Synthesis of Novel 1,4-Benzodiazepine-3,5-dione Derivatives: Reaction of 2-Aminobenzamides under Bargellini Reaction Conditions

Abstract

In this paper, we report on a user-friendly synthesis of 1,4-benzodiazepine-3,5-dione derivatives via Bargellini-type reaction. The corresponding products were obtained using various 2-aminobenzamides under Bargellini reaction conditions, in good yields without unfavorable side reaction.

Key words

Bargellini-type reaction - 1,4-benzodiazepine-3,5-di­ones - 2-aminobenzamides - heterocycles - dichloro epoxide

• References and Notes

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• 25 Synthesis of 1,2-Dihydro-4H-benzo[e][1,4]diazepine-3,5-dione Derivatives – General Procedure A mixture of anhydrous acetone–ethyl methyl ketone (40 mmol, 3 mL) and CHCl₃ (60 mmol, 4.6 mL) in the presence of NaOH powder (60 mmol, 2.3 g) was stirred at r.t. for 10 min (in the case of ethylmethyl ketone it should be stirred for 15 min). After this time, 2-aminobenzamide derivatives (2 mmol) were added to the reaction mixture and it continued for the corresponding time, as indicated in Table 1, at the same temperature. Upon completion of reaction the solution was extracted with CHCl₃ (3 × 20 mL). The organic layer was separated, dried (Na₂SO₄), and concentrated in vacuo to yield the crude product which was purified by column chromatography eluting with PE–EtOAc (6:1). 1,2-Dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11a) Yield 0.17 g (85%); white crystals; mp 228–230 °C. IR (KBr): 3337 (NH), 1698 (C=O), 1636 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.48 (s, 6 H, CH₃), 4.11 (s, 1 H, NH), 6.78 (d, J = 7.6 Hz, 1 H, H₉), 7.02 (t, J = 7.6 Hz, 1 H, H₇), 7.40 (td, J = 7.6, 1.4 Hz, 1 H, H₈), 8.20 (dd, J = 7.6, 1.4 Hz, 1 H, H₆), 8.11 (s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 23.5, 56.5, 116.8, 118.6, 120.0, 131.8, 134.0, 146.8, 165.0, 173.6. Anal. Calcd for C₁₁H₁₂N₂O₂: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.80; H, 6.10; N, 13.55. 2-Ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11b) Yield 0.18 g (85%); white crystals; mp 160–162 °C. IR (KBr): 3359 (NH), 1698 (C=O), 1645 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.87 (t, J = 7.4 Hz, 3 H, CH₂CH₃ ), 1.48 (s, 3 H, CH₃), 1.75 (dq, J = 14.8, 7.4 Hz, 1 H, CH₂ CH₃), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 4.16 (s, 1 H, NH), 6.79 (d, J = 7.5 Hz, 1 H, H₉), 7.00 (t, J = 7.5 Hz, 1 H, H₇), 7.40 (dt, J = 7.5, 1.3 Hz, 1 H, H₈), 8.19 (dd, J = 7.5, 1.3 Hz, 1 H, H₆), 8.21 (s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ = 7.5, 22.7, 27.9, 60.8, 120.3, 120.6, 133.1, 134.8, 145.5, 164.3, 173.8. Anal. Calcd for C₁₂H₁₄N₂O₂: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.90; H, 6.55; N, 12.99. 4-Benzyl-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]-diazepine-3,5-dione (11c) Yield 0.23 g (80%); white crystals; mp 100–102 °C. IR (KBr): 3335 (NH), 1698 (C=O), 1650 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.35 (s, 6 H, CH₃), 5.03 (s, 2 H, NCH₂), 6.80 (s, 1 H, NH), 6.99–7.05 (m, 2 H, H₉, H_4′), 7.17–7.19 (m, 3 H, H₇, H_2′, H_6′), 7.27–7.37 (m, 3 H, H₈, H_3′, H_5′), 7.98 (d, J = 7.2 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 23.3, 48.5, 56.5, 116.4, 117.9, 119.1, 126.7, 126.9, 128.2, 132.2, 133.9, 138.2, 145.8, 167.6, 176.4. Anal. Calcd for C₁₈H₁₈N₂O₂: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.30; H, 6.40; N, 10.21. 4-Benzyl-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e]-[1,4]diazepine-3,5-dione (11d) Yield 0.23 g (75%); white crystals; mp 134–136 °C. IR (KBr): 3467 (NH), 1695 (C=O), 1641 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.78 (t, J = 7.4 Hz, 3 H, CH₂CH ₃), 1.46 (s, 3 H, CH₃), 1.77–1.83 (m, 2 H, CH ₂CH₃), 4.53 (s, 1 H, NH), 5.13 (d, J = 15.7 Hz, 1 H, NCH₂), 5.31 (d, J = 15.7 Hz, 1 H, NCH₂), 6.77 (d, J = 8.1 Hz, 1 H, H₉), 6.89 (t, J = 7.5 Hz, 1 H, H₇), 6.98–7.00 (m, 1 H, H_4′), 7.06–7.11 (m, 2 H, H_2′, H_6′), 7.29–7.39 (m, 3 H, H₈, H_3′, H_5′), 8.11 (d, J = 7.5 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 8.4, 20.3, 28.3, 47.1, 61.2, 118.1, 119.0, 119.6, 126.5, 126.8, 127.7, 129.2, 132.6, 133.2, 134.2, 134.9, 144.7, 167.5, 173.7. Anal. Calcd for C₁₉H₂₀N₂O₂: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.80; H, 6.35; N, 9.30. 4-(2-Chlorobenzyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11e) Yield 0.27 g (82%); yellow crystals; mp 130–132 °C. IR (KBr): 3338 (NH), 1697 (C=O), 1622 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.51 (s, 6 H, CH₃), 4.37 (s, 1 H, NH), 5.26 (s, 2 H, NCH₂), 6.76 (dd, J = 8.2, 1.0 Hz, 1 H, H₉), 6.95 (ddd, J = 8.2, 6.5, 1.1 Hz, 1 H, H_4′), 7.05 (t, J = 7.0 Hz, 1 H, H₇), 7.14–7.17 (m, 2 H, H_5′, H_6′), 7.34 (dd, J = 6.5, 3.0 Hz, 1 H, H_3′), 7.38 (ddd, J = 8.2, 7.0, 1.5 Hz, 1 H, H₈), 8.20 (dd, J = 7.0, 1.5 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 24.7, 47.3, 58.0, 118.4, 119.1, 119.9, 126.6, 127.0, 127.9, 129.4, 132.9, 133.5, 134.3, 135.1, 144.8, 167.6, 173.5. MS: m/z (%) = 330 (17) [M + 2]⁺, 328 (51) [M⁺], 300 (20), 203 (25), 160 (100). 132 (85), 92 (28), 65 (20). Anal. Calcd for C₁₈H₁₇ClN₂O₂: C, 65.75; H, 5.21; N, 8.52. Found: C, 65.90; H, 5.45; N, 8.40. 4-(2-Chlorobenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11f) Yield 0.26 g (75%); yellow crystals; mp 134–136 °C. IR (KBr): 3350 (NH) 1697 (C=O), 1623 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.81 (t, J = 7.4 Hz, 3 H, CH₂CH ₃), 1.49 (s, 3 H, CH₃), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 1.87 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 4.50 (s, 1 H, NH), 5.19 (d, J = 15.7 Hz, 1 H, NCH₂), 5.36 (d, J = 15.7 Hz, 1 H, NCH₂), 6.77 (d, J = 8.0 Hz, 1 H, H₉), 6.92 (t, J = 7.5 Hz, 1 H, H_4′), 7.05 (t, J = 8.2 Hz, 1 H, H₇), 7.12–7.18 (m, 2 H, H_5′, H_6′), 7.32–7.39 (m, 2 H, H₈, H_3′), 8.16 (d, J = 8.2 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 7.5, 27.2, 47.2, 61.3, 119.1, 119.7, 126.6, 127.1, 127.8, 128.6, 129.0, 129.3, 132.8, 133.3, 134.2, 144.7, 167.5, 173.7. Anal. Calcd for C₁₉H₁₉ClN₂O₂: C, 66.57; H, 5.59; N, 8.17. Found: C, 66.80; H, 5.40; N, 7.95. 4-(4-Methoxybenzyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11g) Yield 0.24 g (75%); white crystals; mp 120–122 °C. IR (KBr): 3329 (NH), 1694 (C=O), 1609 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.43 (s, 6 H, CH₃), 3.77 (s, 3 H, OCH₃), 4.42 (s, 1 H, NH), 5.12 (s, 2 H, NCH₂), 6.70 (d, J = 8.1 Hz, 1 H, H₉), 6.82 (d, J = 8.5 Hz, 2 H, H_3′, H_5′), 6.91 (t, J = 7.6 Hz, 1 H, H₇), 7.31–7.34 (m, 3 H, H₈, H_2′, H_6′), 8.20 (dd, J = 7.6, 1.4 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 24.4, 48.7, 55.1, 57.7, 113.6, 114.1, 118.4, 118.8, 119.4, 129.4, 130.2, 133.4, 134.0, 144.5, 158.5, 167.8, 173.0. Anal. Calcd for C₁₉H₂₀N₂O₃: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.50; H, 6.44; N, 8.80. 4-(4-Methoxybenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11h) Yield 0.24 g (70%); white crystals; mp 110–111 °C. IR (KBr): 3320 (NH), 1698 (C=O), 1617 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.71 (t, J = 7.4 Hz, 3 H, CH₂CH ₃), 1.47 (s, 3 H, CH₃), 1.67 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 1.76 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 3.76 (s, 3 H, OCH₃), 4.43 (s, 1 H, NH), 5.09 (d, J = 14.0 Hz, 1 H, NCH₂), 5.15 (d, J = 14.0 Hz, 1 H, NCH₂), 6.71 (d, J = 7.3 Hz, 1 H, H₉), 6.81 (d, J = 8.6 Hz, 2 H, H_3′, H_5′), 6.90 (t, J = 7.3 Hz, 1 H, H₇), 7.32 (dt, J = 7.3, 1.5 Hz, 1 H, H₈), 7.36 (d, J = 8.6 Hz, 2 H, H_2′, H_6′), 8.19 (dd, J = 7.3, 1.5 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 7.4, 23.1, 26.9, 48.7, 55.1, 60.9, 113.5, 118.3, 118.8, 119.3, 129.8, 130.2, 133.2, 134.0, 144.3, 158.5, 167.7, 173.1. MS: m/z (%) = 338 (76 [M⁺], 281 (20), 217 (20), 174 (59), 146 (52), 121 (100), 77 (25). Anal. Calcd for C₂₀H₂₂N₂O₃: C, 70.99; H, 6.55; N, 8.28. Found: C, 71.15; H, 6.80; N, 8.35. 4-[(Furan-2-yl)-methyl]-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11i) Yield 0.18 g (65%); white crystals; mp 103–105 °C. IR (KBr): 3366 (NH), 1695 (C=O), 1625 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.45 (s, 6 H, CH₃), 4.37 (s, 1 H, NH), 5.17 (s, 2 H, NCH₂), 6.28–6.29 (m, 2 H, furan), 6.71 (dd, J = 7.6, 0.9 Hz, 1 H, H₉), 6.92 (dt, J = 7.6, 0.9 Hz, 1 H, H₇), 7.30 (dd, J = 3.0, 1.0 Hz, 1 H, furan), 7.34 (dt, J = 7.6, 1.4 Hz, 1 H, H₈), 8.21 (dd, J = 7.6, 1.4 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 24.5, 42.1, 57.8, 108.1, 110.2, 118.2, 118.9, 119.6, 133.5, 134.1, 141.6, 144.6, 151.4, 167.2, 173.2. MS: m/z (%) = 284 (35) [M⁺], 257 (15), 241 (20), 203 (20), 160 (100), 132 (90), 96 (71), 53 (28). Anal. Calcd for C₁₆H₁₆N₂O₃: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.66; H, 5.86; N, 10.00. 2-Ethyl-4-[(furan-2-yl)-methyl]-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-3,5-dione (11j) Yield 0.18 g (60%); white crystals; mp 102–104 °C. IR (KBr): 3336 (NH), 1697 (C=O), 1621 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.73 (t, J = 7.4 Hz, 3 H, CH₂CH ₃), 1.49 (s, 3 H, CH₃), 1.66 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH ₂CH₃), 4.37 (s, 1 H, NH), 5.09 (d, J = 14.7 Hz, 1 H, NCH₂), 5.23 (d, J = 14.7 Hz, 1 H, NCH₂), 6.28–6.31 (m, 2 H, furan), 6.72 (d, J = 8.0 Hz, 1 H, H₉), 6.91 (t, J = 7.7 Hz, 1 H, H₇), 7.31–7.35 (m, 2 H, H₈, furan), 8.20 (d, J = 7.7 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 7.3, 23.2, 26.9, 42.1, 61.1, 108.5, 110.2, 118.1, 118.9, 119.5, 133.3, 134.1, 141.5, 144.4, 151.4, 167.1, 173.1. MS: m/z (%) = 298 (65) [M⁺], 271 (14), 241 (42), 217 (26), 174 (97), 146 (75), 81 (100), 53 (45). Anal. Calcd for C₁₇H₁₈N₂O₃: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.25; H, 5.90; N, 9.15. 4-(3,5-Dimethoxyphenethyl)-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-3,5-dione (11k) Yield 0.26 g (70%); white crystals; mp 125–127 °C. IR (KBr): 3367 (NH), 1687 (C=O), 1634 (C=O) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (s, 6 H, CH₃), 2.88 (t, J = 7.8 Hz, 2 H, NCH₂CH ₂), 3.85 (s, 6 H, OCH₃), 4.13 (t, J = 7.8 Hz, 2 H, NCH ₂CH₂), 4.45 (s, 1 H, NH), 6.72–6.80 (m, 4 H, H₉, H_2′, H_4′, H_6′), 6.90 (t, J = 7.5 Hz, 1 H, H₇), 7.32 (t, J = 7.5 Hz, 1 H, H₈), 8.12 (d, J = 7.5 Hz, 1 H, H₆). ¹³C NMR (125 MHz, CDCl₃): δ = 24.5, 34.9, 48.2, 55.7, 55.8, 57.8, 111.1, 112.1, 118.8, 119.5, 120.7, 132.4, 133.1, 134.0, 144.4, 147.4, 148.6, 168.1, 173.2. Anal. Calcd for C₂₁H₂₄N₂O₄: C, 68.46; H, 6.57; N, 7.60. Found: C, 68.15; H, 6.30; N, 7.77.