Enantioenriched Isoindolinones from Chiral Phase-Transfer-Catalyzed Intramolecular Aza-Michael Reactions

Abstract

Optically active isoindolinones are synthesized by asymmetric intramolecular aza-Michael reactions using cinchoninium phase-transfer organocatalysts. The resulting compounds are useful intermediates for the synthesis and development of benzodiazepine-receptor agonists.

Key words

organocatalysis - phase-transfer catalysis - aza-Michael - heterocycles - isoindolinone

• References

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• 11 General Procedure: Benzamide 4a (0.078 mmol), base (1.3 equiv) and catalyst (10 mol%) were stirred for 20 h at r.t. in toluene (1 mL). The resulting reaction was monitored by TLC until completion. The crude product was purified by flash chromatography on silica gel (EtOAc–hexane, 40:60) to afford, after evaporation of solvents, product 3a as a white solid. The enantiomeric excess of 3a was determined by HPLC analysis (Daicel Chiralpak AD CSP; hexane–EtOH (7:3); 20 °C; 0.5 mL/min; 275 nm). Compound 3a: Mp 185 °C; R_f = 0.40 (EtOAc–hexane, 40:60); [α]_D ²⁰ +76 (c 0.43, CHCl₃, for 76% ee). IR: 1689, 1627, 1446, 1388, 1149, 758, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.74–1.83 (m, 4 H, 2 × CH₂), 2.40 (dd, J = 15.6, 8.8 Hz, 1 H, CH₂CO), 2.85 (dd, J = 15.6, 4.3 Hz, 1 H, CH₂CO), 3.07–3.19 (m, 2 H, NCH₂), 3.34–3.55 (m, 2 H, NCH₂), 5.88 (dd, J = 8.8, 4.3 Hz, 1 H, NCH), 7.23 (t, J = 7.3 Hz, 1 H, Ar-H), 7.42–7.63 (m, 4 H, Ar-H), 7.63–7.68 (m, 3 H, Ar-H), 7.92 (d, J = 7.1 Hz, 1 H, Ar-H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.1 (CO), 166.9 (CO), 145.3 (C), 136.7 (C), 132.3 (CH), 131.7 (C), 129.1 (2 × CH), 128.7 (CH), 125.5 (CH), 124.1 (CH), 123.3 (2 × CH), 123.2 (CH), 57.8 (CH), 46.6 (CH₂), 45.8 (CH₂), 38.5 (CH₂), 25.9 (CH₂), 24.3 (CH₂). Anal. Calcd for C₂₀H₂₀N₂O₂: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.20; H, 6.41; N, 8.64. Compound 4a: Obtained from 6a (2 mmol). Yield: 429 mg (67%); mp 194 °C; R_f = 0.62 (EtOAc). IR: 2970, 1672, 1647, 1585, 1442, 1327, 754, 690 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.78–1.94 (m, 4 H, 2 × CH₂), 3.36–3.42 (m, 4  H, 2 × NCH₂), 6.53 (d, J = 15.6 Hz, 1 H, =CH), 7.11 (t, J = 7.4 Hz, 1 H, Ar-H), 7.28–7.43 (m, 5 H, Ar-H), 7.53 (d, J = 6.9 Hz, 1 H, Ar-H), 7.65–7.71 (m, 2 H, Ar-H), 7.76 (d, J = 15.6 Hz, 1 H, CH=), 8.67 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 167.6 (CO), 164.4 (CO), 138.8 (CH), 138.3 (C), 137.1 (C), 133.2 (C), 129.9 (CH), 129.0 (2 × CH), 128.0 (CH), 124.5 (CH), 122.1 (2 × CH), 120.1 (CH), 46.6 (CH₂), 46.0 (CH₂), 26.0 (CH₂), 24.1 (CH₂). Anal. Calcd for C₂₀H₂₀N₂O₂: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.05; H, 6.20; N, 8.83.