Using 2,4-difluorobenzonitrile (2.78 g, 20 mmol) and 3,4,5-trimethoxybenzylamine (3.94 g, 20 mmol) as raw material, the two were mixed and heated at 140 °C for 40 min. After completion of the reaction, the mixture was cooled to room temperature and subsequently dissolved in trifluoroacetic acid (TFA, 20 mL) and stirred at room temperature overnight. Afterwards, the mixture was concentrated using a rotary evaporator and subsequently partitioned between 1N NaOH solution (~100 mL, adjusted to alkaline) and ethyl acetate (100 mL). After separation of the organic layer, the aqueous layer was extracted with additional ethyl acetate (100 mL). All organic layers were combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate (MgSO4) and concentrated to give an oil. Separation of the mixture by column chromatography (eluent: 10% to 40% hexane solution of ethyl acetate) gave two well separated isomeric products. Further concentration gave 4-amino-2-fluorobenzonitrile (1.07 g, 39% yield) as a white solid. The structure of the product was confirmed by LC/MS (m/z = 177.8, corresponding to the determination of [M+H]+ in acetonitrile).
