4-Fluoro-2-methylbenzaldehyde

452-63-1

68-12-2

63082-45-1

Example 1: This example illustrates the synthesis of 4-fluoro-2-methylbenzaldehyde (see Figure III, Scheme I). The procedure was as follows: 2-bromo-5-fluorotoluene (37.5 mL, 56.1 g, 297 mmol) was dissolved in 500 mL of anhydrous tetrahydrofuran (THF) and the solution was cooled to -78 °C. A hexane solution of 2.5 M butyllithium (119 mL, 297 mmol, 1.0 eq.) was slowly added over 35 min at -75 to -78 °C, followed by stirring of the reaction mixture at -78 °C for 20 min. Dry N,N-dimethylformamide (27.6 mL, 26.0 g, 356 mmol, 1.2 eq.) was added over 26 min at the same temperature range. After addition, the reaction solution was continued to be stirred at -78 °C for 60 min, and then slowly warmed to 15 °C, taking about 2 hours. An aqueous ammonium chloride solution (100 g, 15.9%) was added over 5 min at 15-20 °C. The reaction mixture was concentrated by fractional distillation (50-61°C fractions were collected, totaling 597 mL) and the distillate layer was separated. The aqueous layer was extracted three times with methyl tert-butyl ether (MTBE, 25 mL x 3). The organic layers were combined, washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and fractionated again (boiling point 54-62 °C) to give 59.3 g of yellow oil. The crude product was further purified by fractional distillation under reduced pressure (boiling point 60-62 °C, pressure 1.6-2.0 mmHg) to finally obtain 28.041 g (68.4% yield) of the target product 4-fluoro-2-methylbenzaldehyde in the form of a colorless oil.