New Synthesis of peri -Fused Tetrahydro[1,3]diazepino[1,2- a ]benzimidazoles from 1-Aroylmethyl-2-[(4-hydroxybutyl)amino
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Synthesis of peri-Fused Tetrahydro[1,3]diazepino[1,2-a]benzimidazoles from 1-Aroylmethyl-2-[(4-hydroxybutyl)amino]benzimidazoles T. A. Kuzʼmenkoa, L. N. Divaevaa,*, and A. S. Morkovnika a
Institute of Physical and Organic Chemistry, Southern Federal University, Rostov-on-Don, 344090 Russia *e-mail: [email protected] Received June 17, 2020; revised June 28, 2020; accepted June 30, 2020
Abstract—Treatment of 2-[(4-hydroxybutyl)amino]-1H-benzimidazole with ω-bromoacetophenones gave 1-aroylmethyl-substituted derivatives which underwent cyclization to 2-aryl-1-(4-bromobutyl)imidazo[1,2-a]benzimidazole hydrobromides on heating in concentrated hydrobromic acid when Ar = Ph, 4-ClC6H4, 4-BrC6H4, and 4-O2NC6H4. The corresponding bases were readily converted into peri-fused tetrahydro[1,3]diazepino[1,2-a]benzimidazoles via intramolecular alkylation with closure of seven-membered ring. If an electrondonating methoxy group was present in the aryl fragment of the initial ketone, 1-(4-hydroxyphenyl)-2-[2-(pyrrolidin-1-yl)-1H-benzimidazol-1-yl]ethan-1-one was formed in the reaction with HBr. Keywords: 2-[(4-hydroxybutyl)amino]-1H-benzimidazole, ω-bromoacetophenones, 2-{2-[(4-hydroxybutyl)amino]-1H-benzimidazol-1-yl}-1-arylethan-1-ones, 2-aryl-1-(4-bromobutyl)-1H-imidazo[1,2-a]benzimidazoles, 3,4,5,6-tetrahydro-2a,6a,10b-triazabenzo[a]cyclopenta[cd]azulen-2a-ium bromides, cyclization
DOI: 10.1134/S1070428020100097 We previously reported [1] that 11-aroylmethyl2,3,4,5-tetrahydro[1,3]diazepinobenzimidazoles obtained from 2-(4-hydroxybutylamino)-1H-benzimidazole (1) [2] were converted to peri-fused structures 2 by heating in concentrated aqueous HBr; in this case, the new imidazole ring was formed with participation of the ketone carbonyl carbon atom and nitrogen atom of the diazepine ring. Some derivatives of this series were found to exhibit a high anxiolytic activity [3]. Analogous tetracyclic structures with a hydrogenated six-membered ring were synthesized in less steps [4]. For this purpose, 2-(3-hydroxypropylamino)benzimidazole was alkylated with ω-bromacetophenones, the resulting 1-acylmethyl derivatives were subjected to cyclization in concentrated aqueous HBr to 2-aryl1-(3-bromopropyl)imidazo[1,2-a]benzimidazoles, and the six-membered ring closure was achieved in the final step as a result of facile intramolecular alkylation of the N9 atom. In the present work we tried to utilize a similar approach to the synthesis of diazepinobenzimidazoles 2. Initial 1-aroylmethyl derivatives 3a–3e were readily obtained from amino alcohol 1 and the corresponding ω-bromoacetophenones in boiling propan-2-
ol (Scheme 1). However, further transformations of compounds 3a–3e on heating in concentrated aqueous HBr followed different pathways depending on the substit uent in the aroyl fragment. The yields and reaction rates were also different. Ketones 3a–3d underwent simultaneous replacement of the side-chain hydroxy group by bromine and cyclization to 1-(4-bromobutyl)imidazobenzimidazoles 4a–4d. Phenacyl derivative 3a (Ar = Ph) was converted t
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