2-Bromo-5-chlorophenol (2.85 g, 13.7 mmol) and iodomethane (1.28 mL, 20.6 mmol) were stirred for 2 hours at room temperature in the presence of potassium carbonate (1.89 g, 13.7 mmol), n-BU4NI (50 mg, 0.137 mmol) and N,N-dimethylformamide (8.0 mL). After completion of the reaction, ice water was added and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to give 2-bromo-5-chloroanisole (2.94 g, 97%) as a colorless oil.
Subsequently, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to a solution of 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for 5 hours. The solvent was removed under reduced pressure and the yellow oil obtained was dissolved in chloroform (5 mL). To this solution was added a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol), and aluminum chloride (2.07 g, 15.5 mmol) was added in batches at -10 °C. After stirring for 1 h at 5 °C, the mixture was brought to room temperature and continued to stir for 13 h. The reaction was carried out at 5 °C. The reaction mixture was poured into ice water and extracted three times with chloroform. The organic layers were combined and washed sequentially with 1 M hydrochloric acid, water and brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by NH-type silica gel column chromatography (hexane:ethyl acetate=9:1) to afford (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as colorless crystals.
Finally, Et3SiH (1.62 mL, 10.1 mmol) and BF3*Et2O (0.772 mL, 6.09 mmol) were sequentially added to a chloroform-acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl) methanone (1.50 g, 4.06 mmol) at -5 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. Saturated aqueous sodium carbonate solution was added and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to afford the target compound 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene (1.48 g, 99%) in the form of a colorless oil.1H NMR (200 MHz, chloroform-d) δ ppm 1.40 (t, J=7.0 Hz, 3H) 3.87 (s, 3H), 3.93 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 6.77-6.87 (m, 2H), 6.90 (s, 1H), 7.03-7.12 (m, 2H), 7.29 (s, 1H). ei 354 (M+), 356 (M+2), 358 (M+4).
