One-Pot Construction of 3-Phthalimido-1,5-benzodiazepine-2-one Derivatives via in situ Activation of N,N-Phthaloyl-serine

Abstract

The Michael addition of dehydroalanine-activated ester in situ generated from N,N-phthaloyl-serine with o-phenylenediamine followed by cyclization has been established under mild conditions, which afforded 3-phthalimido-1,5-benzodiazepine-2-one derivatives in moderate to good yields.

Key words

3-amino-1,5-benzodiazepine-2-one - dehydroalanine - o-phenyl-enediamine - Michael addition reaction - in situ generation - one pot synthesis - intramolecular amidation

• References and Notes

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Reaction Conditions
• 11a To a solution of 1 (4.62 mmol) and 4-methylmorpholine (4.62 mmol) in CH₂Cl₂ (5 mL) under an argon atmosphere at 2–4 °C was added ClCO₂ i-Bu (4.62 mmol), followed by stirring for 1 min. Compound 2 (4.62 mmol) was added to the mixture, followed by stirring at room temperature for 30–40 min.
• 11b To a solution of 1 (4.62 mmol), 2 (4.62 mmol), and NEt₃ (4.62 mmol) in CH₂Cl₂ (5 mL) under an argon atmosphere at 2 °C was added diphenylphosphinic chloride (4.62 mmol), followed by stirring at room temperature for 1–1.5 h.
• 11c To a solution of 1 (4.62 mmol) and DMF (5 μL) in CH₂Cl₂ (12 mL) under an argon atmosphere at 2 °C was added oxalyl chloride (6.93 mmol), followed by stirring at room temperature for 3 h. Excess oxalyl chloride and solvent were evaporated away to yield the crude intermediate. To a solution of 2 (4.62 mmol) in CH₂Cl₂ (5 mL) at 2 °C was added a solution of crude intermediate and NEt₃ (4.62 mmol) in CH₂Cl₂ (5 mL), followed by stirring for 3 h.
• 12 N-(2-Aminophenyl)-2-(1,3-dioxoisoindolin-2-yl)acrylamide (4a) ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.75 (1 H, s), 7.88–8.00 (4 H, m), 6.94–7.01 (2 H, m), 6.73 (1 H, dd, J = 8.3, 1.3 Hz), 6.55 (1 H, td, J = 7.4, 1.3 Hz), 6.46 (1 H, s), 5.91 (1 H, s), 4.82 (2 H, br) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.73, 161.15, 143.63, 134.77, 132.28, 131.89, 127.16, 123.50, 123.38, 121.87, 116.04, 115.63 ppm. FTIR (KBr): 3365, 1717, 1651, 1623, 1540, 1463, 1379, 1308, 887, 731 cm^–1. HRMS (ESI): m/z calcd for C₁₇H₁₂N₃O₃ [M – H]^–: 306.0884; found: 306.0854. N,N'-(1,2-Phenylene)bis[2-(1,3-dioxoisoindolin-2-yl)acrylamide] (5a) ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.89 (2 H, s), 7.86–7.99 (8 H, m), 7.52–7.58 (2 H, m), 7.21–7.29 (2 H, m), 6.35 (2 H, s), 5.97 (2 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.43, 161.30, 134.85, 131.89, 131.70, 130.02, 125.87, 125.06, 124.37, 123.64 ppm. FTIR (KBr): 3244, 1730, 1662, 1630, 1517, 1375, 1294, 1084, 886, 714 cm^–1. HRMS (ESI): m/z calcd for C₂₈H₁₇N₄O₆ [M – H]^–: 505.1154; found: 505.1108.
• 13 2-Aetamido-N-(2-aminophenyl)acrylamide (4b) ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.41 (1 H, s), 9.34 (1 H, s), 7.03 (1 H, dd, J = 7.8, 1.4 Hz), 6.95 (1 H, td, J = 7.8, 1.4 Hz), 6.72 (1 H, dd, J = 7.8, 1.4 Hz), 6.54 (1 H, td, J = 7.8, 1.4 Hz), 5.81 (1 H, s), 5.47 (1 H, s), 4.90 (2 H, br), 2.01 (3 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.07, 163.16, 143.68, 137.17, 126.96, 126.79, 122.21, 115.81, 115.59, 104.54, 23.51 ppm. FTIR (KBr): 3317, 1655, 1630, 1505, 1456, 1404, 1313, 1259, 887, 759, 611 cm^–1. HRMS (ESI): m/z calcd for C₁₁H₁₄N₃O₂ [M + H]⁺: 220.1081; found: 220.1068. Benzyl {3-[(2-Aminophenyl)amino]-3-oxoprop-1-en-2-yl}carbamate (4c) ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.51 (1 H, s), 8.94 (1 H, s), 7.30–7.44 (5 H, m), 7.02 (1 H, dd, J = 7.8, 1.4 Hz), 6.95 (1 H, td, J = 7.8, 1.4 Hz), 6.72 (1 H, dd, J = 7.8, 1.4 Hz), 6.54 (1 H, td, J = 7.8, 1.4 Hz), 5.56 (1 H, s), 5.43 (1 H, s), 5.12 (2 H, s), 4.92 (2 H, br) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.91, 153.55, 143.67, 137.18, 136.46, 128.42, 128.01, 127.93, 126.97, 126.86, 122.19, 115.85, 115.65, 103.34, 65.93 ppm. FTIR (KBr: 3379, 3347, 1729, 1614, 1487, 1457, 1214, 1206, 1066, 751, 699 cm^–1. HRMS (ESI): m/z calcd for C₁₇H₁₇N₃O₃Na [M + Na]⁺: 334.1162; found: 334.1180. Dibenzyl [(1,2-Phenylenebis(azanediyl)]bis(1-oxoprop-2-ene-1,2-diyl))dicarbamate (5c) ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.69 (2 H, s), 9.03 (2 H, s), 7.52–7.60 (2 H, m), 7.28–7.44 (10 H, m), 7.18–7.27 (2 H, m), 5.55 (2 H, s), 5.41 (2 H, s), 5.09 (4 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.10, 153.59, 137.25, 136.36, 130.52, 128.39, 128.00, 127.92, 125.50, 125.26, 104.74, 66.02 ppm. FTIR (KBr): 3306, 1732, 1704, 1660, 1628, 1501, 1453, 1241, 1077, 751, 697 cm^–1. HRMS (ESI): m/z calcd for C₂₈H₂₆N₄O₆Na [M + Na]⁺: 537.1745; found: 537.1768.
• 14 The reaction of 4a with 4-methylmolpholine hydrochloride in CH₂Cl₂ led to no reaction. Additionally, no cyclized form was also obtained from 4a under toluene reflux conditions.
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• 16 Two doublets (δ = 6.80 and 6.18 ppm, J = 1.0 Hz) appeared in the ¹H NMR spectrum (CDCl₃) of the reaction solution after the addition of ClCO₂ i-Pr and 4-methylmorpholine. This indicates that the vinyl proton of dehydroalanine was generated. Similar signals were observed when other alkyl chloroformates were used.
• 17 Reaction of 2a with N,N-Phth-serine Using ClCO₂ i-Pr To a solution of N,N-Phth-serine (1.63 g, 6.93 mmol) and 4-methylmorpholine (1.53 mL, 13.9 mmol) in CH₂Cl₂ under an argon atmosphere at –20 °C was added ClCO₂ i-Pr (1.70 g, 13.9 mmol) and 4-methylmorpholine (0.762 mL, 6.93 mmol), followed by stirring for 0.5 h. Compound 2a (500 mg, 4.62 mmol) was added to the mixture, followed by stirring at room temperature for 0.5 h. The precipitate was filtered and washed with CH₂Cl₂. EtOH was added to the residue and stirred for 0.5 h. The precipitate was filtered and washed with EtOH to give 3a (1.01 g, 3.29 mmol, 71% yield) as a yellow solid.
• 18 1-Methyl-3-phthalimido-1,5-benzodiazepine-2-one (3ab) ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.85–7.93 (4 H, m), 7.31 (1 H, dd, J = 7.9, 1.3 Hz), 7.12 (1 H, td, J = 7.9, 1.3 Hz), 7.02 (1 H, dd, J = 7.9, 1.5 Hz), 6.98 (1 H, td, J = 7.9, 1.5 Hz), 5.62 (1 H, d, J = 5.7 Hz), 4.93 (1 H, dd, J = 11.4, 5.7 Hz), 4.59 (1 H, t, J = 11.4 Hz), 3.73 (1 H, dt, J = 11.4, 5.7 Hz), 3.25 (3 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.60, 140.63, 134.82, 132.92, 131.19, 126.66, 123.33, 123.29, 121.15, 51.06, 49.75, 36.08 ppm. FTIR (KBr): 3363, 1777, 1718, 1678, 1508, 1384, 1339, 1285, 1129, 1114, 753, 718 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₁₅N₃O₃Na [M + Na]⁺: 344.1006; found: 344.1000. 5-Methyl-3-phthalimido-1,5-benzodiazepine-2-one (3ab′) ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.1 (1 H, s), 7.85–7.95 (4 H, m), 7.16 (1 H, td, J = 8.1, 1.6 Hz), 7.12 (1 H, dd, J = 8.1, 1.6 Hz), 7.07 (1 H, dd, J = 8.1, 1.6 Hz), 7.00 (1 H, td, J = 8.1, 1.6 Hz), 4.82 (1 H, dd, J = 11.1, 6.5 Hz), 4.41 (1 H, t, J = 11.1 Hz), 3.39 (1 H, dd, J = 11.1, 6.5 Hz), 2.85 (3 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.89, 167.47, 141.75, 134.87, 131.16, 130.98, 125.42, 123.36, 122.01, 121.69, 119.09, 56.82, 50.68, 41.15 ppm. FTIR (KBr): 2916, 1723, 1680, 1505, 1379, 879, 717 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₁₅N₃O₃Na [M + Na]⁺: 344.1006; found: 344.0962.
• 19 1,5-Dimethyl-3-phthalimido-1,5-benzodiazepine-2-one (3ac) ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.85–7.93 (4 H, m), 7.42 (1 H, dd, J = 7.9, 1.5 Hz), 7.32 (1 H, td, J = 7.9, 1.5 Hz), 7.24 (1 H, dd, J = 7.9, 1.5 Hz), 7.20 (1 H, td, J = 7.9, 1.5 Hz), 4.79 (1 H, dd, J = 12.4, 6.7 Hz), 4.71 (1 H, dd, J = 12.4, 8.9 Hz), 3.20–3.28 (4 H, m), 2.80 (3 H, s) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.55, 166.97, 142.81, 136.58, 134.86, 131.05, 127.09, 123.46, 123.30, 122.98, 119.86, 58.04, 50.60, 40.89, 35.75 ppm. FTIR (KBr): 2946, 1718, 1670, 1503, 1387, 1349, 1275, 1123, 877, 760, 720, 519 cm^–1. HRMS (ESI): m/z calcd for C₁₉H₁₇N₃O₃Na [M + Na]⁺: 358.1162; found: 358.1170.
• 20 Hugenberg V. Fröhlich R. Haufe G. Org. Biomol. Chem. 2010; 8: 5682