General procedure for the synthesis of 3-bromo-5-methoxyaniline from 3-bromo-5-nitroanisole:
1. 30.0 g of 3,5-dinitrobenzene (0.18 mol) was dissolved in 180 mL of concentrated sulfuric acid and heated to 80 °C, maintaining the temperature between 80-90 °C. 44.5 g of N-bromosuccinimide (NBS, 0.25 mol) was added to the above solution in 9 batches and the reaction lasted for 30 min. After cooling, the reaction mixture was poured into 600 mL of ice water and a white precipitate was separated, which was filtered, washed and dried to give 41.3 g of white solid 3,5-dinitrobromobenzene in 93.7% yield.
2. Preparation of sodium solution in methanol: 1 g of sodium (43.4 mmol) was dissolved in methanol. Add 8.7 g of 3,5-dinitrobromobenzene (35.2 mmol) to the above sodium methanol solution, and reflux the reaction at 45°C for 2 hours. After cooling to room temperature, it was treated with 50 mL of 1N hydrochloric acid solution and then extracted with dichloromethane. The organic phases were combined, washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated. The crude product was separated by column chromatography (petroleum ether:dichloromethane=5:1) to give 4.6g of 3-methoxy-5-nitrobromobenzene as a white powdery solid in 56.3% yield.
3. 2.32 g of 3-methoxy-5-nitrobromobenzene (10 mmol) was dissolved in 25 mL of methanol, 400 mg of Pd/C catalyst and 10 mL of acetone solution were added, and the reaction was carried out by passing hydrogen for 3 hours at room temperature. After completion of the reaction, the Pd/C was removed by filtration and the solvent was evaporated. The crude product was separated by column chromatography (petroleum ether:ethyl acetate=4:1) to give 1.95 g of 3-bromo-5-methoxyaniline as a light yellow solid in 96.5% yield.
