Hydrochloric Acid → 7-bromo-5-methoxy-1H-indazole

Participants

Reaction Conditions

Reaction Steps

To a suspension of 2-bromo-4-methoxy-6-methylaniline hydrobromide (18.5 g, 62.3 mmol) in hydrochloric acid (8 M, 56 mL, 448 mmol) at 0° C. was added a solution of sodium nitrite (4.51 g, 65.4 mmol) in water (ca. 14 mL) drop wise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (7.02 mL, 62.3 mmol) in ethanol (140 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (35 mL) and transferred to a solution of potassium tert-butoxide (55.9 g, 498 mmol) in dimethylsulfoxide (350 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Preparative HPLC gave 10.1 g (86%) as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 3.82 (s, 3H); Mass spec.: 226.95 (MH)+.

Provenance & Evidence