76% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 70.0℃; for 18.0h; |
Step B: Synthesis of ethyl 5-bromo-2-(bromomethyl)benzoate as an intermediate; [0134] A mixture of ethyl 5-bromo-2-methylbenzoate (7.52 g, 30.9 mmol), N- bromosuccinimide (6.05 g, 34.0 mmol) and benzoyl peroxide (0.75 g, 3.10 mmol) in carbon tetrachloride (150 ml) was heated to 70 0C in an oil bath for 18 h. The mixture was cooled to room temperature, and the solids were removed by filtration. The filtrate was then concentrated under reduced pressure and purified by flash chromatography (silica, gradient 1- 10%, ethyl acetate/hexanes) to afford ethyl 5-bromo-2-(bromomethyl)benzoate (7.57 g, 76%) <n="53"/>as a clear oil: 1H NMR (300 MHz, CDCl3) 8.09 (d, J= 2.2 Hz, IH), 7.61 (dd, J= 8.3, 2.2 Hz, IH), 7.33 (d, J= 8.2 Hz, IH), 4.90 (s, 2H), 4.42 (q, J= 7.2 Hz, 2H), 1.43 (t, J= 7.1 Hz, 3H). |
76% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 70.0℃; for 18.0h; |
Step D: Synthesis of ethyl 5-bromo-2-(bromomethyl)benzoate as an Intermediate; A mixture of ethyl 5-bromo-2-methylbenzoate (7.52 g, 30.9 mmol), N-bromosuccinimide (6.05 g, 34.0 mmol) and benzoyl peroxide (0.75 g, 3.10 mmol) in carbon tetrachloride (150 ml) was heated to 70 C. in an oil bath for 18 h. After this time, the mixture was cooled to room temperature and the solids removed by filtration. The filtrate was then concentrated under reduced pressure and purified by flash chromatography (silica, gradient 1-10%, ethyl acetate/hexanes) afforded ethyl 5-bromo-2-(bromomethyl)benzoate (7.57 g, 76%) as a clear oil: 1H NMR (300 MHz, CDCl3) 8.09 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.3, 2.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.90 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). |
70.9% |
With tetrachloromethane; N-Bromosuccinimide; dibenzoyl peroxide; for 10.0h;Reflux; |
General procedure: To a solution of ethyl 5-bromo-2-methylbenzoate (7a, 10.53g, 43.51mmol) and BPO (0.21g, 0.87mmol) in CCl4 (80mL) was added NBS (8.08g, 45.67mmol) in portions. The mixture was stirred under reflux for 10h. When TLC showed the completion of the reaction, the precipitate was filtered off and the filtrate was evaporated to give a residue, which was purified by column chromatography (petroleum ether) to afford compound 8a (9.87g, 70.9%). It was obtained as a white solid. 1H NMR (600MHz, DMSO-d6) delta 7.98 (d, J=2.2Hz, 1H), 7.82 (dd, J=8.2, 2.2Hz, 1H), 7.57 (d, J=8.3Hz, 1H), 4.98 (s, 2H), 4.34 (t, J=7.1Hz, 2H), 1.35 (m, 3H). ESI-MS m/z: 320.9 [M+H]+. |