The general procedure for the synthesis of 3,5-dibromotoluene from 2,6-dibromo-4-methylaniline was as follows: 1.5 L of water was added to a 5 L reaction flask and cooled to 0-5 °C in an ice bath. Under stirring conditions, 500 g of 2,6-dibromo-4-methylaniline was added in five batches, keeping the temperature between 0-5 °C to form a light yellow suspension. The temperature was controlled not to exceed 5 °C. Sodium nitrite solution (156 g of sodium nitrite dissolved in 500 mL of water) was added slowly, a small amount of reddish brown gas was released during the reaction, and the solid was gradually dissolved. After the addition was completed, stirring was continued at 0-5°C for 30 min, and the reaction solution became a transparent liquid with some foam on the surface and a small amount of black solid attached to the wall of the bottle. Subsequently, hypophosphite solution (prepared by mixing 524 g of sodium hypophosphite monohydrate and 601 g of 30% hydrochloric acid, and filtered to remove undissolved sodium chloride solid after mixing for 1 hr) was added slowly and dropwise at 0-5 °C. After completion of the dropwise addition, the reaction was maintained at 0-5°C with stirring for 5 hours. The ice bath was removed to allow the reaction temperature to rise rapidly to 15-20 °C and stirring was continued for 16 hours. The amount of diazonium salt intermediate remaining in the reaction solution was detected as 0.87% by HPLC. The reaction mixture was filtered under reduced pressure and washed with water to give 570 g of wet product. The wet product was mixed with 800 mL of methanol and heated to 50 °C with stirring until completely dissolved and layered. The heating was stopped and the stirring was cooled to 0-10 °C, and 514 g of wet product was obtained by filtration. The wet product was dried under reduced pressure at 30 °C to give 440 g of the yellow solid product 3,5-dibromotoluene (HPLC purity: 94%, yield: 93%), which could be used directly in the next step of the reaction.The NMR spectrum of 3,5-dibromotoluene is shown in Figure 2.
