-Substituted Aziridines with Phenols for Direct Synthesis of β-Arylethylamines

Abstract

A metal-free chemo- and regioselective nucleophilic ring opening of 2-substituted aziridines with ortho-C(sp²) atom of phenols enables facile access to medicinally relevant β-arylethylamine derivatives. In this approach, phenols act as aryl nucleophiles that favor CC bond formation selectively at the ortho-C(sp²) position with the more substituted carbon of aziridines to generate branched, selective arylated products. Despite the significant advancement of transition-metal-catalyzed cross-coupling and nucleophilic ring opening of 2-substituted azirines, only linear arylated products are widely demonstrated. The first metal-free branched selective nucleophilic ring opening of 2-alkyl and 2-aryl aziridines with phenols is reported to address this challenge. Furthermore, the diversity of the substrate scope by using N-heterocycles as nucleophiles empowers the generation of β-heteroarylethylamine derivatives. A combination of computational and experimental investigation reveals that the reaction proceeds via a borane-promoted proton transfer, followed by aziridine ring opening and Fridel–Crafts alkylation involving a π-complex of carbocation-anion ion pair. This protocol is further applicable for the synthesis of pharmaceutically relevant compounds like serotonin and tryptamine.