A Simple and Efficient Synthesis of 1,6-Disubstituted 1,4,5,6-Tetrahydropyridazines by Ring Enlargement of 2,5-Dibenzotriazolyl-N-Aminopyrrolidines

Abstract

1,6-Disubstituted 1,4,5,6-tetrahydropyridazines 3a-l are readily accessible in good to high yields by Grignard reagent induced ring enlargement of 2,5-dibenzotriazolyl-N -arylaminopyrrolidines 2a-c . Compounds 2a-c are prepared in high yields by reaction of benzotriazole with succinic dialdehyde and the corresponding arylhydrazines.The chemistry of pyridazine derivatives has been extensively studied 1 reflecting their wide range of pharmaceutical activities, interalia as anti-inflammatory and cardiovascular agents, antidepressants and GABA antagonists. 2 However, the chemistry of tetrahydropyridazines has received less attention, although 1,4,5,6-tetrahydropyridazines in particular are herbicides 3 and intermediates for the preparation of herbicides and fungicides. 4 Several routes exist for the preparation of 1,4,5,6-tetrahydropyridazines: (i) hydrazones, obtained by treatment of α,β -unsaturated ketones containing an activated methylene group with aryl diazonium salts according to the Japp-Klingemann procedure, undergo intramolecular ring closure into 1,4,5,6-tetrahydropyridazin-4-ones in fair to excellent yields; 5 (ii) analogously, reactions of hydrazine with γ -ketooxazoles in acidic conditions yielded fused tetrahydropyridazines, via hydrazone intermediates; 6 (iii) substituted tetrahydropyridazines have also been prepared from azoalkenes intermediates by intermolecular Diels-Alder reactions; 7 (iv) reaction of the appropriate ene-hydrazines with acetylenedicarboxylic esters; 8 (v) hydrogenation of pyridazine in the presence of hydrated ruthenium oxide; 9 (vi) thermal isomerisation of cis -3,6-diphenyl-3,4,5,6-tetrahydropyridazine; 10 and (vii) reaction of hydrazines with 2,5-dimethoxytetrahydrofuran in the presence of sodium borohydride in acidic conditions. 11 Reported ring enlargement routes to 1,4,5,6-tetrahydropyridazines proceed from 4,5-dihydropyrazoles, 12 pyrrolidines 13 and especially from 1-aminopyrrolidines 14 via diazene intermediates. These afford 1,4,5,6-tetrahydropyridazines in average to good yields (40-70%) but require a multi-step synthesis of the 1-aminopyrrolidine substrates and are restricted to unsubstituted amino groups. 14 We now report that 2,5-bisbenzotriazolyl-N -aminopyrrolidines 2 are efficient reagents for the preparation of 1,4,5,6-tetrahydropyridazines.The preparation of substrates 2a-c was achieved in excellent yields in a one-pot procedure by mixing two equivalents of benzotriazole and succinic dialdehyde with the appropriate hydrazine in water and THF at room temperature (Scheme). We previously used an analogous route for the preparation of 2,5-bisbenzotriazolyl-N -aminopiperidines 15 but the method needed to be modified for the present preparation of the pyrrolidines analogues 2a-c (longer times of reaction and a small amount of THF or diethylether were required to improve solubility). Compounds 2a-c were isolated and characterized as complex mixtures ( cis-and trans-and benzotriazol-1-yl and benzotriazol-2-yl, a total of 6 isomers). In a previous investigation, 16 we...

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

“…[201]. Prolonged heating of hydrazones 295 with dimethylformamide dimethyl acetal resulted in the formation of pyridazin-4-ones 298.…”

Synthesis of Heterocycles Mediated by Benzotriazole. 1. Monocyclic Systems

“…Coordination of the benzotriazolyl N-3 atoms by additional organomagnesium molecules enhances the leaving ability of the benzotriazolyl groups. Yields of products 621 vary from 55% to 89% and are generally higher for phenyl and 4-methylphenyl as R 1 than for their 4-chlorophenyl analogues (Scheme ) …”

“…Yields of products 621 vary from 55% to 89% and are generally higher for phenyl and 4-methylphenyl as R 1 than for their 4-chlorophenyl analogues (Scheme 176). 184 Hydrazones 622A are smoothly prepared in 76-78% yields by coupling of benzotriazol-1-ylmethyl methyl ketone (310) with appropriate aryldiazonium salts in ethanolic NaOH. Prolonged heating of 622A with N,N-dimethylformamide dimethyl acetal results in formation of 1-aryl-3benzotriazol-1-ylpyridazin-4-ones 625A in 79-83% yields.…”

1,2,3-Triazoles

“…Thus, hydrazine derivative 644 reacts with electron-rich unsaturated compounds according to [3+2] cyclocondensation pattern to produce pyrazolidines 645 ( Scheme 100 ) <1997JOC8210> . Condensation of succinaldehyde with arylhydrazines and benzotriazole gives 1-aminopyrrolidines 646 that upon treatment with organomagnesium reagents rearrange to 1,4,5,6-tetrahydropyridazines 647 <1998S1627> .

Scheme 100

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