The general procedure for the synthesis of 4-fluoro-3-formylbenzonitrile from p-fluorobenzonitrile is as follows:
Example 112 Synthesis of 2-fluoro-5-cyanobenzaldehyde
To a stirred solution of cooled diisopropylamine (15.4 mL, 0.11 mol) in anhydrous tetrahydrofuran (200 mL) under argon protection, n-butyllithium (40 mL, 2.5 M hexane solution, 0.11 mol) was slowly added through a dropping funnel over a period of 30 minutes, keeping the reaction temperature at 0°C. The mixture was continued to be stirred at this temperature for 30 minutes. Subsequently, the reaction system was cooled to -78 °C. A solution of anhydrous tetrahydrofuran (50 mL) of 4-fluorobenzonitrile (12.1 g, 0.1 mol) was added dropwise over 15 minutes. The reaction mixture was stirred at -78 °C for 1 h via syringe. Then, dimethylformamide (8 mL) was added dropwise and stirring was continued at -78 °C for 20 min. The reaction was quenched by rapid addition of acetic acid (20 mL) followed by water (500 mL). The product was extracted with ether (2 x 500 mL). The combined organic layers were washed sequentially with 1N HCl, water and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. After evaporation of the solvent, 2-fluoro-5-cyanobenzaldehyde (11.8 g, 79% yield) was obtained as a light yellow solid.
1H NMR (CDCl3): δ 10.32 (s, 1H), 8.18 (dd, 1H, J = 6.5, 2.5 Hz), 7.88 (m, 1H), 7.33 (t, 1H, J = 9.5 Hz).
