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The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate.

Kaczor AA, Kijkowska-Murak U, Pihlaja K, Sinkkonen J, Wysocki W, Karczmarzyk Z, Matosiuk D - Monatsh. Chem. (2013)

Bottom Line: The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.Heating of the enamines to the temperature of 120-140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates.The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.

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Affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St, 20093 Lublin, Poland.

ABSTRACT

Abstract: The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is investigated. At -10 °C reaction takes place on the exocyclic nitrogen atom, giving exclusively ethyl esters of 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)amino]prop-2-enoic acid. The formation of isomeric enamines which may be a theoretical product of the reaction on N3 ring nitrogen atom is not observed. The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the enamines to the temperature of 120-140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.

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Mentions: The hydrobromides 3a–3f of 4,5-dihydro-1H-imidazol-2-amines 4a–4f were obtained from the respective N-aryl-1,2-diaminoethanes and cyanogen bromide, as previously reported [29, 39, 40]. The hydrobromides 3a–3f were then transformed into free bases 4a–4f by action of sodium hydroxide and extraction with methylene chloride. The 4,5-dihydro-1H-imidazol-2-amines 4a–4f were subjected to the pseudo-Michael reaction with EMCA in propan-2-ol solution at −10 °C (Scheme 2). In these conditions the only isolated products were chain enamines (5a, 5c–5h), formed as a result of the reaction on the N6 exocyclic nitrogen atom. The attempt to obtain derivative 5b with 2-chloro substituent failed, probably due to the steric hindrance. The reaction on the N6 nitrogen atom was in contrast to our earlier results on the pseudo-Michael reaction of 4,5-dihydro-1H-imidazol-2-amines with DEEM [29]. In the case of DEEM, at −10 °C reaction took place on the N3 ring nitrogen atom, but the isolation of the respective chain enamines was not possible due to the fast cyclization process, even at low temperature. Instead, ethyl 1-aryl-7-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates were obtained exclusively. As was found previously, the pseudo-Michael reaction of 4,5-dihydro-1H-imidazol-2-amines with DEEM was temperature-dependent; therefore, we tried first to perform the corresponding reaction with EMCA at room temperature and then at higher temperatures (up to the boiling point of propan-2-ol). Theoretically, formation of the mixture of isomeric N3 and N6 enamines is possible in the case of both Michael reagents, but in the case of EMCA we observed the formation of N3 enamines neither at −10 °C nor at higher temperatures. The N6 enamines 5a, 5c–5h formed exclusively underwent cyclization to 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles 6a, 6c–6h when the pseudo-Michael reaction was performed at ambient or higher temperature (the derivative 6b could not be obtained by this method as the preparation of enamine 5b was not successful). On the contrary, in the case of DEEM, at room temperature the reaction yielded mixtures with varying ratio of isomeric 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates and 1-aryl-7-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. Alternatively, to obtain compounds 6a and 6c–6h, the enamines 5a and 5c–5h should be heated in boiling acetic acid (Scheme 2). In such conditions the cyclization takes place via the ester group of 5a and 5c–5h, giving 6a and 6c–6h exclusively. Myiamoto [41], when performing the similar cyclization reaction under acidic conditions (MeOH saturated with HCl), observed the cyclization via cyano group only, leading to appropriate imines. Analogs of 6a–6h were obtained by Myiamoto [41] in basic conditions (Et3N/MeOH).


The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate.

Kaczor AA, Kijkowska-Murak U, Pihlaja K, Sinkkonen J, Wysocki W, Karczmarzyk Z, Matosiuk D - Monatsh. Chem. (2013)

© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4495018&req=5

Mentions: The hydrobromides 3a–3f of 4,5-dihydro-1H-imidazol-2-amines 4a–4f were obtained from the respective N-aryl-1,2-diaminoethanes and cyanogen bromide, as previously reported [29, 39, 40]. The hydrobromides 3a–3f were then transformed into free bases 4a–4f by action of sodium hydroxide and extraction with methylene chloride. The 4,5-dihydro-1H-imidazol-2-amines 4a–4f were subjected to the pseudo-Michael reaction with EMCA in propan-2-ol solution at −10 °C (Scheme 2). In these conditions the only isolated products were chain enamines (5a, 5c–5h), formed as a result of the reaction on the N6 exocyclic nitrogen atom. The attempt to obtain derivative 5b with 2-chloro substituent failed, probably due to the steric hindrance. The reaction on the N6 nitrogen atom was in contrast to our earlier results on the pseudo-Michael reaction of 4,5-dihydro-1H-imidazol-2-amines with DEEM [29]. In the case of DEEM, at −10 °C reaction took place on the N3 ring nitrogen atom, but the isolation of the respective chain enamines was not possible due to the fast cyclization process, even at low temperature. Instead, ethyl 1-aryl-7-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates were obtained exclusively. As was found previously, the pseudo-Michael reaction of 4,5-dihydro-1H-imidazol-2-amines with DEEM was temperature-dependent; therefore, we tried first to perform the corresponding reaction with EMCA at room temperature and then at higher temperatures (up to the boiling point of propan-2-ol). Theoretically, formation of the mixture of isomeric N3 and N6 enamines is possible in the case of both Michael reagents, but in the case of EMCA we observed the formation of N3 enamines neither at −10 °C nor at higher temperatures. The N6 enamines 5a, 5c–5h formed exclusively underwent cyclization to 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles 6a, 6c–6h when the pseudo-Michael reaction was performed at ambient or higher temperature (the derivative 6b could not be obtained by this method as the preparation of enamine 5b was not successful). On the contrary, in the case of DEEM, at room temperature the reaction yielded mixtures with varying ratio of isomeric 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates and 1-aryl-7-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. Alternatively, to obtain compounds 6a and 6c–6h, the enamines 5a and 5c–5h should be heated in boiling acetic acid (Scheme 2). In such conditions the cyclization takes place via the ester group of 5a and 5c–5h, giving 6a and 6c–6h exclusively. Myiamoto [41], when performing the similar cyclization reaction under acidic conditions (MeOH saturated with HCl), observed the cyclization via cyano group only, leading to appropriate imines. Analogs of 6a–6h were obtained by Myiamoto [41] in basic conditions (Et3N/MeOH).

Bottom Line: The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.Heating of the enamines to the temperature of 120-140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates.The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.

View Article: PubMed Central - PubMed

Affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St, 20093 Lublin, Poland.

ABSTRACT

Abstract: The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is investigated. At -10 °C reaction takes place on the exocyclic nitrogen atom, giving exclusively ethyl esters of 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)amino]prop-2-enoic acid. The formation of isomeric enamines which may be a theoretical product of the reaction on N3 ring nitrogen atom is not observed. The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the enamines to the temperature of 120-140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.

No MeSH data available.