A Synthesis of 4-Quinolone N-Oxides and NMR Evidence of Their Protonation-Assisted Enolisation

An operationally simple procedure for the synthesis of 2-alkyl-4-quinolone N-oxides, relying on controlled platinum-catalyzed partial hydrogenation of 2-nitrobenzoyl enamines, has been developed. The Pseudomonas aeruginosa metabolite 2-heptyl-4-quinolone-N-oxide (HQNO) and four analogous products have been prepared in good yield and high purity by this method. All products showed ampholytic properties, with a tendency to form isolable organic-soluble hydrochlorides by switching from the N-hydroxy-4-quinolone to 4-hydroxyquinoline-N-oxide tautomeric form upon partitioning between dichloromethane and 1M aqueous HCl. In basic medium, on the other hand, water-soluble salts of the N-hydroxy-4-quinolone tautomers were formed. NMR measurements indicate pH-dependent equilibrium with fast exchange between the 4-quinolone and the protonated 4-quinolinol tautomer.