Pyridine → methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

Participants

Reaction Steps

To a stirred mixture of 5-bromo-6-chloro-1H-indole (60 g, 260 mmol), N,N-dimethylaminopyridine (3.21 g, 26.0 mmol), pyridine (56.5 mL, 703 mmol), and tetrahydrofuran (400 mL) was added in drops at 0° C. neat trichloroacetyl chloride (70.1 mL, 625 mmol). The obtained mixture was warmed to room temperature in 2 h (a precipitate began to form) and was stirred at room temperature for 3 days. Added in drops 110 ml of methanol at 0-10° C. followed by 70 ml of 25% sodium methoxide in methanol (680 mmol) at 0° C. The mixture was then stirred at 45° C. for 3 h. Then 250 ml of water and 200 ml of MTBE were added. The organic extract was separated, washed with brine, dried over magnesium sulfate, and concentrated at 50° C. and 90 mm Hg to ˜¼ of the initial volume. Precipitate was filtered off, washed with MTBE, and dried in vacuum at 45° C. to obtain the title compound (39.9 g, 53% yield). The mother liquor was concentrated to a heavy slurry. Methanol (400 ml) was added and the mixture was stirred at 65° C. for 4 h and slowly cooled to room temperature and stirred overnight. The solid was filtered off, washed with methanol, and dried in vacuo at 45° C. to obtain additional title compound (16.88 g, 22%). Total yield=75%. MS (ES−): 288.0, 290.0 (M+H)+1H NMR (500 MHz, DMSO-d6) ppm 12.17 (br. s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 3.82 (s, 3H).

Provenance & Evidence