Multicomponent Synthesis of Novel Unsymmetric 6-Aryl Substituted 5-Nitropyridines

Abstract

We have previously studied a multicomponent reaction for the synthesis of unsymmetrical 5-nitro-1,4-dihydropyridines using unsubstituted 2-nitroacetophenone, 1,3-dicarbonyl compounds, and various aldehydes such as formaldehyde, acetaldehyde, and furfural. This paper reports the use of unsymmetrical 3-acetyl-5-nitro-1,4-dihydropyridines containing aryl substituents at the 6-position in a multicomponent synthesis reaction. The starting aryl-substituted nitroacetophenones were prepared by two methods. The first method involved the two-step Katritzky method, which is described in the literature. This method consists of preparing N-acylbenzotriazoles from the corresponding substituted derivatives of benzoic acid and 1,2,3-benzotriazole in the presence of thionyl chloride. This is followed by C-acylation of nitromethane in supernatron medium (t-BuOK – DMSO). A number of 2-nitroacetophenone derivatives were prepared from more commercially available aromatic aldehydes by the Henry reaction with nitromethane followed by oxidation of the resulting secondary nitroalcohols. The multicomponent reaction of 6-aryl-substituted 5-nitro-1,4-dihydropyridines and their subsequent aromatization into 5-nitropyridines allowed us to reduce the overall reaction time by more than 40 times and to increase the total yield of 5-nitro-6-arylpyridines by an average of twofold compared to the method described in the literature. Furthermore, the 3-acetyl-5-nitropyridines we have obtained are significant intermediates in the synthesis of novel, more complex heterocyclic systems with potential biological activity. These systems include δ-carbolines and epoxybenzooxocyno[4,3-b]pyridines, which are currently of great interest for the study of their properties.