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Synlett 2005(18): 2805-2807  
DOI: 10.1055/s-2005-917114
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthesis of 1-Substituted Uracil Ring Systems and Their Thio Analogues

Aélig Robin, Karine Julienne, Sophie Raimbault, Jean-Claude Meslin, David Deniaud*
Laboratoire de Synthèse Organique, UMR CNRS 6513, FR 2465, Faculté des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax: +33(2)51125402; e-Mail: david.deniaud@chimie.univ-nantes.fr;
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Publication History

Received 21 July 2005
Publication Date:
10 October 2005 (online)

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Abstract

A facile and simple regioselective synthesis of uracils and their thio analogues has been achieved by cyclocondensation of a common precursor, diazadienium iodide 1, and isothiocyanates 2a,b. The key step in this synthetic process is the preparation of 4-methylsulfanylpyrimidine-2-thiones 3a,b, which after ­further elaboration gave the expected uracil analogues 4a,b-8a,b.

Key words

cycloadditions - uracil analogues - pyrimidine - sulfur - heterocycles

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Methylsulfanylpyrimidinethiones 3.
Isothiocyanate (2.2 mmol) was added to a solution of diazadienium iodide 1 (272 mg, 1.0 mmol) in CH2Cl2 (10 mL). After 15 min, Et3N (300 µL, 2.2 mmol) was added and the reaction mixture was stirred at r.t. over a period of 4 h for 3a and 4 h for 3b. Then, the organic mixture was washed twice with H2O, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (CH2Cl2-PE-Et3N, 50:47:3).
Spectroscopic data of compound 3a: IR (KBr): ν = 1605, 1589, 1481, 1405, 1323, 1175 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.66 (s, 3 H, CH 3S), 6.60 (d, 1 H, 3 J = 7.0 Hz, CH-5), 7.40 (m, 5 H, 5 × CH ar), 7.43 (d, 1 H, 3 J = 7.0 Hz, CH-6). 13C NMR (50 MHz, CDCl3): δ = 13.2 (CH3S), 107.7 (CH-5), 126.6 (2 × CHar), 129.3 (CHar), 129.9 (2 × CHar), 144.0 (2 C, CH-6 and C ar), 173.4 (C-4), 182.0 (CS). Mp 173-175 °C. HRMS (ESI+): m/z calcd for C11H10N2S2Na [M + Na]+: 257.0183; found: 257.0182.

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Methylthiouracils 6.
Oxone® (1.23 g, 2.0 mmol) and wet alumina (1.0 g) were added to a solution of methylsulfanylpyrimidinethiones (1.0 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at r.t. for 48 h. Then, the inorganic salts were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (CH2Cl2-PE-Et3N, 90:7:3).
Spectroscopic data of compound 6a: IR (KBr): ν = 1664, 1614, 1493, 1287 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.52 (s, 3 H, CH 3S), 6.22 (d, 1 H, 3 J = 7.0 Hz, CH-5), 7.28 (m, 6 H, 5 × CH ar and CH-6). 13C NMR (50 MHz, CDCl3): δ = 13.0 (CH3S), 103.7 (CH-5), 126.1 (2 × CHar), 128.7 (CHar), 129.5 (2 × CHar), 140.3 (C ar), 144.0 (CH-6), 153.9 (CO), 178.6 (C-4). Mp 156-158 °C. HRMS (ESI+): m/z calcd for C11H10N2OSNa [M + Na]+: 241.0412; found: 241.0410.

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Spectroscopic data of compound 7b: IR (KBr): ν = 1742, 1734, 1719, 1630, 1325, 1109 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 3.25 (s, 3 H, CH 3N), 6.22 (d, 1 H, 3 J = 6.8 Hz, CH-5), 7.53 (d, 1 H, 3 J = 6.8 Hz, CH-6). 13C NMR (50 MHz, DMSO-d 6): δ = 36.0 (CH3N), 111.7 (CH-5), 142.4 (CH-6), 148.8 (CO), 190.1 (CS). Mp 193-196 °C. HRMS (ESI+): m/z calcd for C5H6N2SONa [M + Na]+: 165.0099; found: 165.0098.
Spectroscopic data of compound 8b: IR (KBr): ν = 1695, 1423, 1379, 1331. 1H NMR (400 MHz, DMSO-d 6): δ = 3.21 (s, 3 H, CH 3N), 5.51 (d, 1 H, 3 J = 8.0 Hz, CH-5), 7.60 (d, 1 H, 3 J = 8.0 Hz, CH-6). 13C NMR (50 MHz, DMSO-d 6): δ = 34.4 (CH3N), 99.7 (CH-5), 145.6 (CH-6), 150.5 (CO-2), 163.1 (CO-4). Mp 229-234 °C. HRMS (ESI+): m/z calcd for C5H6N2O2Na [M + Na]+: 149.0327; found: 149.0325.