General procedure for the synthesis of 5-bromo-2-methylbenzonitrile from 2-methyl-5-aminobenzonitrile:
Example 22: To a flask was added water (13.5 mL), HBr (74%, 14.4 mL), and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL). The mixture was heated to 50 °C and kept for 20 min. Subsequently, the mixture was cooled to 0-5 °C and an aqueous solution of NaNO2 (1.2 g, 17.4 mmol) was added. The reaction mixture was stirred at 0-5 °C for 10 min and then warmed up to 40 °C. Next, a solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added. The mixture was refluxed for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (AcOEt) and the organic layer was washed sequentially with saturated NaHCO3 solution and brine and dried with Na2SO4. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%).
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H).
