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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)

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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

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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).