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

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

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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).