Synthesis and aromatization of 2-(3,6-diaryl-2,5-dihydropyridazin-4-yl)-1H-benzimidazoles

Abstract

We have previously reported the methodology of synthesizing novel benzimidazole derivatives based on 2-phenacyl-1H-benzimidazoles [1,2]. In particular, C-alkylation of the latter using phenacyl bromides gave the 1,4-diaryl-2-(1H-benzimidazol-2-yl)butane-1,4-diones 1a-g [3]. It is known [4] that 1,4-diketones can undergo cyclocondensation with hydrazine to form dihydropyridazines which are readily oxidized to pyridazines. Similar reactions of the 2-hetaryl-1,4-diketones of type 1 were unknown and are studied in this work.We have found that the cyclocondensation of compounds 1a-g with hydrazine hydrate occurs upon heating in a mixture of ethanol and pyridine and is accompanied by 1,3-migration of a proton from the methine group to the nitrogen atom in a direction leading not to compounds 2a-g with a 1,3-dihydrobenzimidazole fragment but to the 2-(3,6-diaryl-2,5-dihydropyridazin-4-yl)-1-benzimidazoles 3a-g. These products are obtained in 87-97% yields and are selectively oxidized by nitrous acid in pyridine (75-80ºC) undergoing aromatization to give 82-96% yields of the 2-(3,6-diarylpyridazin-4-yl)-1H-benzimidazoles 4a-g (compounds 4a,d,g crystallize in the form of molecular compounds with acetic acid with the compositions 4a·AcOH, 4d·AcOH, and 4g·AcOH).Evidently the formation of compounds of type 3 and their relative stability (they are not oxidized significantly when recording the NMR spectra in DMSO-d 6 ) is connected to the presence of an energetically favored conjugative chain in which the NH group of the dihydropyridazine ring is a donor and the benzimidazole fragment an acceptor of electrons. The conjugated chain constitutes a chromophoric system thus making compounds 3a-f yellow and the compound 3g with a nitrophenyl substituent orange colored. According to literature data, structural analogs of compound 3a with a Ph or Me group in place of the benzimidazole fragment are colorless [5,6] and with a C≡N group yellow [7]. We have found that, even with excess hydrochloric acid, the product 3a forms the orange mono hydrochloride 5 in which the dihydropyridazine ring can be involved in the delocalization of the positive charge (see the limiting structure 5"). Treatment of the salt 5 with ammonia regenerates the starting base 3a.

Synthesis of methyl 6-aryl-5-(1H-benzimidazol-2-yl)-2-methylnicotinates

“…It therefore follows that the adducts also do not have a salt like nature in DMSO-d 6 . We have recently reported a similar structure for the adducts in a series of 2-(3,6-diarylpyridazin-4-yl)-1H-benzimidazoles [11].…”