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Synlett 2009(4): 607-610  
DOI: 10.1055/s-0028-1087563
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel Synthesis of 2,4-Dihydro-5-amino[1,2,4]triazol-3-ones from 1,3-Disubstituted Thioureas

Can Jin, Chuangwei Liu, Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax: +86(571)88320752; e-Mail: suweike@zjut.edu.cn;
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Publication History

Received 8 October 2008
Publication Date:
16 February 2009 (online)

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Abstract

A facile two-step synthesis of 2,4-dihydro-5-amino-[1,2,4]triazol-3-ones is described. Firstly, 1,3-disubstituted thioureas reacted with bis(trichloromethyl) carbonate (BTC) in the presence of a base such as NaHCO3 to form the intermediate 4-(arylimino)-1,3-thiazetidin-2-ones almost quantitatively. Then the intermediates were treated with hydrazine monohydrate to give 2,4-dihydro-5-amino[1,2,4]triazol-3-ones in high yields. In the case of highly sterically hindered thioureas, carbodiimides were unexpectedly obtained in high yields under the same conditions.

Key words

cyclizations - thiourea - regioselectivity - 1,2,4-triazol-3-ones - heterocycles

    References and Notes

  • 1a Sheppeck JE. Gilmore JL. Tebben A. Xue C. Liu R. Decicco CP. Duan JJ.-W. Bioorg. Med. Chem. Lett.  2007,  17:  2769 
    Google Scholar
  • 1b Ramla MM. Omar MA. El-Khamry AM. El-Diwani HI. Bioorg. Med. Chem.  2006,  14:  7324 
    Google Scholar
  • 1c Pevarello P. Brasca MG. Orsini P. Traquandi G. Longo A. Nesi M. Orzi F. Piutti C. Sansonna P. Varasi M. Cameron A. Vulpetti A. Roletto F. Alzani R. Ciomei M. Albanese C. Pastori W. Marsiglio A. Pesenti E. Fiorentini F. Bischoff JR. Mercurio C. J. Med. Chem.  2005,  48:  2944 
    Google Scholar
  • 2 Sheng C. Zhang W. Ji H. Zhang M. Song Y. Xu H. Zhu J. Miao Z. Jiang Q. Yao J. Zhou Y. Zhu J. Lv J. J. Med. Chem.  2006,  49:  2512 
    CrossrefGoogle Scholar
  • 3 Kane JM. Baron BM. Dudley MW. Sorensen SM. Staeger MA. Miller FP. J. Med. Chem.  1990,  33:  2772 
    CrossrefGoogle Scholar
  • 4 Watanabe Y. Usui H. Kobayashi S. Yoshiwara H. Shibano T. Tanaka T. Morishima Y. Yasuoka M. Kanao M. J. Med. Chem.  1992,  35:  189 
    CrossrefGoogle Scholar
  • 5a Shibuya I, and Kaba Y. inventors; JP  2003171369. 
  • 5b Chiu C. Kuo C. Kuo W. Yeh M. J. Chin. Chem. Soc.  2002,  49:  239 
    Google Scholar
  • 5c Mazurkiewicz R. Grymel M. Polish J. Chem.  1997,  71:  77 
    Google Scholar
  • 5d Frenna V. Spinelli D. Consiglio G.
    J. Chem. Soc., Perkin Trans. 2  1990,  8:  1289 
    Google Scholar
  • 5e Arrowsmith JE. Campbell SF. Cross PE. Burges RA. Gardiner DG. J. Med. Chem.  1989,  32:  562 
    Google Scholar
  • 5f Godfrey LEA. Kurzer F. J. Chem. Soc.  1960,  3437 
    Google Scholar
  • 6a Kurzer F. Hanks DR. Chem. Ind. (London, U.K.)  1966,  26:  1143 
    Google Scholar
  • 6b Kurzer F. Wilkinson M. J. Chem. Soc. C.  1970,  19 
    Google Scholar
  • 6c Kurzer F. Hanks DR. J. Chem. Soc. C.  1967,  746 
    Google Scholar
  • 6d Kurzer F. Wilkinson M. J. Chem. Soc. C  1970,  26 
    Google Scholar
  • 6e Tilley JW. Ramuz H. Levitan P. Blount JF. Helv. Chim. Acta  1980,  63:  841 
    Google Scholar
  • 7 Su W. Liu C. Shan W. Synlett  2008,  5:  725 
    Article in Thieme ConnectGoogle Scholar
  • 8 Su W. Jin C. Org. Lett.  2007,  9:  993 
    CrossrefGoogle Scholar
  • 9 The thiazetidin-2-one ring system was reported only once from dithiazolines with Ph3P, see: Tittelbach F. Seeboth H. Z. Chem.  1987,  27:  142 
    Google Scholar
10

General Procedure for the Preparation of Compound 2 from 1
To a mixture of EtOAc (25 mL), NaHCO3 (11.5 mmol, 0.97 g), and thioureas 1 (5 mmol), BTC (1.7 mmol, 0.5 g) was added carefully in portions. The reaction mixture was stirred at r.t. for 15 min. After completion (TLC), CH2Cl2 (20 mL) was added, the mixture was filtered, the organic solvent was condensed, and the intermediate 2 was obtained as crystal almost quantitatively.
3- p -Tolyl-4-( p -tolylimino)-1,3-thiazetidin-2-one (2b)
White needle crystals; mp 117.6-118.6 ˚C. MS (EI): m/z (%) = 282 (100) [M+], 283 (17) [M+ + 1], 253 (45). Anal. Calcd for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C, 68.08; H, 5.05; N, 9.91. IR (KBr): νmax = 1810, 1696, 1505, 1368 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H), 2.34 (s, 3 H), 6.99-7.01 (m, 2 H), 7.17 (d, 2 H, J = 8.0 Hz), 7.20 (d, 2 H, J = 8.0 Hz), 7.74-7.76 (m, 2 H). ¹³C NMR (125 MHz, CDCl3): δ = 21.0, 21.1, 121.0, 121.3, 124.0, 130.0, 130.1, 132.7, 135.8, 136.4, 139.7, 157.9.
3-(4-Methoxyphenyl)-4-(4-methoxyphenylimino)-1,3-thiazetidin-2-one (2i) White crystals; mp 88.5-90.1 ˚C. MS (EI): m/z (%) = 314 (100) [M+], 315 (18) [M+ + 1], 271 (16). Anal. Calcd for C13H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C, 61.11; H, 4.54; N, 8.94. IR (KBr): νmax = 1802, 1693, 1502, 1375cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 3.79 (S, 3 H), 3.80 (s, 3 H), 6.88-6.93 (m, 4 H), 7.04-7.07 (m, 2 H), 7.75 (dd, 2 H, J 1 = 6.8 Hz, J 2 = 2.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 55.5 (2 × CH), 114.3, 114.7, 122.3, 123.4, 125.1, 128.1, 139.2, 139.3, 157.9, 158.0.

11

Typical Procedure for the Preparation of Compound 4f from 1
To a mixture of EtOAc (25 mL), NaHCO3 (11.5 mmol, 0.97 g), and thioureas 1f (5 mmol), BTC (1.7 mmol, 0.5 g) was added carefully in portions. The reaction mixture was stirred at r.t. for 15 min. After completion (TLC), the mixture was filtered, the organic solvent was condensed and the compound 4f was obtained by flash chromatography under N2.
2,6-Diisopropylphenyl Carbodiimide (4f) Colorless oil. MS (EI): m/z (%) = 219 (100), 204 (74), 170 (32), 162 (39), 128 (43) 84 (29). Anal. Calcd for C25H34N2: C, 82.82; H, 9.45; N, 7.73. Found: C, 82.83; H, 9.48; N, 7.70. IR (KBr): νmax = 2965, 2069, 1461, 930cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.25 (s, 12 H), 1.27 (s, 12 H), 3.21-3.28 (m, 4 H), 7.12 (d, 4 H, J = 7.5 Hz), 7.22 (dd, 2 H, J 1 = 8.3Hz, J 2 = 7.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 22.9, 29.8, 123.5 (2  CH), 127.6 (2  CH), 145.1.

12

One-Pot Preparation of Compound 3 from 1
To a mixture of EtOAc (25 mL), NaHCO3 (11.5 mmol, 0.97 g), and thioureas 1 (5 mmol), BTC (1.7 mmol, 0.5 g) was added carefully in portions. The reaction mixture was stirred at r.t. for 15 min. After completion (TLC), then N2H4˙H2O (10 mmol) was added to the mixture and stirred for 20 min at 60 ˚C. The organic layer was washed with H2O (2 × 10 mml) and dried (MgSO4). The solvent was removed under vacuum. The residual was purified by recrystallization in PE-EtOAc to give 3 as a white crystal. 4-(2,5-Dimethylphenyl)-5-(2,5-dimethylphenylamino)-[1,2,4]triazol-3-one (3d) White crystals; mp 194.1-195.3 ˚C. MS (EI): m/z (%) = 308 (100) [M+], 309 (22) [M+ + 1], 249 (13), 145 (25), 131 (22), 121 (42), 91 (15), 77 (30). Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 70.10; H, 6.58; N, 18.14. IR (KBr): νmax = 3188, 1716, 1557, 1372, 1036 cm-¹. ¹H NMR (500 MHz, DMSO): δ = 1.99 (s, 3 H), 2.12 (s, 3 H), 2.18 (s, 3 H), 2.26 (s, 3 H), 6.67 (t, 1 H, J = 1.0 Hz), 6.91 (d, 1 H, J = 8.0 Hz), 7.01 (d, 1 H, J = 1.0 Hz), 7.08 (s, 1 H), 7.14 (t, 2 H, J = 7.5 Hz), 7.20 (d, 1 H, J = 8.0 Hz), 11.13 (s, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 17.4, 17.5, 20.7, 21.1, 121.8, 123.9, 126.2, 129.8, 130.2, 130.5, 131.0, 133.7, 135.6, 136.4, 138.9, 145.0, 153.5.
4-(4-Methoxyphenyl)-5-(4-methoxyphenylamino)-[1,2,4]triazol-3-one (3i)
White crystals; mp 211.2-215.5 ˚C. MS (EI): m/z (%) = 312 (100), 313 (18) [M+ + 1], 297 (35), 134 (17), 122 (22), 77 (8). Anal. Calcd for C16H16N4O3: C, 61.53; H, 5.16; N, 17.94; Found: C, 61.51; H, 5.19; N, 17.98. IR (KBr): νmax = 3085, 1701, 1601, 1085 cm-¹. ¹H NMR (500 MHz, DMSO): δ = 3.68 (s, 3 H), 3.81 (s, 3 H), 6.78-6.82 (m, 2 H), 7.05-7.08 (m, 2 H), 7.29-7.36 (m, 4 H), 7.85 (s, 1 H), 11.05 (s, 10 H). ¹³C NMR (125 MHz, DMSO): δ = 55.6, 55.9, 114.2, 115.0 (2 ↔CH), 119.6, 125.1, 129.7 (2  CH), 134.3
(4 ↔CH), 144.7, 153.7, 154.2, 159.6.