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

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.

cycloadditions - uracil analogues - pyrimidine - sulfur - heterocycles

References

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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 × CH_ar), 129.3 (CH_ar), 129.9 (2 × CH_ar), 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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<A NAME="RG23305ST-16">16</A>

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 × CH_ar), 128.7 (CH_ar), 129.5 (2 × CH_ar), 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.

<A NAME="RG23305ST-17">17</A>

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.