The general procedure for the synthesis of 4-bromo-1-iodo-2-methoxybenzene from 2-methoxy-4-bromoaniline was as follows: to a concentrated mixture of hydrochloric acid (1 ml) and acetic acid (15 ml), 0.75 g (11 mmol) of sodium nitrite was slowly added under ice-bath conditions, keeping the internal temperature not exceeding 10 °C. Subsequently, 2.0 g (9.0 mmol) of a solution of 4-bromo-2-methoxyaniline (purchased from Tokyo Chemical Industry Co., Ltd.) was added and stirred at room temperature for 30 min. Next, the reaction mixture was added dropwise to a 48 wt% aqueous hydrobromic acid solution (30 ml) containing 1.0 g (30 mmol) of potassium iodide and stirred for 1 hour at room temperature. Upon completion of the reaction, the reaction mixture was added batchwise to a mixture of aqueous sodium carbonate solution and dichloromethane. After confirming that the aqueous phase was basic, liquid-liquid separation was carried out. The organic phase was washed sequentially with 10 wt% aqueous sodium bisulfite, saturated aqueous sodium bicarbonate and saturated brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane:ethyl acetate = 100:0 to 91:9 (V/V)), the fraction containing the target compound was collected and concentrated under reduced pressure to give the title compound 2.2 g (7.2 mmol, 73% yield) as an orange solid. Mass spectrum (EI, m/z): 312 [M]+. 1H-NMR spectrum (400 MHz, CDCl3) δ: 7.61 (1H, d, J=8.3 Hz), 6.94 (1H, d, J=2.1 Hz), 6.87 (1H, dd, J=8.2, 2.1 Hz), 3.88 (3H, s).
