Reaction Steps
A suspension of 2-(3-bromo-2-methylphenyl)hexahydro-1H-isoindole-1,3(2H)-dione (Intermediate 3-6, 4.5 g, 13.97 mmol) in methanol (150 mL) was treated with sodium borohydride (2.64 g, 69.8 mmol) and stirred at rt for 4 h. The mixture was concentrated, and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water, and dried and concentrated to provide 2-(3-bromo-2-methylphenyl)-3-hydroxyoctahydro-1H-isoindol-1-one as a yellow solid (3.94 g, 87%). Mass spectrum m/z 324, 326 (M+H)+. Without purification, a portion of this material (1.8 g, 5.55 mmol) was dissolved in DCM (50 mL) and treated with triethylsilane (6.46 g, 55.5 mmol). The solution was treated dropwise at rt with TFA (2.14 mL, 27.8 mmol) and stirred at rt for 30 min. The mixture was concentrated and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)octahydro-1H-isoindol-1-one (Intermediate 4-1, 1.35 g, 79%). 1H NMR (400 MHz, chloroform-d) δ 7.48-7.53 (1 H, m), 7.06-7.09 (2 H, m), 3.78 (1 H, dd, J=9.5, 5.7 Hz), 3.19 (1 H, dd, J=9.5, 2.4 Hz), 2.64-2.70 (1 H, m), 2.45-2.54 (1 H, m), 2.30 (3 H, s), 2.10-2.17 (1 H, m), 1.80-1.88 (1 H, m), 1.62-1.71 (2 H, m), 1.56-1.62 (1 H, m), 1.40-1.51 (1 H, m), 1.31 (2 H, s). Mass spectrum m/z 308, 310 (M+H)+. Also isolated was 2-(3-bromo-2-methylphenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one (Intermediate 4-2, 224 mg, 13%). 1H NMR (400 MHz, chloroform-d) δ 7.51-7.55 (1 H, m), 7.05-7.14 (2 H, m), 4.09 (2 H, t, J=1.9 Hz), 2.28-2.37 (4 H, m), 2.28 (3 H, s), 1.73-1.85 (4 H, m). Mass spectrum m/z 306, 308 (M+H)+.
