3-Azidothieno[2,3-b]pyridine Thermolysis as a Route to Novel peri-Annelated Heterocyclic Derivatives – Benzo(furo)thieno[2,3,4-ij]-2,7-naphthyridines

Abstract

Synthesis of novel benzo(furo)thieno[2,3,4-ij]-2,7-naphthyridines based on alkyl(aryl) 3-azido-4-aryl(furyl)thieno[2,3-b]pyridine-2-carboxylate thermolysis is elaborated. The structures of the synthesized materials were assigned by their NMR, IR, and MS analysis.

Key words

thieno[2,3-b]pyridine - azides - fused-ring systems - thermolysis - nitrene - cyclization - naphthyridine

• References and Notes

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• 12 Alkyl(aryl) 3-Aminothieno[2,3-b]pyridine-2-carboxylates 3; General Procedure A solution of the requisite pyridine-2-thione (1, 2 mmol) in DMF (20 mL) and aq KOH (10%, 11.2 mL, 2 mmol) was stirred for 30–40 min until a solid formed. The precipitate was filtered off, washed with cold EtOH (7 mL), and air-dried. Then the solid was dissolved in DMF (10 mL), another portion of KOH solution (5.6 mL, 1 mmol) was added, and the mixture was stirred for a further 0.5–1 h until a yellow precipitate formed. The crystals were filtered off, washed with cold EtOH, and dried to yield 3-aminothieno[2,3-b]pyridines 4a–e in 58–68% yields. Ethyl 3-Amino-4,6-diphenyl-thieno[2,3-b]pyridine-2-carboxylate (4a) Yield 59%; bright yellow powder; mp 154–155 °C. IR (ATR): 3493 (asym. NH₂), 3355 (sym. NH₂), 1674 (C=O) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.27 (3 H, t, J = 7.2 Hz, CH ₃CH₂O), 4.24 (2 H, q, J = 7.2 Hz, CH₃CH ₂O), 5.78 (2 H, br s, NH₂), 7.45–7.53 (3 H, m, H_Ph), 7.58 (5 H, s, H_Ph), 7.75 (1 H, s, H_Py), 8.15–8.22 (2 H, m, H_Ph). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.8, 60.6, 95.4, 118.6, 120.7, 127.7 (2 C), 129.1 (2 C), 139.32 (2 C), 139.34 (2 C), 129.8, 130.4, 136.8, 137.7, 147.9, 148.5, 156.8, 161.4, 164.8. MS (EI, 70 eV): m/z (%) = 375 (26) [M + 1], 374 (100) [M]⁺, 345 (14), 327 (22), 326 (44), 301 (17), 300 (10), 299 (16), 298 (53), 59 (10), 58 (11), 43 (41), 42 (26). Anal. Calcd for C₂₂H₁₈N₂O₂S: C, 70.57; H, 4.85; N, 7.48. Found: C, 70.64; H, 4.76; N, 7.50. Ethyl 3-Amino-4-(5-methyl-2-furyl)-6-phenyl-thieno[2,3-b]pyridine-2-carboxylate (4c) Yield 61%; yellow powder; mp 140–141 °C. IR (ATR): 3454 (asym. NH₂), 3344 (sym. NH₂), 1666 (C=O) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.30 (3 H, t, J = 7.1 Hz, CH ₃CH₂O), 2.44 (3 H, s, CH₃-Fur), 4.25 (2 H, q, J = 7.1 Hz, CH₃CH ₂O), 6.43 (1 H, d, J = 3.6 Hz, 4-H Fur), 6.84 (2 H, br s, NH₂), 7.24 (1 H, d, J = 3.6 Hz, 3-H Fur), 7.45–7.55 (3 H, m, H_Ph), 7.97 (1 H, s, H_Py), 8.18 (2 H, d, J = 8.1, H_Ph). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.0, 14.9, 60.7, 94.9, 109.7, 115.6, 115.9, 118.7, 127.6 (2 C), 129.3 (2 C), 130.5, 136.2, 137.6, 148.2, 148.7, 155.6, 156.9, 162.5, 165.0. MS (EI, 70 eV): m/z (%) = 379 (31) [M + 1], 378 (100) [M]⁺, 350 (15), 332 (19), 331 (48), 306 (11), 262 (15), 261 (13), 189 (4), 152 (4), 53 (17), 44 (13), 43 (37). Anal. Calcd for C₂₁H₁₈N₂O₃S: C, 66.65; H, 4.79; N, 7.40. Found: C, 66.80; H, 4.85; N, 7.51. Phenyl 3-Amino-4,6-diphenylthieno[2,3-b]pyridine-2-carboxylate (4d) Yield 58%; bright yellow crystals; mp 178–179 °C. IR (ATR): 3493 (asym. NH₂), 3356 (sym. NH₂), 1686 (C=O) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.95 (2 H, br s, NH₂), 7.21 (2 H, d, J = 8.1 Hz, 2,6-H OPh), 7.27 (1 H, t, J = 7.3 Hz, 4-H OPh), 7.38–7.46 (2 H, m, H_Ph), 7.47–7.53 (3 H, m, H_Ph), 7.58–7.64 (5 H, m, H_Ph), 7.79 (1 H, s, H_Py), 8.21 (2 H, dd, J = 7.7, 2.5 Hz, H_Ph). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 93.7, 118.8, 120.4, 122.5 (2 C), 126.3, 127.8 (2 C), 129,0 (2 C), 129.4 (2 C), 129.5 (2 C), 129.8, 129.9 (2 C), 130.6, 136.6, 137.6, 148.8, 149.7, 150.6, 157.4, 161.8, 163.2. MS (EI, 70 eV): m/z (%) = 423 (16) [M + 1], 422 (90) [M]⁺, 331 (12), 330 (24), 329 (100), 301 (18), 300 (35), 299 (11), 241 (5), 227 (4), 224 (4). Anal. Calcd for C₂₆H₁₈N₂O₂S: C, 73.91; H, 4.29; N, 6.63. Found: C, 73.98; H, 4.38; N, 6.54.
• 13 Alkyl(aryl) 3-Azidothieno[2,3-b]pyridine-2-carboxylates 1a–e; General Procedure To a stirred solution of compound 4a–e (10 mmol) in AcOH (75 mL) H₂SO₄ (10 mmol, 0.52 mL) was added, and the mixture was cooled to 7–10 °C. After that a solution of NaNO₂ (15 mmol, 1.02 g) in H₂O (2 mL) was added, and the mixture was stirred for 15 min. The excess HNO₂ was neutralized with urea, and a solution of NaN₃ (15 mmol, 0.96 g) in H₂O (2 mL) was added. After 30 min the mixture was poured into 200 mL of cold H₂O, the resultant solid was filtered off, washed thoroughly with H₂O, and dried over P₂O₅ to give azides 1a–e in 75–84% yield. Due to their instability, compounds 1 were used for the next stage without additional purification. Ethyl 3-Azido-4,6-diphenylthieno[2,3-b]pyridine-2-carboxylate (1a) Yield 75%; bright yellow powder; mp (decomp.) 165–166 °C. IR (ATR): 2125 (N₃), 1703 (C=O) cm^–1. Ethyl 3-Azido-4-(5-methyl-2-furyl)-6-phenyl-thieno[2,3-b]pyridine-2-carboxylate (1c) Yield 79%; dark red powder; mp (decomp.) 149–150 °C. IR (ATR): 2119 (N₃), 1696 (C=O) cm^–1. Phenyl 3-Azido-4,6-diphenylthieno[2,3-b]pyridine-2-carboxylate (1d) Yield 84%; orange powder; mp (decomp.) 184–185 °C. IR (ATR): 2122 (N₃), 1709 (C=O) cm^–1.
• 14 Thermolysis of Alkyl(aryl) 3-Azidothieno[2,3-b]pyridine-2-carboxylates 4; General Procedure A solution of azide 3 (3 mmol) in chlorobenzene (100 mL) was heated to reflux for 30 min until termination of gas evolution and full consumption of the initial compound (TLC control). Next, the mixture was evaporated under reduced pressure to 1/3 of the initial volume, the hot solution was diluted with PE (10–15 mL) and left to allow crystallization. The crystals formed were filtered off, washed with PE and recrystallized from DMF to give products 5a–e in 57–67% yields. Ethyl 2-Phenyl-6H-benzo[c]thieno[2,3,4-ij]-2,7-naphthyridine-5-carboxylate (5a) Yield 57%; yellow crystals; mp 202–203 °C. IR (ATR): 3317 (NH), 1645, 1618, 1594, 1536, 1458, 1415, 1289, 1274, 1223, 1157, 1075, 1024, 743 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.34 (3 H, t, J = 6.9, CH ₃CH₂O), 4.32 (2 H, q, J = 6.9 Hz, CH₃CH ₂O), 7.13 (1 H, dd, J = 8.1, 8.1, 1.1 Hz, H-9), 7.44 (1 H, dd, J = 8.1, 8.2 Hz, H-8), 7.48 (2 H, dd, J = 8.1, 8.3 Hz, 3,5-H Ph), 7.51 (1 H, dd, J = 8.3, 1.7 Hz, 4-H Ph), 7.57 (1 H, dd, J = 8.2, 1.1 Hz, H-7), 8.11 (1 H, s, H-1), 8.16 (2 H, dd, J = 8.1, 1.7 Hz, 2,6-H Ph), 8.24 (1 H, d, J = 8.1 Hz, H-10), 9.97 (1 H, s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.9, 60.5, 92.0, 106.2, 117.2, 118.4, 122.7, 123.6, 125.3, 127.8 (2 C), 129.0 (2 C), 130.0, 132.5, 139.0, 139.4, 139.5, 140.2, 160.3, 161.3, 163.6. MS (EI, 70 eV): m/z (%) = 373 (8) [M + 1], 372 (30) [M]⁺, 371 (15), 327 (10), 326 (32), 300 (36), 299 (31), 298 (100), 297 (20), 254 (10), 252 (10), 239 (17), 226 (10), 148 (10), 43 (36). Anal. Calcd for C₂₂H₁₆N₂O₂S: C, 70.95; H, 4.33; N, 7.52. Found: C, 71.08; H, 4.39; N, 7.44. Ethyl 8-Methyl-2-phenyl-6H-furo[3,2-c]thieno[2,3,4-ij]-2,7-naphthyridine-5-carboxylate (5c) Yield 63%; yellow crystals; mp 231–232 °C. IR (ATR): 3308 (NH), 1633, 1601, 1538, 1415, 1367, 1266, 1239, 1165, 1083, 954, 766 cm^–1. 1H NMR (400 MHz, DMSO-d ₆): δ = 1.27 (3 H, t, J = 7.2 Hz, CH₂CH ₃), 2.30 (3 H, s, CH₃-Fur), 4.21 (2 H, q, J = 7.2 Hz, CH ₂CH₃), 6.37 (1 H, s, 4-H_Fur), 7.15 (1 H, s, H_Py), 7.42 (3 H, m, 3,4,5-H_Ph), 8.02 (2 H, m, 2,6-H_Ph), 10.75 (1 H, s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.5, 15.0, 60.0, 99.2, 101.3, 123.1, 127.4 (2 C), 128.9 (2 C), 129.2, 129.9, 131.7, 132.4, 136.7, 138.9, 140.8, 158.5, 159.8, 160.7, 163.3. MS (EI, 70 eV): m/z (%) = 377 (15) [M + 1], 376 (71) [M]⁺, 332 (14), 331 (15), 330 (100), 304 (15), 303 (53), 302 (81), 301 (11), 261 (7), 259 (7), 258 (10), 242 (5), 216 (6), 165 (19), 164 (19), 152 (13), 151 (34), 140 (7), 106 (21), 105 (24), 102 (10), 92 (20), 91 (59), 77 (13), 76 (39), 51 (16), 44 (13), 43 (33). Anal. Calcd for C₂₁H₁₆N₂O₃S: C, 67.00; H, 4.28; N, 7.44. Found: C, 67.05; H, 4.36; N, 7.39. Phenyl 2-Phenyl-6H-benzo[c]thieno[2,3,4-ij]-2,7-naphthyridine-5-carboxylate (5d) Yield 60%; yellow crystals; mp 214–216 °C. IR (ATR): 3375, 1665, 1618, 1594, 1559, 1532, 1481, 1453, 1391, 1294, 1278, 1196, 1165, 1141, 1044, 747 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.17 (1 H, t, J = 7.1 Hz, 4-H OPh), 7.23–7.38 (3 H, m, H_Ar), 7.40–7.58 (6 H, m, H_Ar), 7.73 (1 H, d, J = 8.3 Hz, H-7), 8.24 (2 H, d, J = 6.7, 2,6-H OPh), 8.29 (1 H, s, H-1), 8.57 (1 H, d, J = 7.9 Hz, H-10), 10.63 (1 H, s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 106.4, 117.2, 118.7, 122.7 (2 C), 123.0, 123.4, 125.5, 126.2, 127.9 (2 C), 129.2 (2 C), 129.8 (2 C), 130.3, 132.7, 136.2, 138.7, 139.7, 140.1, 140.9, 159.9, 160.4, 161.5, 161.7. MS (EI, 70 eV): m/z (%) = 217 (100) [M]⁺,421 (13) [M + 1], 420 (48) [M]⁺, 328 (25), 327 (100), 301 (11), 299 (53), 298 (16), 265 (10), 255 (10), 229 (10), 228 (13), 218 (10), 140 (13), 107 (14), 94 (57), 80 (15), 58 (19), 52 (10), 43 (33), 42 (14), 40 (17). Anal. Calcd for C₂₆H₁₆N₂O₂S: C, 72.27; H, 3.84; N, 6.66. Found: C, 72.34; H, 3.79; N, 6.59.