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Reactions of ring‐expanded xanthines containing the imidazo[4,5‐ e ][1,4]diazepine ring system
Author(s) -
Bhan Anila,
Hosmane Ramachandra S.
Publication year - 1993
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570300544
Subject(s) - chemistry , diazepine , halogenation , medicinal chemistry , ring (chemistry) , diethyl malonate , bromine , dimer , stereochemistry , catalysis , organic chemistry
4,5,7,8‐Tetrahydro‐6 H ‐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 hypobro‐mite. 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‐carbon‐yl)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‐nitroimid‐azolyl‐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‐diaminomalon‐ate 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 meth‐oxide/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 aminoimidazo‐lone derivative 11 which upon ring‐closure with sodium methoxide in methanol produced imidazo[4,5‐ e ][1,4]‐diazepine‐2,5,8‐trione ( 12 ).