Ν. M. Goudgaon,, C. U. Reddy
2008
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0
Influential Citations
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Journal
Heterocyclic Communications
Abstract
6-Phenylthio-2,4-disubstituted pyrimidines were prepared in five steps starting from barbituric acid. Reaction of barbituric acid with POCI3 in presence of N, iV-dimethylaniline furnishes the 2,4,6-trichloropyrimidine, which on reaction with aq. NaOH under reflux yielded the 6-chlorouracil. Reaction of 6-chlorouracil with thiophenol under basic condition furnishes the 6-phenylthiouracil, which on chlorination using excess POCI3 under reflux yielded the key synthon, 6-phenylthio2,4-dichloropyrimidine. Aromatic nucleophilic substitution reaction of 6-phenylthio2,4-dichloropyrimidine with a oxygen nucleophile like sodium benzylate and nitrogen nucleophiles like heterocyclic primary amines, aliphatic primary amines and substituted aromatic primary amines furnished the target compounds, 6-phenylthio2,4-disubstituted pyrimidines respectively in 40-80% yield. Introduction In the last few years, uracil and pyrimidinone analogs substituted at the Ce-position have emerged as potential antiviral agents in the field of chemotherapy. Among the important 6-substituted uracil derivatives, l-[(2-hydroxyethyl)methyl]-6phenylthiouracil (HEPT) and its analog, 6-benzyl-l-(ethoxymethyl)-5-isopropyluracil (Emivirine, EMV) have been chosen as a candidate for clinical trials in the treatment of acquired immunodeficiency virus (AIDS). 3,4-Dihydro-2-alkoxy-6-benzyl-4oxopyrimidines (DABOs) shown potent and selective activity against human immunodeficiency type-1 (HIV-1). The C6-substituted pyrimidine analogs also exhibited selective antitumor, antiviral and antibacterial activity" suggesting the importance of this class of compounds as broad-spectrum drugs. Thus, the excellent biological activities exhibited by these 6-substituted uracil analogs prompted us to develop a novel methodology in order to generate a large number of various 2,4,6substituted pyrimidine analogs for biological evaluation. Our initial interest is to synthesize various 6-phenylthio-2,4-alkoxy and/or aryloxy and/or amine pyrimidines. In this context, 6-phenylthio-2,4-bis(benzyloxy)pyrimidine was prepared starting from barbituric acid. This method requires expensive reagents like organolithiums, diphenyldisulphide, etc. The key reaction in this method is the metal halogen exchange reaction under inert atmosphere followed by addition of electrophile at very low temperature (-80°C). Hence, this method is not suitable to synthesize a series of 6-phenylthio-2,4-aryloxy pyrimidines in normal laboratory conditions. Herein, we report a facile methodology for the synthesis of various 6phenylthio-2,4-aryloxy and/or amine pyrimidines starting from barbituric acid. Experimental Barbituric acid, thiophenol, POCI3, benzyl alcohol and anilines were purchased from SISCO Research Laboratories Pvt. Ltd., Mumbai (India). All the solvents used were