Pub Date : 2019-01-01DOI: 10.26565/2220-637x-2019-32-05
We have developed some available and effective methods for the synthesis of substituted pyrrolo[2,3-d]pyrimidines and 5,8-dihydropyrido[2,3-d]pyrimidines based on the three-component condensation of 6-amino-2-thiouracil with arylglyoxal hydrates and N,N-dimethylbarbituric acid or acyclic β-dicarbonyl compounds: acetylacetone (acetoacetic ester). It was shown that the optimal product yields were obtained by boiling the reagents in acetic acid. Thus, the synthesis of pyrrolo[2,3-d]pyrimidines took 15-20 minutes, while the precipitation of 5,8‑dihydropyrido[2,3-d]pyrimidines formed only after 2 hours. We proposed possible mechanisms for the formation of anelated pyrrole and pyridine rings. In both cases, the reaction includes the formation of an intermediate of α,β-unsaturated ketone with the participation of arylglyoxal and CH-acid (N,N-dimethylbarbituric or acetylacetone (acetoacetic ester)), nucleophilic addition of 6-aminothiouracil via an activated double bond, condensation of carbonyl and amino groups. The formation of the cycle takes place exclusively with the participation of the acetyl moiety, while the pyrrol one forms during the condensation of the aroyl moiety and the 6-amino group of thiouracil. A series of synthesized pyrrolo[2,3-d]pyrimidines was modified by alkylation. As it was expected, alkylation proceeds at the sulfur atom, that allowed a significant increase in the solubility of the obtained products. The reaction was carried out in DMF by stirring the initial reagents at 60ºC (reaction with methyl iodide) or boiling them (alkylation with phenacyl bromide), whereby S-methyl and S-phenacyl derivatives of pyrrolo[2,3-d]pyrimidines were obtained. The spectral data of 1H NMR showed that S-methylation products form solvates with DMF as 1:1. The synthesized compounds can become the basis to create small libraries of anelated pyrimidines with improved antiviral activity profile.
{"title":"Synthesis of substituted pyrrolo[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines in the one-pot condensation of 2-thio-6-aminouracil, arylglyoxals and CH-acids","authors":"","doi":"10.26565/2220-637x-2019-32-05","DOIUrl":"https://doi.org/10.26565/2220-637x-2019-32-05","url":null,"abstract":"We have developed some available and effective methods for the synthesis of substituted pyrrolo[2,3-d]pyrimidines and 5,8-dihydropyrido[2,3-d]pyrimidines based on the three-component condensation of 6-amino-2-thiouracil with arylglyoxal hydrates and N,N-dimethylbarbituric acid or acyclic β-dicarbonyl compounds: acetylacetone (acetoacetic ester). It was shown that the optimal product yields were obtained by boiling the reagents in acetic acid. Thus, the synthesis of pyrrolo[2,3-d]pyrimidines took 15-20 minutes, while the precipitation of 5,8‑dihydropyrido[2,3-d]pyrimidines formed only after 2 hours. We proposed possible mechanisms for the formation of anelated pyrrole and pyridine rings. In both cases, the reaction includes the formation of an intermediate of α,β-unsaturated ketone with the participation of arylglyoxal and CH-acid (N,N-dimethylbarbituric or acetylacetone (acetoacetic ester)), nucleophilic addition of 6-aminothiouracil via an activated double bond, condensation of carbonyl and amino groups. The formation of the cycle takes place exclusively with the participation of the acetyl moiety, while the pyrrol one forms during the condensation of the aroyl moiety and the 6-amino group of thiouracil. A series of synthesized pyrrolo[2,3-d]pyrimidines was modified by alkylation. As it was expected, alkylation proceeds at the sulfur atom, that allowed a significant increase in the solubility of the obtained products. The reaction was carried out in DMF by stirring the initial reagents at 60ºC (reaction with methyl iodide) or boiling them (alkylation with phenacyl bromide), whereby S-methyl and S-phenacyl derivatives of pyrrolo[2,3-d]pyrimidines were obtained. The spectral data of 1H NMR showed that S-methylation products form solvates with DMF as 1:1. The synthesized compounds can become the basis to create small libraries of anelated pyrimidines with improved antiviral activity profile.","PeriodicalId":34181,"journal":{"name":"Visnik Kharkivs''kogo natsional''nogo universitetu Seriia ximiia","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69001821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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