A Facile Synthesis and Chemoselective Reactions of Dihydrothiouracils

Abstract

A highly efficient procedure was devised for the synthesis of 3-(3-arylthioureido)propanoic/butanoic acid and its cyclization to (3-aryl/3-aryl-6-methyl)-2-thioxotetrahydropyrimidin-4(1H)-one derivatives. Carbonyl diimidazole proved to be a very effective coupling reagent for the cyclization. Studies carried out to examine the ambident nature of the thioamide moiety towards substitution reactions demonstrated the preference for alkylation at sulfur, and acylation and 1,4-addition at nitrogen.

Key words

uracils - amino esters - carbonyl diimidazole - thioamide - ambident nucleophile

• References and Notes

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• 15 General procedure for the preparation of 3-aryl-2-thioxotetrahydropyrimidin-4(1H)-ones: Aryl isothiocyanate (3.0 mmol) was dissolved in methanol (20 mL) and β-amino ester (3.0 mmol) was added, followed by 10 M KOH (2 mL). The reaction mixture was stirred at 20 °C for 2 h. After completion of the reaction, the solution was concentrated under reduced pressure and then neutralized by 1 M HCl until precipitation occurred. The product obtained was filtered and dried to give the desired acid. The acid was dissolved in acetonitrile (15 mL) and CDI (4.0 mmol) was added. The reaction mixture was stirred for 20 min (progress was monitored by TLC). Upon completion, the reaction mixture was concentrated and the product was precipitated in water, filtered, dried and recrystallized in methanol. 3-(4-Chlorophenyl)-2-thioxotetrahydropyrimidin-4(1H)-one (4aa): Yield: 90%; white solid; mp 201–203 °C; MS (APCI): m/z [M + H]⁺ calcd for C₁₀H₉ClN₂OS: 241.02; found: 241.13. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.81–2.85 (m, 2 H), 3.47–3.51 (m, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 10.01 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 30.96, 37.89, 128.80, 132.05, 132.63, 138.71, 167.76, 181.48. 3-(4-Chlorophenyl)-6-methyl-2-thioxotetrahydropyrim- idin-4(1H)-one (4ab): Yield: 93%; white solid; mp 249–251 °C. MS (APCI): m/z [M + H]⁺ calcd for C₁₁H₁₁ClN₂OS: 255.03; found: 255.13. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.26 (d, J = 6.4 Hz, 3 H), 2.66–2.73 (m, 1 H), 2.84–2.89 (m, 1 H), 3.86–3.87 (m, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 10.06 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.75, 38.10, 45.41, 128.85, 132.03, 132.68, 138.63, 167.57, 180.87
• 16 Energy calculations were performed using the Gaussian 03 program
• 17 The MESP surfaces were obtained by using the software SPARTAN
• 18 General procedure for alkylation reaction: To a solution of 3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one (1.0 mmol) in DMF (5 mL) was added K₂CO₃ (1.6 mmol) followed by alkyl halide (1.1 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. After completion of the reaction, the solution was concentrated under reduced pressure and the crude product was precipitated from water. The product was purified by column chromatography on silica gel (60–120 mesh; hexane–EtOAc, 85:15). 2-(Benzylthio)-3-(4-chlorophenyl)-5,6-dihydropyrimidin-4(3H)-one (5a): Yield: 88%; white solid; mp 180–182 °C. MS (APCI): m/z [M + H]⁺ calcd for C₁₇H₁₅ClN₂OS: 331.07; found: 331.12. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.69 (t, J = 7.3 Hz, 2 H), 3.86 (t, J = 7.3 Hz, 2 H), 4.12 (s, 2 H), 7.11–7.15 (m, 2 H), 7.20–7.27 (m, 5 H), 7.35–7.40 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 30.96, 36.83, 44.56, 124.47, 128.54, 129.20, 129.43, 131.02, 133.93, 135.43, 136.04, 154.77, 168.87
• 19 General procedure for acylation reaction: A solution of NaH (1.2 mmol) in THF (10 mL) was cooled to 0 °C and 3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one (1.0 mmol) was added. The reaction mixture was stirred for 30 min, then acyl chloride (1.1 mmol) was added. The reaction was monitored by TLC and, after completion, quenched with water and extracted into ethyl acetate. The organic layer was dried and concentrated to provide a gummy compound, which, upon purification by column chromatography on silica gel (60–120 mesh; hexane–EtOAc, 85:15), afforded the pure product. 1-Acetyl-3-(4-chlorophenyl)-2-thioxotetrahydropyrimidin-4(1H)-one (6a): Yield: 70%; light-yellow solid; mp 192–194 °C; MS (APCI): m/z [M + H]⁺ calcd for C₁₂H₁₁ClN₂O₂S: 283.03; found: 282.88. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.70 (s, 3 H), 2.99 (t, J = 6.6 Hz, 2 H), 4.23 (t, J = 6.6 Hz, 2 H), 7.07 (d, J = 8.3 Hz, 2 H), 7.45 (d, J = 8.5 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 27.60, 33.19, 40.82, 129.69, 130.38, 134.78, 137.08, 166.90, 174.03, 182.58
• 20 General procedure for 1,4-addition reaction: A procedure similar to the preparation of 3-aryl-2-(alkylthio)-5,6-dihydropyrimidin-4(3H)-ones was adopted for the aza-Michael reactions.Methyl 3-[3-(4-chlorophenyl)-4-oxo-2-thioxotetrahydropyrimidin-1(2H)-yl]propanoate (7a): Yield: 70%; light-brown liquid. MS (APCI): m/z [M + H]⁺ calcd for C₁₄H₁₅ClN₂O₃S: 327.06; found: 327.03. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.82–2.84 (m, 4 H), 3.64 (s, 3 H), 3.84 (t, J = 6.5 Hz, 2 H), 4.10 (t, J = 6.5 Hz, 2 H), 6.96–6.99 (m, 2 H), 7.30–7.33 (m, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 31.58, 31.90, 46.88, 51.80, 52.04, 129.26, 130.74, 134.23, 137.77, 166.60, 172.53, 181.04
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