Synthesis
General procedure for the synthesis of 2-fluoro-6-methoxybenzaldehyde from m-fluoroanisole and N,N-dimethylformamide: n-butyllithium (1.6 M in hexane, 74.3 ml, 0.118 mol) was added slowly and dropwise to a solution of diisopropylamine (13.23 g, 0.130 mol) in tetrahydrofuran (50 ml) at 0 °C. After maintaining this temperature for 15 min, the reaction system was cooled to -78°C. Subsequently, a tetrahydrofuran (5 ml) solution of 3-fluoroanisole (15 g, 0.118 mol) was added and stirred at -78 °C for 1 hour. Next, N,N-dimethylformamide (6.75 ml) was added and stirring was continued at the same temperature for 1 hour. After completion of the reaction, the reaction was burst with 2N hydrochloric acid solution followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the target product 2-fluoro-6-methoxybenzaldehyde as a red waxy solid (17.45 g, 95% yield), which could be used in subsequent steps without further purification.
References
[1] Patent: US2012/289496, 2012, A1. Location in patent: Page/Page column 100
[2] Chemistry - A European Journal, 2015, vol. 21, # 29, p. 10322 - 10325
[3] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7499 - 7502
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 12, p. 2998 - 3001
[5] Patent: WO2012/151525, 2012, A1. Location in patent: Page/Page column 100; 101
