A General Synthesis of 7-Phenyl-7,13-dihydro-8H-benzo[6,7]azepino[3,2-c]quinolin-8-ones

Abstract

Complex benzazepinoquinolone scaffolds can be accessed from the reaction of 2-aminoacetophenones and oxindole derivatives and feature the seven-membered azepine ring moiety commonly found in a range of drug molecules. The described reaction is generally applicable and allows for rapid access to a diverse range of new structures with further potential to build more elaborate molecules.

Key words

dihydrobenzo[6,7]azepino[3,2-c]quinolinones - heterocycles - condensation - fused-ring systems - quinolones - umpolung

• References and Notes

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• 17 Representative Procedure for the Preparation of 6i 1-(2-Aminophenyl)-3-(4-bromophenyl)prop-2-en-1-one (0.5 mmol, 0.151 g) and 6-bromooxindole (0.5 mmol, 0.106 g) were dissolved in DMSO (1 mL) at room temperature. Sodium hydroxide (0.5 mmol, 0.020 g) was added, and the reaction mixture was stirred at room temperature in an open vessel for 7 h. After completion of the reaction, water (100 mL) was added and the crude mixture acidified to pH 4–6, followed by extraction with DCM (3 × 50 mL), washing combined organic fractions with brine, and drying over sodium sulfate. The crude product was purified by column chromatography (hexane/ethyl acetate) and concentrated in vacuo to yield an analytically pure pale yellow solid 6i. The product was also crystallised from ethanol to give a single crystal suitable for X-ray crystallographic analysis (0.087 g, 35%); mp 216 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.93 (d, J = 8.8 Hz, 1 H), 7.84 (dd, J = 8.3, 1.5 Hz, 1 H), 7.54–7.48 (m, 2 H), 7.44–7.28 (m, 4 H), 7.23 (d4dd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.10 (s, 2 H), 6.97 (d, J = 2.0 Hz, 1 H), 6.73 (dd, J = 8.4, 1.2 Hz, 1 H), 6.64 (dd, J = 8.7, 2.0 Hz, 1 H), 6.52 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 5.28 (dd, J = 10.8, 3.3 Hz, 1 H), 4.06–3.97 (m, 1 H), 3.20 (dd, J = 17.8, 3.2 Hz, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 199.79, 199.23, 152.84, 151.03, 139.05, 134.23, 133.56, 131.69, 131.28, 130.28, 127.87, 120.16, 118.85, 117.11, 116.90, 116.02, 114.80, 114.41, 46.79, 43.41, 40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89. IR (ATR): ν_max = 3608, 3475, 3349, 2360, 2356, 2035, 1606, 1549 cm^–1. HRMS (ESI⁺, 47 V): m/z calcd for C₂₂H₁₈Br₂N₂O₂ [M + H]: 500.9808; found: 500.9807.
• 18 Representative Procedure for the Preparation of 7b 1,4-Bis(2-aminophenyl)-2-(4-bromophenyl)butane-1,4-dione (0.57 mmol, 0.240 g) was dissolved in T3P^®in 50% DMF (1.14 mmol, 0.363 g), and the reaction mixture was stirred at 80 °C for 24 h. Water (200 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 60 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (hexane/ethyl acetate) to give an analytically pure pale solid 7b. The product was also crystallised from ethanol to give a single crystal suitable for X-ray crystallographic analysis (0.132 g, 56%); mp 281 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.95 (s, 1 H), 8.88 (s, 1 H), 8.59 (dd, J = 8.7, 1.2 Hz, 1 H), 8.08 (dd, J = 8.4, 1.3 Hz, 1 H), 7.94 (dd, J = 8.0, 1.7 Hz, 1 H), 7.83 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.72 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 7.61 (dd, J = 8.4, 1.1 Hz, 1 H), 7.49 (ddd, J = 8.5, 7.0, 1.7 Hz, 1 H), 7.40–7.31 (m, 2 H), 7.03 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 6.74–6.68 (m, 2 H), 5.58 (s, 1 H). ¹³C NMR (151 MHz, DMSO): δ = 189.01, 152.97, 147.74, 142.79, 142.02, 135.21, 133.63, 131.26, 130.50, 129.83, 129.39, 128.92, 126.50, 123.03, 122.35, 120.27, 120.17, 120.11, 120.03, 114.04, 60.46. IR (ATR): ν_max = 3254, 3179, 3078, 3017, 2321, 2115, 1657, 1595, 1522 cm^–1. HRMS (ESI⁺, 47 V): m/z calcd for C₂₃H₁₅BrN₂O [M + H]: 415.0441; found: 415.0443.