General procedure for the synthesis of 6-bromo-2-fluoro-3-methoxybenzaldehyde from 2-fluoro-4-bromoanisole and N,N-dimethylformamide:
1. n-Butyllithium/hexane solution (1.56 mol/L, 93.8 mL, 146 mmol) was slowly added to a tetrahydrofuran (THF, 10 mL) solution of diisopropylamine (22.2 mL, 159 mmol) under argon protection, keeping the reaction temperature at -78°C.
2. the mixture was warmed to 0 °C and stirred for 10 min, followed by cooling again to -78 °C.
3. a solution of 4-bromo-2-fluoroanisole (25.0 g, 122 mmol) in THF (10 mL) was added slowly and dropwise to the above LDA-THF solution.
4. After continuing to stir the reaction mixture at -78 °C for 30 min, N,N-dimethylformamide (DMF, 14.2 mL, 183 mmol) was added dropwise at the same temperature.
5. The reaction mixture was gradually brought to room temperature and stirred for 1 hour.
6. Upon completion of the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride solution to the mixture, followed by extraction with ethyl acetate.
7. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate.
8. The solvent was removed by depressurized concentration and the resulting solid was collected by filtration and washed with a solvent mixture of hexane/ethyl acetate (5:1) to afford the target product 6-bromo-2-fluoro-3-methoxybenzaldehyde (22.8 g, 80% yield) as colorless crystals.
Product characterization data: 1H NMR (CDCl3, δ): 3.91 (s, 3H), 7.04 (t, J = 8.7 Hz, 1H), 7.39 (dd, J = 1.8, 8.7 Hz, 1H), 10.32 (d, J = 1.0 Hz, 1H).
