Synthesis of Quinoline N-Oxides from the Baylis-Hillman Adducts of 2-Nitrobenzaldehydes: Conjugate Addition of Nitroso Intermediate

Abstract

The Baylis-Hillman reaction is a useful carbon-carbon bond-forming method from activated vinyls and carbonyl compounds. Chemical transformation of the BaylisHillman adducts or their derivatives into useful heterocyclic compounds has been studied recently by us and other groups. Especially, conversion of the Baylis-Hillman adducts derived from 2-nitrobenzaldehydes into quinoline skeleton is a useful entry for the quinoline chemistry. Kaye and co-workers have reported the synthesis of quinoline skeleton from the Baylis-Hillman adducts. We have also reported the synthesis of 4-hydroxyquinoline Noxides from the Baylis-Hillman adducts of 2-nitrobenzaldehydes. As a continuing study, we examined the synthesis of quinoline N-oxides 2 by reduction of the nitro functionality of the Baylis-Hillman adducts 1 into nitroso group followed by dehydrative cyclization strategy. Among the various examined reduction conditions, the use of zinc and ammonium chloride system in aqueous THF was found to be effective. The nitro group is readily converted to a series of functions of various degrees of reduction: very exceptionally to a nitroso group, more often to a hydroxylamino group and most frequently to the amino group. Nitroso compounds are usually not obtained directly but rather by reoxidation of hydroxylamino compounds, which can be prepared from nitro compounds by zinc and aqueous ammonium chloride. Moreover there have been few instances in which nitroso compounds have been isolated as intermediates in reductions of nitro compounds. In some instances the nitroso nitrogen behaves as a nucleophile with formaldehyde, glyoxylic acid and pyruvic acid. Only one example of the conjugate addition of arylnitroso compound to the conjugated azoalkene system was known to the best of our knowledge. The reaction of the Baylis-Hillman adduct 1a and zinc (2.0 equiv) and ammonium chloride (2.0 equiv) in aqueous THF at 60-70 C gave the quinoline N-oxide 2a in 49% isolated yield (Scheme 1) together with many intractable side products. In the reaction, quenching of the unstable nitroso intermediate (I) occurred before further reduction to a hydroxylamine stage due to the facile intramolecular Michael addition process. This might be the first example of conjugate addition of the nitroso intermediate to the Michael acceptor in an intramolecular fashion as mentioned Scheme 1