PDF herunterladen
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;
Weitere Informationen

Publikationsverlauf

Received 18 December 2003
Publikationsdatum:
29. Januar 2004 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

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.

Key words

isatin - N-benzylisatin - microwave - thiosemicarbazones - triazinoindoles

    References

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