Efficient Synthesis of Pyrrolo[3,4-b]hexahydro-1H-1,5-benzodiazepine Derivatives

Abstract

A variety of pyrrolo [3,4-b]hexahydro-1H-1,5-benzodiazepine derivatives have been prepared in a new one-pot reaction from thiophene-2,3-dione as well as pyrrolidinetrione derivatives and trans -(±)-1,2-diaminocyclohexane. The reactivity of 2,3-dicarbonyl fragment of thiophene-2,3-dione was exploited in the synthesis of fused quinoxaline systems.The pharmacological activity of diazepine derivatives 1 in conjunction with their structural variety has made this class of compounds a continuing target on which the utility of novel synthetic methodology is tested. It is known that benzodiazepine derivatives are the most frequently prescribed drugs for the pharmacotherapy of anxiety, epilepsy, convulsive states and emotional disorder. 2 In contrast to benzodiazepine based tranquilizers hexahydrobenzodiazepine derivatives have been selected as promising candidates for potential anticancer drugs 3 and as antagonists of arginine vasopressin. 4 We have been interested in the synthesis and application of polycarbonyl heterocyclic systems 5 as potential building-blocks for the construction of fused heterocyclic compounds. Recently we have described a very effective synthesis of thiophene-2,3-dione derivatives 6 3 based on the reaction of 3-aminovinylthioamides 2 with ethyl oxalyl chloride. Thophene-2,3-dione derivatives were used in the synthesis of fused heterocyclic system such as pyrrolo[3,2-c]pyridine. 6 Knoevenagel condensation of thiophene-2,3-dione derivatives with malononitrile resulted in the ring transformation of thiophene system followed by elimination of sulfur, leading to pyrrolo[3,2-c]pyridine derivatives. In continuation of these efforts we have investigated reactivity of thiophene-2,3-dione towards binucleophiles such as 1,2-diamines.In contrast to our earlier results a nucleophilic amino group of trans-1,2-diaminocyclohexane attacks preferentially the C-2 position of thiophene-2,3-dione 3 leading to the ring opening and transformation to pyrrolidine system. The simultaneous attack of the second amino group on C-6 position results in the transamination and formation of 1,5-diazepine ring (Scheme 1).A conclusion, that the reaction of thiophene-2,3-dione 3 with trans-1,2-diaminocyclohexane 7 provided 1,5-diazepine derivatives 5 (method A) was supported by the re- Scheme 1Downloaded by: University of Liverpool. Copyrighted material.

Synthesis of 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepines and 11-methyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indoles

“…The benzotriazole moiety can easily be replaced by a variety of nucleophiles. [20][21][22][23] Reaction of compound 2 with different Grignard reagents afforded novel 2-substituted-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a] [1,4]diazepines (3a-f) in 63-81% yields. Compounds 3a-f were fully characterized by 1 H, and 13 C NMR spectra, microanalysis and/or HRMS results (Scheme 3).…”

“…Tetrahydro [1,4]diazepino[1,2-a]indoles are 5-HT antagonists, CNS depressants, anti-allergic agents and muscle relaxants.…”

“…To summarize, we have developed a convenient method for the preparation of 2-substituted-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepines and 11-methyl-2,3,4,5-tetrahydro -1H- [1,4] diazepino [1,2-a]indoles by the condensation reaction of 3-(pyrrol-1-yl)-1-propylamine (1) and 3-(3-methyl-1H-indol-1-yl)propylamine (7) respectively with (1-hydroxymethyl) benzotriazole followed by the nucleophilic substitution of benzotriazole with Grignard reagents, sodium borohydride, sodium cyanide and triethyl phosphite. Thus various useful functionalities were introduced via nucleophilic substitutions of the benzotriazole group as a synthetic auxiliary.…”

“…12e Available syntheses of tetrahydro [1,4]diazepino [1,2-a]indoles start from ethyl-3-phenylindole-2-carboxylates by lactam formation (Scheme 2).…”

“…2 They act as antitumor antibiotics with sequence selective DNA binding ability, 3 and antagonists of arginine vasopressin. 4 Syntheses of 1,4-diazepines fused with five and six membered heterocyclic rings, [5][6][7] and octahydropyrrolopyrazines [8][9] are well explored. Two reports address the synthesis of tetrahydropyrrolodiazepines (Scheme 1): (i) Okawara et al 10 synthesized 2-substituted-1-carboxy-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a] [1,4]diazepines by the reaction of 3-(pyrrol-1-yl)-1-propylamine with the glyoxalic acid hydrate in ethanol; (ii) bromopyrrolodiazepines (isolated from marine sponges) were synthesized by Marchais et al 11 via regioselective intramolecular cyclization of 2-substituted pyrroles.…”