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Synlett 2012; 23(16): 2357-2362
DOI: 10.1055/s-0032-1317133
letter
© Georg Thieme Verlag Stuttgart · New York

A Facile Synthesis and Chemoselective Reactions of Dihydrothiouracils

Varun Kumar
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
,
Gopal L. Khatik
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
,
Anang Pal
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
,
Mohan R. Praneeth
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
,
Sanjay Bhattarai
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
,
Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India , Fax: +91(172)2214692   Email: vn74nr@yahoo.com
› Author Affiliations
Further Information

Publication History

Received: 06 June 2012

Accepted: 24 July 2012

Publication Date:
31 August 2012 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • 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