HCID 16113114, compound → 2-Hydroxyquinoline

Participants

Reaction Conditions

Reaction Steps

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent and excess of oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 hours. The solvent was removed and the crude product was purified by chromatography by using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate in 43% yield. To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath) maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinolone product in 27% yield. To a suspension of the above quinolone product (2) (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography using 5% methanol in CH2Cl2 to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). MS (ES) m/z: 297.93 (M); MP 245-247° C.

Provenance & Evidence