Pyridine → 4-Imidazol-1-yl-3,3-dimethyl-2,4-dihydroisoquinolin-1-one

Participants

Reaction Conditions

Reaction Steps

To a solution of 3-imidazol-1-yl-2,2-dimethyl-indan-1-one (350 mg, 1.55 mmol) in methanol (19 mL) is added pyridine (1.6 mL, 19.6 mmol) and then hydroxylamine hydrochloride (270 mg, 3.9 mmol). The reaction is stirred at 55° C. for ca. 14 h and then cooled to room temperature. The reaction is concentrated in vacuo to ca. half of the original volume. The mixture is then diluted with ethyl acetate and 50% saturated aqueous NaCl. The layers are separated and the aqueous layer is extracted two additional times with ethyl acetate. The organic layers are combined, dried over Na2SO4, filtered, and concentrated. The resulting residue is dissolved in pyridine (10 mL) and placed at 0° C. The solution is charged with DMAP (ca. 6 mg, 0.05 mmol) and p-toluenesulfonyl chloride (615 mg, 3.22 mmol), and placed at room temperature for 1 h. The reaction is then warmed to 50° C. and stirred for ca. 14 h. The reaction is then cooled to room temperature, diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue is dissolved in pyridine (11 mL) and heated by microwave irradiation at 190° C. for 35 min in a sealed vessel. The reaction is cooled to room temperature quenched with saturated aqueous NaHCO3 (ca. 0.5 mL) and diluted with ethyl acetate. The mixture is then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:10) to provide 4-imidazol-1-yl-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one; HRMS (ESI) m/z 242.1293 [(M+H)+; Calcd for C14H16N3O: 242.1293]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 3 H), 1.40 (s, 3 H), 5.09 (s, 1 H), 5.73 (br. s., 1 H), 6.82 (s, 1 H), 7.04 (s, 1 H), 7.21-7.26 (m, 1 H), 7.50-7.60 (m, 3 H), 8.17-8.26 (m, 1 H).

Provenance & Evidence