Reaction of 3-aminocyclohex-2-en-1-ones with arylidene­malononitriles: synthesis of N-substituted 1,4,5,6,7,8-hexahydroquinolin-5-ones

Abstract

Reaction of 3-aminocyclohex-2-en-1-ones with AbstractThe reaction of 3-amino-and 3-hydrazinocyclohex-2-en-1-ones derived from cyclohexane-1,3-diones and an appropriate amine or hydrazine with 2-arylidenemalononitriles was investigated. An efficient method for the synthesis of N-substituted 1,4,5,6,7,8-hexahydroquinolin-5-ones was elaborated.Keywords: 3-Aminocyclohex-2-en-1-ones, 3-hydrazinocyclohex-2-en-1-ones, 2-arylidenemalononitriles, 1,4,5,6,7,8-hexahydroquinolin-5-ones Introduction 1,4-Dihydropyridines have received considerable attention because of their pivotal role in various biological processes. Numerous derivatives of dihydropyridines have been reported to have wide biological activity, e.g. being used in the treatment of cardiovascular disease (calcium antagonist).1,2 This applies especially to 4-aryl-or hetaryl-substituted 1,4-dihydropyridines. One of the well-known cardiovascular agents of this kind is Nifedipine 1.It is conceivable that fused 1,4-dihydropyridines of type 2 with different substituents R 1 at involving the reaction of cyclic enaminoketones 3 with arylidene derivatives of malononitrile 4. This method allows the attachment of substituents to the nitrogen atom in the course of the preparation of the enaminoketones 3. It has been shown that heating of 3-anilino-5,5-dimethylcyclohex-2-en-1-one 3a with 2-benzylidenemalononitrile 4a in alcohol and in the presence of catalytic amounts of a base yields the N-phenyl-substituted hexahydroquinoline 5a (Scheme 1).3 Scheme 1Recently, we have extended this approach to the reaction of 3-(2-phenyl-hydrazino)cyclohex-2-en-3-one 3b with 2-(4-bromobenzylidene)malononitrile 4b. 4 The product of this reaction, the N-(phenylamino)hexahydroquinoline derivative 5b was found to undergo an interesting diastereoselective rearrangement forming the previously unknown heterocyclic system 6 with partially hydrogenated fused indole and pyridine moieties 5 (Scheme 2). Scheme 2The present paper presents the results of a somewhat extended investigation of the condensation of N-substituted and N-unsubstituted 3-aminocyclohex-2-en-1-ones 3 with 2-arylidenemalononitriles 4 resulting in 4-aryl-substituted hexahydroquinolin-5-ones 4 with various substituents at the ring nitrogen atom. The optimal reaction conditions for the conversion Results and DiscussionThe N-unsubstituted 3-aminocyclohex-2-en-1-one 3c readily reacted with 2-benzylidenemalononitrile 4a upon short heating of a benzene solution in the presence of catalytic amounts of piperidine and afforded the N-unsubstituted hexahydroquinoline derivative 5c. The reaction proceeded in two steps: Heating the mixture of the reactants without a base catalyst yielded the adduct 7, which was isolated and identified. Only in the presence of a base (piperidine) the intramolecular cyclization was induced leading to the hexahydroquinolin-5-one 5c (Scheme 3). Scheme 3N-Aryl substituents decrease the nucleophilicity of enaminoketones 3 toward 2-arylidenemalononitriles 4; a base catalyst was required to achieve the formation of ...

Microwave-Assisted Combinatorial Synthesis of Polysubstituent Imidazo[1,2-a]quinoline, Pyrimido[1,2-a]quinoline and Quinolino[1,2-a]quinazoline Derivatives

“…To the best of our knowledge, these compounds are scarcely studied and only one product was reported in the literature. 20 Therefore, to obtain the potential pharmacological molecules, the synthesis of imidazo[1,2-a]quinoline, pyrimido[1,2-a]quinoline and quinolino[1,2-a]quinazoline derivatives may be of great significance.…”

“…Herein, we report a high-speed and one-pot combinatorial method for synthesizing diverse sets of imidazo[1,2- a ]quinoline, pyrimido[1,2- a ]quinoline and quinolino[1,2- a ]quinazoline heterocyclic compounds including imidazo[1,2- a ]pyridine or pyrido[1,2- a ]pyrimidine moiety, respectively, from readily available starting materials. To the best of our knowledge, these compounds are scarcely studied and only one product was reported in the literature . Therefore, to obtain the potential pharmacological molecules, the synthesis of imidazo[1,2- a ]quinoline, pyrimido[1,2- a ]quinoline and quinolino[1,2- a ]quinazoline derivatives may be of great significance.…”