Synthesis of Highly Regioselective Bifunctional Tricyclic Tetrazole-1H-benzo[b][1,4]diazepins

Abstract

A new approach for the synthesis of arrays of bifunctional tricyclic tetrazole-1H-benzo[b][1,4]diazepines has been investigated. It includes a sequential two-step isocyanide-based condensation reaction of diamines or 2-nitroanilines, ethyl 3-oxobutanoate or 2,2,6-trimethyl-4H-1,3-dioxin-4-one, isocyanides and trimethylsilyl azide in good yields.

Key words

benzo[b][1,4]diazepin - tetrazole - multicomponent reaction - isocyanide - regioselective

• References and Notes

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• 23 General Procedure for the Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines 9a–h Diamines (1.00 mmol) and ethyl 3-oxobutanoate (1.50 mmol) or 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.20 mmol) in o-xylene (2 mL) were activated by exposure to microwave irradiation (700 W, multimode reactor) for 10 min. The benzo[b][1,4]diazepines 4a–c were recrystallized by cooling in o-xylene. The crystals were filtered and washed with Et₂O (2 × 5 mL) and then recrystallized from acetone to give benzo[b][1,4]diazepines 4a–c.¹⁸ To a solution of 1,4-diazepines 4a–c (0.50 mmol) and PTSA·H₂O (0.05 g, 2.50 mol%) in MeOH (5.00 mL) was added isocyanide (0.50 mmol) and trimethylsilyl azide (0.75 mmol), and the resulting mixture was stirred at r.t. After completion of the reaction, as indicated by TLC (EtOAc–n-hexane, 3:1) after 1 h, the precipitate was filtered off and washed with H₂O and MeOH, and then crystallized from acetone to give products 9a–h. General Procedure for the Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines 9a,b,d,e Ethyl 3-oxobutanoate (1.10 mmol) and 2-nitroanilines (1.00 mmol) were stirred in MeOH (2 mL) at r.t. for 1 h, and then trimethylsilyl azide (1.50 mmol) and isocyanide (1.50 mmol) were added. The reaction mixture was stirred for 48 h at r.t. until the reaction was complete (indicated by TLC).¹⁹ To this solution was added SnCl₂·2H₂O (5 mmol), and the resulting mixture stirred at reflux for 12 h. Then, the solvent was removed under vacuum, and the crude product was purified to give products 8a–d. To a stirred solution of products 8a–d in dry THF (10 mL) was added NaH as a 60% suspension in oil (0.121 g, 2.5 mmol), and the mixture was heated to reflux for 5 h. On completion, the reaction mixture was extracted with EtOAc (3 × 20 mL) and H₂O (30 mL). The organic layer was cooled, dried over Na₂SO₄, and the solvent was removed under vacuum to give products 9a,b,d,e.²⁰ Analytical Data 4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9a) Colorless crystals; mp >270 °C. IR (KBr): 3347, 3295, 3200, 3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526, 1449, 1376 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.00–1.80 (13 H, m, 5 CH₂ of cyclohexyl and CH₃), 2.65 (1 H, AB_q, J = 13.9 Hz, CH₂), 2.79 (1 H, AB_q, J = 13.9 Hz, CH₂), 5.14 (1 H, m, CH of cyclohexyl), 6.01 (1 H, s, NH), 6.80–6.97 (4 H, m, HAr), 9.84 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 25.1, 25.5, 25.6, 29.2, 33.4, 33.8, 47.1, 59.1, 61.2, 122.1, 122.2, 125.2, 129.9, 137.2, 157.9, 170.0. Anal. Calcd for C₁₇H₂₂N₆O: C, 62.56; H, 6.79; N, 25.75. Found: C, 62.52; H, 6.69; N, 25.70. 4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4,7-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9b) Colorless crystals; mp 245–247 °C. IR (KBr): 3347, 3295, 3200, 3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526, 1449, 1376 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.00–1.80 (13 H, m, 5 CH₂ of cyclohexyl and CH₃), 2.20 (3 H, s, CH₃), 2.55 (1 H, AB_q, J = 14.2 Hz, CH₂), 2.79 (1 H, AB_q, J = 13.9 Hz, CH₂), 5.12 (1 H, m, CH of cyclohexyl), 5.89 (1 H, s, NH), 6.58 (1 H, AB_q, J = 7.6 Hz, H-Ar), 6.76 (H, s, HAr), 6.93 (1 H, AB_q, J = 7.7 Hz, HAr), 9.75 (1 H, br s, NHCO).¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.9, 25.1, 25.6, 28.3, 33.4, 33.8, 47.0, 59.1, 61.2, 122.4, 122.6, 127.5, 134.3, 137.1, 157.9, 169.9. Anal. Calcd for C₁₈H₂₄N₆O: C, 63.51; H, 7.11; N, 24.69. Found: C, 63.41; H, 7.02; N, 24.60. 4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methyl-8-nitro-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9c) Red powder; mp 233–234 °C. IR (KBr): 3347, 3295, 3200, 3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526, 1449, 1376 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.00–1.80 (13 H, m, 5 CH₂ of cyclohexyl and CH₃), 3.12 (2 H, m, CH₂), 4.71 (1 H, m, CH of cyclohexyl), 7.04 (1 H, s, NH), 7.70 (1 H, s, HAr), 7.84 (2 H, m, HAr), 10.00 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 23.4, 24.7, 25.1, 29.8, 32.9, 33.9, 46.2, 58.2, 63.2, 115.3, 117.9, 120.5, 123.2, 134.3, 148.0, 158.4, 167.4. Anal. Calcd for C₁₇H₂₁N₇O₃: C, 54.98; H, 5.70; N, 26.40. Found: C, 54.90; H, 5.60; N, 26.35. 4-(1-tert-Butyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9d) Colorless crystals; mp 246–247 °C. IR (KBr): 3348, 3289, 3196, 3128, 3075, 2970, 2917, 2870, 1674, 1648, 1600, 1523, 1467, 1374 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.70 (9 H, m, 3 CH₃), 1.80 (3 H, s, CH₃), 2.61 (1 H, AB_q, J = 13.6 Hz, CH₂), 3.21 (1 H, AB_q, J = 13.9 Hz, CH₂), 6.03 (1 H, br s, NH), 6.70–7.10 (4 H, m, HAr), 9.57 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 31.0, 32.8, 49.0, 63.1, 64.3, 121.0, 121.6, 122.6, 125.2, 127.5, 131.2, 160.0, 170.1. Anal. Calcd for C₁₅H₂₀N₆O: C, 59.98; H, 6.71; N, 27.98. Found: C, 59.88; H, 6.65; N, 27.99. 4-Methyl-4-[1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl]-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9e) White crystals; mp 263–265 °C. IR (KBr): 3357, 3310, 3196, 3075, 2962, 2891, 2860, 1672, 1603, 1507, 1393, 1319 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.70 (12 H, br s, 4 CH₃), 2.25 (2 H, s, CH₂), 2.64 (8 H, s, 2 CH₃ and CH₂), 5.73 (1 H, s, NH), 6.70–7.20 (4 H, m, HAr), 9.70 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 28.1, 30.8, 31.6, 43.6, 45.8, 53.6, 63.0, 67.6, 121.9, 123.3, 125.1, 126.2, 128.9, 130.6, 161.9, 167.2. Anal. Calcd for C₁₉H₂₈N₆O: C, 64.02; H, 7.92; N, 23.58. Found: C, 64.05; H, 7.85; N, 23.55. 4-(1-Benzyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9f) Yellow powder; mp 192–194 °C. IR (KBr): 3354, 3285, 3212, 3028, 2965, 2854, 1681, 1635, 1517, 1450, 1374 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.75 (3 H, br s, CH₃), 2.91 (2 H, br s, CH₂), 5.69 (1 H, AB_q, J = 15.3 Hz, CH₂), 6.01 (1 H, AB_q, J = 15.3 Hz, CH₂), 6.88 (1 H, m, NH), 7.00–7.45 (9 H, m, HAr), 8.70 (1 H, br s, NHCO). 4.30 (2 H, m, CH₂), 5.13 (1 H, br s, NH), 6.66 (1 H, d, J = 7.95 Hz, HAr), 6.76 (2 H, m, HAr), 7.27 (5 H, m, HAr), 8.45 (1 H, m, NHCO), 9.47 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 28.9, 46.5, 52.3, 62.0, 121.8, 122.4, 125.5, 128.0, 128.5, 128.6, 129.1, 130.5, 135.6, 137.4, 159.0, 170.1. Anal. Calcd for C₁₈H₁₈N₆O: C, 64.66; H, 5.43; N, 25.13. Found: C, 64.60; H, 5.33; N, 25.10. 4-Methyl-4-[1-(2-methylbenzyl)-1H-tetrazol-5-yl]-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9g) Yellow powder; mp 192–194 °C. IR (KBr): 3354, 3285, 3212, 3028, 2965, 2854, 1681, 1635, 1517, 1450, 1374 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.75 (3 H, s, CH₃), 1.85 (3 H, s, CH₃), 2.73 (2 H, br s, CH₂), 6.44 (1 H, m, NH), 6.80–7.00 (4 H, m, HAr), 7.20–7.40 (4 H, m, HAr), 9.79 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 23.0, 29.8, 46.1, 58.9, 61.5, 121.9, 122.1, 122.4, 125.4, 126.9, 127.5, 128.5, 128.9, 129.0, 129.4, 137.6, 139.9, 158.6, 169.6. Anal. Calcd for C₁₉H₂₀N₆O: C, 65.50; H, 5.79; N, 24.12. Found: C, 65.50; H, 5.79; N, 24.12. 4-(1-tert-Butyl-1H-tetrazol-5-yl)-4-methyl-8-nitro-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9h) Red powder; mp 237–239 °C. IR (KBr): 3348, 3289, 3196, 3128, 3075, 2970, 2917, 2870, 1674, 1648, 1600, 1523, 1467, 1374 cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.82 (9 H, m, 3 CH₃), 2.31 (3 H, br s, CH₃), 3.19 (2 H, s, CH₂), 4.37 (1 H, br s, NH), 7.65 (2 H, s, HAr), 8.47 (1 H, s, HAr), 9.13 (1 H, br s, NHCO). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 30.7, 31.3, 44.8, 63.8, 64.8, 121.9, 123.9, 124.1, 126.2, 130.5, 148.5, 159.4, 170.4. Anal. Calcd for C₁₅H₁₉N₇O₃: C, 52.17; H, 5.55; N, 28.39. Found: C, 52.11; H, 5.48; N, 28.30.