Metal-free Deamidative Ugi Access to Isoindolinones

Abstract

A two-step isoindolone synthesis has been achieved by using an Ugi/oxidative vicarious nucleophilic substitution sequence starting from 3-nitrobenzoic acid and aromatic aldehydes. Loss of the amido group was observed as well as a further oxidative process towards hydroxyisoindolone derivatives after prolonged stirring open to the atmosphere.

Key words

Ugi reaction - 3-nitrobenzoic acid - intramolecular vicarious nucleophilic substitution - isolindolones - air oxidation

• References and Notes


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• 15 Typical Procedure for the Ugi/Oxidative VNS for 1a/2a To a solution of 4-chlorobenzaldehyde (281 mg, 2.0 mmol) in MeOH (2 mL) were added successively n-butylamine (0.19 mL, 2.0 mmol), 3-nitrobenzoic acid (334 mg, 2.0 mmol), and tert-butyl isocyanide (0.22 mL, 2.0 mmol). The resulting mixture was stirred at rt for 1 d. The solvent was removed under reduced pressure and the crude was purified by flash column chromatography on silica gel (EtOAc/n-pentane 30:70) to afford the Ugi adduct 1a as a white solid in 92 % yield (816 mg, 1.8 mmol). Mp 113–114 °C. R_f 0.4 (AcOEt/n-pentane 30:70). IR (thin film): 3424, 3315, 309, 2968, 2248, 1654, 1577, 1354, 1301. ¹H NMR (400 MHz, CDCl₃): δ = 8.32–8.26 (m, 2 H), 7.80 (dt, J = 7.6, 1.2 Hz, 1 H), 7.63 (td, J = 7.6, 0.9 Hz, 1 H), 7.48–7.37 (m, 4 H), 5.84 (br, 1 H), 5.66 (br, 1H), 3.31–3.19 (m, 2 H), 1.36 (s, 9 H), 1.35–1.22 (m, 2 H), 1.00–0.88 (m, 2 H), 0.58 (br, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 170.1, 168.0, 147.9, 138.1, 134.7, 133.8, 132.8, 130.7, 129.9, 129.2, 124.4, 121.7, 62.9, 51.8, 48.5, 31.7, 28.6, 19.8, 13.3. HRMS: m/z [M – CONHt-Bu] calcd for C₁₈H₁₈ClN₂O₃: 345.1006; found: 345.0999. To a solution of 1a (178 mg, 0.4 mmol) in DMSO (1 mL) was added potassium tert-butoxide (112 mg, 1 mmol, 2.5 equiv). The resulting mixture was stirred at rt for 1 h under an inert atmosphere. After completion of the reaction, HCl (1 mL, 18% solution in water) was added and the mixture diluted with ethyl acetate and washed with water. The organic layer was dried with MgSO₄ and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Et₂O/n-pentane 60:40) to afford isoindolone 2a as a yellow oil in 60% yield (82 mg, 0.24 mmol). R_f 0.22 (Et₂O/n-pentane 60:40). IR (thin film): 2964, 2933, 275, 2249, 1694, 1536, 1349. ¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 2.1 Hz, 1 H), 8.34 (dd, J = 8.3, 2.1 Hz, 1 H), 7.37 (d, J = 8.6 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 2 H), 5.53 (s, 1 H), 3.95 (dt, J = 14.1, 8.0 Hz, 1 H), 2.89–2.82 (m, 1 H), 1.57–1.48 (m, 2 H), 1.34–1.27 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 166.3, 151.3, 148.8, 135.5, 134.0, 133.5, 129.90, 128.9, 126.9, 124.3, 119.5, 63.8, 40.4, 30.3, 20.2, 13.8. HRMS: m/z calcd for C₁₈H₁₇ClN₂O₃: 344.0928; found: 344.0926.