Step 1: Preparation of 3,4-dimethoxyfluorobenzene
10.0 g (65.4 mmol) of 3,4-dimethoxyaniline was dissolved in 40.0 mL of HBF4 (aq 41%) and 40 mL of CH3OH. The solution was cooled to -5 °C in an ice-salt bath. 10.0 mL of n-butyl nitrite was added dropwise under electromagnetic stirring. After stirring for 90 minutes, 200 mL of cold diethyl ether was added. The solution was allowed to stand at 0 °C for 2 hours, and a solid precipitated out. The solution was filtered, washed with 50 mL of cold diethyl ether, and dried under vacuum to obtain 15.0 g (59.8 mmol) of a light purple solid, with a yield of 90%.
20.4 g (81.3 mmol) of the above solid was placed in a 250 mL round-bottom flask, connected to a receiving flask with a U-tube, and cooled in a CaCl2- ice bath. The bottom of the flask was heated with a gas lamp until the solid was completely decomposed, yielding a brown oily liquid. 10 mL of diethyl ether was added to dissolve the liquid, and it was washed once with 5 mL of 10% NaOH solution and once with 5 mL of water. The aqueous layer was extracted twice with 10 mL of diethyl ether. The organic layers were combined, dried over excess anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The liquid was purified by vacuum distillation to obtain 5.2 g of a pale yellow oily liquid, with a yield of 42%.
Step 2: Preparation of 2-fluoro-4,5-dimethoxybenzaldehyde.
5.70 g (36.5 mmol)
3,4-Dimethoxyfluorobenzene was dissolved in 50 mL of CH₂Cl₂ and placed in a 250 mL three-necked flask. The flask was cooled to 0°C in an ice bath, and N₂ was bubbled through to remove air. Then, 7.8 mL of TiCl₄ dissolved in 20 mL of CH₂Cl₂ was added dropwise, followed by 6.2 mL of CH₂Cl₂ dissolved in 15 mL of CH₂Cl₂. After stirring for 30 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a beaker containing 150 g of crushed ice. After the ice melted, the organic layer was separated, and the aqueous layer was extracted twice with 50 mL of diethyl ether. The organic layers were combined, and excess anhydrous sodium sulfate was added for drying. The mixture was filtered, and the solvent was removed by rotary evaporation to obtain a yellow solid. The solid was then recrystallized with a mixture of diethyl ether and petroleum ether, and dried under vacuum to obtain 4.01 g (21.8 mmol) of a pale yellow solid, with a yield of 60%.
