Synthesis
Preparation of Example 12: 2-Chloro-6-fluorobenzaldehyde (51.5 g, 0.30 mol) was dissolved in 500 mL of methanol. Sodium hydroxide (14.4 g, 0.35 mol) was added to the solution and the reaction mixture was stirred and heated to reflux for 3 hours. Upon completion of the reaction, the mixture was cooled to room temperature and the volume was concentrated to about 200 mL by vacuum distillation. Subsequently, water (400 mL) and dichloromethane (200 mL) were added to the concentrate to form a two-phase system. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (100 mL each). All organic layers were combined, dried with anhydrous sodium sulfate, filtered and the dichloromethane was removed by distillation under atmospheric pressure. The solvent was replaced with hexane (450 mL) to a final volume of 300 mL. The product was initially present as an oil and began to crystallize at 45°C. The mixture was cooled to room temperature, allowed to stand for 16 hours for granulation, and then filtered to give 2-chloro-6-methoxybenzaldehyde [35.6 g, 64.2% yield; Rf 0.2 (CHCl3)].
