SYNTHESIS OF S-BENZYL DERIVATIVE OF 4,6-DIAMINOPYRIMIDINE-2-THIOL

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 30 SYNTHESIS OF S-BENZYL DERIVATIVE OF 4,6DIAMINOPYRIMIDINE-2-THIOL G.B. Salieva1, U.Z. Kenjaboev2, S.R. Otajonov2, F.O. Pulatova1 Department of organic synthesis of Tashkent Pharmaceutical Institute, Tashkent Uzbekistan1 The Faculty of Chemistry, the National University of Uzbekistan, Tashkent Uzbekistan2 https://doi.org/10.5281/zenodo.17389230 Abctract. Thiopyrimidines constitute an important class of heterocyclic compounds with diverse biological activities, including antiviral, antimicrobial, antitumor, and anti-inflammatory effects. In this study, we report the synthesis of 2-(benzylthio)pyrimidine-4,6-diamine, an S-benzyl derivative of 4,6-diamino-2-mercaptopyrimidine, through nucleophilic substitution of the thiol group with benzyl chloride under basic conditions in methanol. The reaction proceeded selectively at the sulfur atom, affording the desired product in 71% yield. The structure of the compound was confirmed by infrared (IR) spectroscopy, which revealed characteristic absorption bands corresponding to amino, aromatic, and thioether functionalities. Complementary analyses included thin-layer chromatography (TLC) and melting point determination. The selective reactivity of the sulfur atom over the amino groups highlights the synthetic potential of thiopyrimidines for targeted functionalization. These findings provide a simple and efficient synthetic route to S-benzyl thiopyrimidine derivatives and establish a basis for future evaluation of their antimicrobial and pharmacological properties. Keywords: thiopyrimidines; 4,6-Diamino-2-mercaptopyrimidine; Alkylation; S-Benzyl derivative; IR spectroscopy. Introduction. Thiopyrimidines are a class of heterocyclic compounds known for their wide spectrum of biological activities, including significant in vitro activity against DNA and RNA viruses (such as poliovirus and Herpes simplex), as well as diuretic, spermicidal, herbicidal, and antimicrobial effects [1–2]. Their pharmacological potential has also been demonstrated in antiviral, antitumor, anti-inflammatory, analgesic, antifilarial, anticancer, antileishmanial, antitubercular, and antimicrobial applications [3,4,5,6,7,8]. With the growing concern of multidrug-resistant bacteria, there is an urgent need to develop new antimicrobial agents with novel structures and mechanisms of action. The thiopyrimidine nucleus plays an important role in this regard due to its versatile physiological activity [9,10]. In this work, we focus on the synthesis of derivatives of 4,6-diamino-2mercaptopyrimidine, specifically its alkylation with benzyl chloride. The nucleophilic sulfur atom at the 2-position is more reactive than the amino groups at the 4and 6-positions, as sulfur nucleophiles generally react faster with electrophiles (e.g., alkyl halides) compared to their nitrogen counterparts. This reactivity is attributed to the lower electronegativity of sulfur, which allows easier electron donation. Results and Discussion. The reaction of 4,6-diamino-2-mercaptopyrimidine with benzyl chloride under basic conditions (NaOH) in methanol at room temperature led selectively to the formation of 2-(benzylthio)pyrimidine-4,6-diamine (Scheme 1). SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 10 OCTOBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 31 Scheme 1. Synthesis aryl derivative of diaminomercaptopyrimidine. The selective substitution at sulfur is consistent with the higher nucleophilicity of the thiolate anion compared to the amino groups. The product was obtained in 71% yield as a solid and its structure was confirmed by IR spectroscopy. The IR spectrum of the synthesized compound displayed characteristic absorption bands consistent with the expected structure of 2-(benzylthio) pyrimidine-4,6-diamine. Broad bands in the range 3462–3295 cm⁻¹ correspond to N–H stretching vibrations of the amino groups at the 4and 6-positions. The band at 3119 cm⁻¹ can be assigned to aromatic C–H stretching, while absorptions at 2928 cm⁻¹ indicate aliphatic C–H stretching of the benzyl moiety. Strong absorptions at 1641 and 1612 cm⁻¹ are attributed to C=N and C=C stretching vibrations of the pyrimidine ring. Additional bands observed at 1576–1450 cm⁻¹ correspond to N– H bending and ring skeletal vibrations. The absorptions at 1279 and 1243 cm⁻¹ are characteristic of C–S stretching, confirming substitution at the sulfur atom. Finally, the band at 800 cm⁻¹ is consistent with out-of-plane aromatic C–H bending, typical for the benzyl group. Taken together, these IR signals provide strong evidence for the formation of the target Sbenzyl derivative, supporting the successful alkylation at the sulfur center rather than the amino groups. Experimental Section. Synthesis of 2-(Benzylthio) pyrimidine-4,6-diamine. The infrared (IR) spectrum was recorded on a SHIMADZU IR-4000 spectrometer. Thin-layer chromatography (TLC) was carried out on silica gel 60 F254 plates, with spots visualized under UV light (254 nm). Melting point was determined using a digital melting point apparatus and is uncorrected. All reagents were commercially available and purchased from Sigma-Aldrich. To a solution of 4,6-diaminopyrimidine-2-thiol (1 mmol) in methanol (10 mL), benzyl chloride (1 mmol) was added under basic conditions (NaOH, 1 mmol). The mixture was stirred for 2 h at room temperature. After the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with water. The precipitate was collected and dried to give the target compound. Yield: 71% Conclusion. We have successfully synthesized 2-(benzylthio) pyrimidine-4,6-diamine through the selective alkylation of 4,6-diamino-2-mercaptopyrimidine with benzyl chloride under mild conditions. The reaction proceeded selectively at the sulfur atom, consistent with its higher nucleophilicity compared to amino groups, and provided the desired product in good yield. Given the broad biological potential of thiopyrimidine derivatives, the next stage of this research will focus on evaluating the antimicrobial and other pharmacological activities of the synthesized compound. Such studies may pave the way for the development of new bioactive agents with therapeutic relevance. REFERENCES 1. Prachayasittikul V., Worachartcheewan A., Nantasenamat C., Chinworrungsee M., Sornsongkhram N., Ruchirawat S., Prachayasittikul V. Eur. J. Med. Chem. 2011, 46(2), 738– 758. 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