Exploiting the Reactivity of 1,2-Ketoamides: Enantioselective Synthesis of Functionalized Pyrrolidines and Pyrrolo-1,4-benzodiazepine-2,5-diones

Abstract

A new strategy for the synthesis of optically active pyrrolo[1,4]benzodiazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction–double cyclization sequence leading to the desired substituted benzodiazepine.

Key words

enantioselective Michael addition - benzodiazepine - 1,2-ketoamides

• References and Notes

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• 16 Synthesis of Michael Adducts 3; General Procedure: 1,2-Ketoamide 1 (0.20 mmol, 1.0 equiv), nitroalkene 2 (0.24 mmol, 1.2 equiv) and catalyst 6 (0.02 mmol, 0.1 equiv) were successively added in a sealed tube with a magnetic stir bar and dissolved in CH₂Cl₂ (0.5 mL). The reaction was then stirred at r.t. until consumption of starting ketoamide 1 was observed (48–72 h, reaction monitored by TLC). The crude product was purified directly by flash chromatography on silica gel (EtOAc–petroleum ether (PE), 20:80). Methyl 2-[(3R,4R)-3-Ethyl-5-nitro-2-oxo-4-phenylpentanamido]benzoate (3a): By following the general procedure, the reaction between 1a (49.8 mg, 0.20 mmol), β-nitrostyrene 2a (35.8 mg, 0.24 mmol) and catalyst 6 (8.3 mg, 0.02 mmol) afforded 3a (61%) as a white solid; mp 155–156 °C; R_f = 0.3 (PE–EtOAc, 8:2); HPLC (Chiralpak IA; hexane–EtOH, 90:10; flow rate = 1.0 mL/min; λ = 220nm): t _R = 10.12 (major), 10.91 (minor) min; ee = 95%. ¹H NMR (400 MHz, CDCl₃): δ = 12.21 (br s, NH, 1 H), 8.75 (dd, J = 8.4, 0.9 Hz, 1 H), 8.15–8.13 (m, 1 H), 7.68–7.64 (m, 1 H), 7.34 (d, J = 4.3 Hz, 4 H), 7.28–7.23 (m, 2 H), 4.89–4.81 (m, 2 H), 4.29 (td, J = 9.1, 3.9 Hz, 1 H), 4.10–4.06 (m, 1 H), 4.03 (s, 3 H), 1.99–1.86 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.6 (C), 168.1 (C), 158.3 (C), 139.5 (C), 137.5 (C), 134.6 (CH), 131.4 (CH), 129.0 (CH), 128.2 (CH), 128.1 (CH), 124.1 (CH), 120.4 (C), 116.7 (C), 77.8 (CH₂), 52.8 (CH₃), 48.0 (CH), 44.5 (CH), 22.2 (CH₂), 11.3 (CH₃). HRMS (ESI+): m/z calcd for [C₂₁H₂₂N₂O₆ + H⁺]: 399.1551; found: 399.1548. Synthesis of Pyrrolidines 4; General Procedure: Michael adduct 3 (0.3 mmol, 1.0 equiv) was dissolved in anhydrous THF (15 mL) and activated zinc powder (2.77 g, 42 mmol, 70.0 equiv) was added followed by acetic acid (15 mL). The mixture was stirred for 2 h at r.t., then the mixture was concentrated and saturated aqueous NaHCO₃ solution (15 mL) was added. The aqueous phase was extracted with CH₂Cl₂ (2 × 20 mL) and the combined organic layers were washed with water (20 mL), dried over sodium sulfate, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc–PE, 40:60). Methyl 2-[(2S,3R,4R)-3-Ethyl-4-phenylpyrrolidine-2-carboxamido]benzoate (4a): Yield: 55%; colorless oil; R_f = 0.5 (PE–EtOAc, 3:2); HPLC (Lux-Cellulose-2; heptane–EtOH, 80:20; flow rate = 1.0 mL/min; λ = 254 nm): t _R = 6.75 (major), 8.83 (minor) min; ee = 91%. ¹H NMR (400 MHz, CDCl₃): δ = 12.34 (br s, NH, 1 H), 8.84 (dd, J = 8.5, 1.2 Hz, 1 H), 8.05 (dd, J = 8.0, 1.7 Hz, 1 H), 7.58–7.54 (m, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.25–7.20 (m, 1 H), 7.18–7.14 (m, 2 H), 7.13–7.08 (m, 1 H), 3.93 (s, 3 H), 3.80 (d, J = 3.7 Hz, 1 H), 3.56 (d, J = 2.4 Hz, 1 H), 3.47 (d, J = 5.1 Hz, 2 H), 2.52–2.43 (m, 1 H), 1.32–1.29 (m, 1 H), 1.20–1.11 (m, 1 H), 0.92 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.1 (C), 168.1 (C), 141.0 (C), 139.9 (C), 134.5 (CH), 131.2 (CH), 128.4 (CH), 128.4 (CH), 126.5 (CH), 122.7 (CH), 120.6 (CH), 116.2 (C), 66.3 (CH₃), 52.4 (CH), 51.1 (CH), 50.0 (CH₂), 47.2 (CH), 21.6 (CH₂), 12.5 (CH₃). HRMS (ESI+): m/z calcd for [C₂₁H₂₄N₂O₃ + H⁺]: 353.1860; found: 353.1862. Synthesis of Pyrrolo[1,4]benzodiazepine-2,5-dione 5; General Procedure: A reaction vessel equipped with a magnetic stir bar was charged with pyrrolidine 4 (0.2 mmol) and ethylene glycol (0.6 mL), and the mixture was subjected to microwave irradiation at 210 °C for 10–20 min. The crude reaction mixture was extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic layers were washed with water (10 mL), dried over sodium sulfate, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc–PE, 40:60). (1R,2R,11aS)-1-Ethyl-2-phenyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione (5a): Yield: 50%; white solid; mp 234 °C; R_f = 0.2 (PE–EtOAc, 6:4); HPLC (Chiralpak AD-H; heptane–EtOH, 80:20; flow rate = 1.0 mL/min; λ = 254 nm): t _R = 15.47 (major), 19.39 (minor) min; ee = 86%. ¹H NMR (400 MHz, CDCl₃): δ = 8.10–8.06 (m, 2 H), 7.56–7.50 (m, 1 H), 7.28–7.26 (m, 1 H), 7.36–7.31 (m, 3 H), 7.24–7.19 (m, 2 H), 7.03 (dd, J = 8.0, 1.1 Hz, 1 H), 4.08 (dd, J = 8.7, 1.4 Hz, 2 H), 3.94 (d, J = 2.4 Hz, 1 H), 3.81–3.73 (m, 1 H), 3.16–3.09 (m, 1 H), 1.23–1.07 (m, 2 H), 0.77 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.0 (C), 165.7 (C), 138.0 (C), 135.1 (C), 132.7 (CH), 131.4 (CH), 128.6 (CH), 127.9 (CH), 126.9 (CH), 126.8 (C), 125.3 (CH), 121.0 (CH), 60.7 (CH), 49.2 (CH₂), 45.3 (CH), 44.6 (CH), 20.1 (CH₂), 12.3 (CH₃). HRMS (ESI+): m/z calcd for [C₂₀H₂₀N₂O₂ + H⁺]: 321.1598; found: 321.1596. Other examples of compounds 3, 4 and 5 as well as ¹H and ¹³C NMR spectra and chiral HPLC analyses are available in the Supporting Information.