Synlett 2004(4): 723-725  
DOI: 10.1055/s-2004-815437
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave Irradiation for Accelerating each Step for the Synthesis of 1,2,4-Triazino[5,6-b]indole-3-thiolsand their Derivatives from Isatin and 5-Chloroisatin

El Sayed H. El Ashry*, El Sayed Ramadan, Hamida M. Abdel Hamid, Mohamed Hagar
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Fax: +20(3)4271360; e-Mail: eelashry60@link.net; e-Mail: eelashry60@hotmail.com;
Further Information

Publication History

Received 18 December 2003
Publication Date:
29 January 2004 (online)

Abstract

Microwave irradiation has been used to accelerate the conversion of isatin (1), 5-chloroisatin (2), and N-benzylisatin (3) to their thiosemicarbazones and their subsequent cyclization into 1,2,4-triazino[5,6-b]indole-3-thiols 7 and 8; and the N-benzyl derivative 9. Selective and complete alkylation of 1, 7, 8, and 9 has also been achieved under microwave irradiation.

    References

  • 1 Bell MR. Zalay AW. Osterlin R. Clemans SD. Dumas DJ. Bradford JC. Rozitis J. J. Med. Chem.  1977,  20:  537 
  • 2 Popp FD. J. Heterocycl. Chem.  1984,  21:  1641 
  • 3 Jan KC. Pathak VN. Jain SK. Pharmazie  1980,  35:  677 
  • 4 Bauer DJ. Sadler PW. Br. J. Pharmacol.  1960,  15:  101 
  • 5 Bauer DJ. Apostolov K. Selway JWT. Ann. N. Y. Acad. Sci.  1970,  173:  314 
  • 6 Bauer DJ. Apostolov K. Science  1966,  154:  796 
  • 7 Gladych JMZ. Hornby R. Hunt JH. Jack D. Boyle JJ. Ferlauto RJ. Haff RF. Kormendy CG. Stanfield FJ. Stewart RC. J. Med. Chem.  1972,  15:  277 
  • 8 Gladych JMZ. Hunt JH. Jack D. Haff RF. Boyle JJ. Stewart RC. Ferlauto RJ. Nature (London, U.K.)  1969,  221:  286 
  • 9 Boyle JJ. Raupp WG. Stanfield FJ. Haff RF. Dick EC. D’Alessio D. Dick CR. Ann. N. Y. Acad. Sci.  1970,  173:  477 
  • 10 Gwaltney JM. Proc. Soc. Exp. Biol. Med.  1970,  133:  1148 
  • 11 Haff RF. Flagg WB. Gallo JJ. Hoover JRE. Miller JA. Pinto CA. Pagano JF. Proc. Soc. Exp. Biol. Med.  1972,  141:  475 
  • 12 El Ashry ESH. Rashed N. Taha M. Ramadan E. Adv. Heterocycl. Chem.  1994,  59:  39 
  • 13 El Ashry ESH. Rashed N. Mousaad A. Ramadan E. Adv. Heterocycl. Chem.  1994,  61:  207 
  • 14 Mousaad A. Abdel Hamid H. El Nemr A. El Ashry ESH. Bull. Chem. Soc. Jpn.  1992,  65:  546 
  • 15 Mousaad A. Rashed N. Ramadan E. El Ashry ESH. Spectrosc. Lett.  1994,  27:  677 
  • 16 Rashed N. El Nemr A. El Ashry ESH. Spectrosc. Lett.  1993,  26:  1817 
  • 17 El Ashry ESH. Rashed N. Abdel Hamid H. Ramadan E. Z. Naturforsch., B: Chem. Sci.  1997,  52:  873 
  • 18 Rashed N. Abdel Hamid H. Ramadan E. El Ashry ESH. Nucleosides Nucleotides  1998,  17:  373 
  • 19 Abdel Hamid H. Mousaad A. Ramdan E. El Ashry ESH. Heterocyl. Commun.  1999,  5:  473 
  • 20 El Ashry ESH. Abdel Hamid H. Mousaad A. Ramadan E. J. Chem. Res., Miniprint  2002,  752 
  • 21 Abdel-Rahman AAH. El Ashry ESH. Synlett  2002,  2043 
  • 22 Abdel Hamid H. Ramadan E. Hagar M. El Ashry ESH. Synth. Commun.  2004,  34:  365 
  • 23 Lidstrom P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
  • 24 Gedye RN. Smith FE. Westaway KC. Can. J. Chem.  1988,  66:  17 
  • 25 Mingos DMP. Baghurst DR. Chem. Soc. Rev.  1991,  20:  1 
  • 26 Abramovitch RA. Org. Prep. Proced. Int.  1991,  23:  683 
  • 27 Caddick S. Tetrahedron  1995,  51:  10403 
  • 28 Laurent R. Laporterie A. Dubac J. Berlan J. Lefeuvre S. Audhuy M. J. Org. Chem.  1992,  57:  7099 
  • 29 Bogdal D. Pielichowski J. Jaskot K. Org. Prep. Proced. Int.  1998,  30:  427 
  • 30 Dandia A. Sachdeva H. Devi R. J. Chem. Res., Synop.  2000,  272 
  • 31 Mojtahedi MM. Saidi MR. Heravi MM. Bolourtchain M. Monatsh. Chem.  1999,  130:  1175 
  • 33 Hellmann H. Hallmann G. Lingens F. Chem. Ber.  1953,  86:  1346 
  • 34 Soliman FSG. Salama HM. Pharmazie  1983,  38:  585 
  • 35 Autrey RL. Tahk FC. Tetrahedron  1967,  33:  901 
  • 37 Bernstein J. Yale HL. Losee K. Holsing M. Martius J. Lott WA. J. Am. Chem. Soc.  1951,  73:  906 
  • 38 Antrich O. Justus Liebigs Ann. Chem.  1885,  227:  364 
  • 39 Jancevska M. Glas. Hem. Tehnol. Makedonkja.  1974,  1:  57 ; Chem. Abstr. 1977, 87, 184415
  • 40 inventors; Allen and Hanburys Ltd Neth. Pat.  6410823.  ; Chem. Abstr. 1965, 63, 13295
  • 42 Holla BS. Udupa KV. J. Indian Chem. Soc.  1988,  65:  524 
  • 43 Holla BS. Udupa KV. Heterocycles.  1991,  32:  1081 
  • 45 Abdel Hamid H. J. Chem. Res., Synop.  2004,  in press: 
32

A mixture of 1 (1.0 g, 6.8 mmol) and K2CO3 (2.0 g, 14.5 mmol) in H2O (10 mL) was irradiated (microwave oven EM-230M; 800 watt output power) until dry (ca. 2 min). Benzyl chloride (1.5 mL, 12.9 mmol) and NaI (2.0 g, 13.3 mmol) were added and the mixture was irradiated for 7 min. The product was triturated with EtOH (15 mL) and the N-benzylisatin (3) was recrystallized from EtOH as orange crystals (1.15 g, 72%), mp 130-132 °C; lit. [33] mp 131-132 °C.

36

A mixture of 1, 2, or 3 (0.21 mmol) and thiosemicarbazide (0.023 g, 0.25 mmol) in EtOH (5 mL) and one drop of HOAc was irradiated for 2.5 min. The product was recrystallized from EtOH-DMF to afford isatin 3-thiosemicarbazone (4) (0.043 g, 93%), mp 246-248 °C, lit [37] mp 247-248 °C; 5-chloroisatin 3-thiosemicarbazone (5) (0.048 g, 90%), mp 272 °C; 1-benzylisatin 3-thiosemicarbazone (6) (0.06 g, 92%), mp 262-264 °C, lit. [38] mp 268 °C.

41

A mixture of 4, 5, or 6 (0.68 mmol) and K2CO3 (0.12 g, 0.86 mmol) in water (30 mL) was irradiated for 15-30 min. The reaction mixture was acidified with acetic acid and the product was recrystallized from EtOH-DMF to give 1,2,4-triazino [5,6-b]indole-3-thiol (7) (0.12 g, 87%), mp > 300 °C, lit. [40] mp > 300 °C; 8-chloro-1,2,4-triazino[5,6-b]indole-3-thiol (8) (0.13 g, 83%), mp > 300 °C; 5-benzyl-1,2,4-triazino[5,6-b]indole-3-thiol (9) (0.12 g 64%), mp 263-265 °C, lit. [7] mp 269-271 °C. Compound 9 was also obtained by microwave irradiation of 3 (0.2 g, 0.84 mmol), thiosemicarbazide (0.10 g, 1.10 mmol), and K2CO3 (0.35 g, 2.5 mmol) in water (30 mL) for 30 min (0.2 g, 81%).

44

A mixture of 7, 8, or 9 (0.34 mmol) and K2CO3 (0.072 g, 0.52 mmol) in water (10 mL) was irradiated by microwave till dissolution, then benzyl chloride or ethyl chloroacetate (1.75 mmol) was added and reirradiated for 2.5 min and the product was recrystallized from EtOH-DMF to give 3-benzylthio-1,2,4-triazino[5,6-b]indole (10) (0.08 g, 83%), mp 272-274 °C; 3-benzylthio-8-chloro-1,2,4-triazino[5,6-b]indole (11) (0.09 g, 82%) mp 296 °C; 3-carbethoxy-methylthio-1,2,4-triazino[5,6-b]indole (12) (0.087 g, 89%), mp 234 °C, lit. [45] mp 235-237 °C; 3-benzylthio-5-benzyl-1,2,4-triazino[5,6-b]indole (13) (0.11 g, 84%), mp 149-150 °C. Microwave irradiation of a mixture of 10, 11, or 12 (0.9 mmol) in DMF (20 mL), NaH (0.05 g, 2 mmol), benzyl chloride or ethyl chloroacetate (4.3 mmol) and NaI (0.32 g, 2.15 mmol) for 6 min gave 13 (0.29 g, 85%); 3-benzylthio-5-benzyl-8-chloro-1,2,4-triazino[5,6-b]indole (14) (0.3 g, 78%), mp 182 °C; 3-carbethoxymethylthio-5-carbethoxymethyl-1,2,4-triazino[5,6-b]indole (15) (0.24 g, 70%), mp 162 °C, lit. [45] mp160-162 °C. 1H NMR (CDCl3, 300 MHz): 10: δ = 4.55 (s, 2 H, S-CH2), 7.42 (ddd, 1 H, H-8, J 8,7 = 7.1 Hz, J 8,9 = 7.8 Hz, J 8,6 = 0.8 Hz), 7.58 (d, 1 H, H-6, J 6,7 = 8.2 Hz), 7.69 (ddd, 1 H, H-7, J 7,6 = 8.2 Hz, J 7,8 = 7.1 Hz, J 7,9 = 1.2 Hz), 8.31 (d, 1 H, H-9, J 9,8 = 7.8 Hz), 7.22-7.28 (m, 1 H, Ph-H), 7.30-7.35 (m, 2 H, Ph-H), 7.50-7.53 (m, 2 H, Ph-H); 11: δ = 4.52 (s, 2 H, S-CH2), 7.56 (d, 1 H, H-6, J 6,7 = 9.1 Hz), 7.66 (dd, 1 H, H-7, J 7,6 = 9.1 Hz, J 7.9 = 2.2 Hz), 8.29 (d, 1 H, H-9, J 9,7 = 2.2 Hz), 7.22 [d, 1 H, Ph-H (p), J p , m = 7.6 Hz], 7.30 [t, 2 H, Ph-H (m), J m , p = 7.6 Hz, J m , o = 7.2 Hz], 7.49 [d, 2 H, Ph-H (o), J o , m = 7.2 Hz]; 13: δ = 4.51 (s, 2 H, S-CH2), 5.43 (s, 2 H, N-CH2), 7.25 (d, 1 H, H-6, J 6,7 = 8.2 Hz), 7.33 (t, 1 H, H-8, J 8,7 = 7.6 Hz, J 8,9 = 7.6 Hz), 7.49 (ddd, 1 H, H-7, J 7,6 = 8.2 Hz, J 7,8 = 7.6 Hz, J 7,9 = 1.0 Hz), 8.33 (d, 1 H, H-9, J 9,8 = 7.6 Hz), 7.13-7.18 (m, 4 H, Ph-H), 7.20-7.22 (m, 4 H, Ph-H), 7.41-7.43 (m, 2 H, Ph-H), 13C NMR (CDCl3, 75.47 MHz): δ = 35.7 (S-CH2), 45.4 (N-CH2), 187.7 (C-3), 168.4 (C-4a), 141.5 (C-5a), 111.2 (C-6), 135.5 (C-7), 123.5 (C-8), 122.8 (C-9), 99.6 (C-9a), 147.1 (C-9b), 141.2, 128.9, 129.6, 131.1, 137.8, 127.7, 129.4, 128.6 (2 × C6H5). 14: δ = 4.58 (s, 2 H, S-CH2), 5.49 (s, 2 H, N-CH2), 7.19 (d, 1 H, H-6, J 6,7 = 6.9 Hz), 7.51 (dd, 1 H, H-7, J 7,6 = 6.9 Hz), 8.34 (d, 1 H, H-9, J 9,7 = 1.5Hz), 7.24-7.27 (m, 4 H, Ph-H), 7.29-7.30 (m, 4 H, Ph-H), 7.48-7.49 (m, 2 H, Ph-H).