Reactions of ring-expanded xanthines containing the imidazo[4,5- e][1,4]diazepine ring system

Article abstract of DOI:10.1002/jhet.5570300544

4,5,7,8-Tetrahydro-6H-imidazo[4,5-e][1,4]diazepine-5,8-dione underwent bromination at the 2-position with or without substituents at the 3-, 4- or 7-position, using bromine, N-bromosuccinimide, or acetyl hypobromite. The activation of position 6 with an ester functionality, as in 7, did not alter the site of bromination. The base-catalyzed bromination of the ring-open precursor, diethyl 2-[N-(1-benzyl-5-nitroimidazolyl-4- carbonyl)amino]malonate (5), resulted either in introduction of an alkoxy functionality in the above aminomalonate side-chain, yielding 17 when the reaction was quenched with an alcohol, or in degradation of the side-chain, yielding 1-benzyl-5-nitroimidazole-4-carboxamide (19) when the reaction was quenched with water. Both 17 and 19 are formed by oxidative bromination of 5 via the bromo intermediate 15. An indirect evidence for the latter was obtained by base-catalyzed methylation of 5 which gave diethyl 2-methyl-2- [N-(1-benzyl-5-nitroimidazolyl-4-carbonyl)amino]malonate (21). The base- catalyzed bromination of 5 with N-bromosuccinimide gave rise to two products, the dimer 24a and the monomer 24b that contained the substituted 2,2- diaminomalonate side-chain. The structure of 24b was confirmed by single- crystal X-ray diffraction analyses. Reduction of the 5-nitro group of 17 to the corresponding amino derivative 25, followed by ring-closure with sodium methoxide/methanol, yielded three products, a 5:6-fused system 26 and two 5:7 fused systems 27 and 28. The structures of 26 and 27 were confirmed by single-crystal X-ray diffraction analyses. A tentative reaction pathway for the formation of all three products has been proposed. Hydrolysis of 27 with aqueous hydrochloric acid resulted in ring-opening to form 5-amino-1- benzylimidazole-4-carboxamide (40). A mechanism for the hydrolysis reaction has been proposed. Catalytic hydrogenation of 5 in acetic acid yielded the aminoimidazolone derivative 11 which upon ring-closure with sodium methoxide in methanol produced imidazo[4,5-e][1,4]-diazepine-2,5,8-trione (12).