Construction of Quinoline N-Oxides and Synthesis of Aurachins A and B: Discovery, Application, and Mechanistic Insight

Abstract

AbstractA method to synthesize 3-hydroxyquinoline N-oxides from ketones having a 2-nitrophenyl group at the α-position relative to the carbonyl group was developed. The substrates were easily prepared via a SNAr reaction or a Sonogashira coupling, and treatment with sodium tert-butoxide in dimethyl sulfoxide produced the corresponding quinoline N-oxides. The method was successfully applied to the total synthesis of aurachins A and B. On the basis of the quinoline N-oxide synthesis, related reactions of α-(2-nitrophenyl)ketones, including nitrone formation and photoinduced rearrangement, were also investigated. These investigations provided clues about the reaction mechanism, and the following mechanism for the quinoline N-oxide synthesis is proposed: Deprotonation of the α-position of α-(2-nitrophenyl)ketone with tert-butoxide generates an enolate, which reacts with a nitro group via single-electron transfer to form an α-hydroxyketone having a nitroso group. An intramolecular alkoxide-mediated hydride shift reduces the nitroso group, and condensation of the resultant hydroxylamine and diketone moieties produces a 3-hydroxyquinoline N-oxide.