467442-15-5

Under nitrogen protection, 2.5 M tert-butyllithium (4.4 mL) was slowly added dropwise to a stirred solution of N,N-diisopropylethylamine (1.1 g, 11 mmol) in anhydrous tetrahydrofuran (100 mL), keeping the reaction temperature at -78 °C. The reaction system was then slowly warmed to 0 °C and stirred continuously for 1 hour. After that, the reaction solution was re-cooled to -78 °C and 3,5-difluorobenzonitrile (1.39 g, 10 mmol) was added. After continued stirring at -78 °C for 1 h, N,N-dimethylformamide (877 mg, 12 mmol) was added to the reaction solution and the reaction was carried out for 0.5 h. The reaction was carried out at -78 °C for 0.5 h. Upon completion of the reaction, the reaction was quenched by the addition of 10% v/v aqueous acetic acid (20 mL). The reaction mixture was gradually warmed up to room temperature, extracted with ethyl acetate, and concentrated under reduced pressure after combining the organic phases to afford 3,5-difluoro-4-formylbenzonitrile (1.29 g, 77% yield) as a yellow solid.

[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 9, p. 1339 - 1352
[2] Patent: WO2013/174895, 2013, A1. Location in patent: Page/Page column 66
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4575 - 4579
[4] Patent: WO2012/160464, 2012, A1. Location in patent: Page/Page column 68
[5] Patent: US2014/155398, 2014, A1. Location in patent: Paragraph 0413