Example 1. Preparation of 3,5-difluoro-4-formylbenzoic acid. To a solution of 3,5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added N,N,N',N'-tetramethylethylenediamine (TMEDA) (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to -78 °C. Subsequently, n-butyllithium (n-BuLi) (2.5 M hexane solution) (1.77 L, 4.43 mol) was added slowly and dropwise, ensuring that the temperature of the mixture was maintained below -65 °C during the process. After dropwise addition, the reaction mixture was continued to be stirred at -78 °C for 1.5 hours. Next, anhydrous methyl formate (MeOCHO) (239 mL, 3.88 mol) was added dropwise at a rate that kept the temperature below -65 °C. The reaction solution was gradually warmed to room temperature and stirred continuously at this temperature for 18 hours. Upon completion of the reaction, the mixture was cooled to 0-5 °C and the excess base was quenched with 6 M aqueous hydrochloric acid (2.2 L, 13.2 mol). The organic and aqueous phases were separated and the aqueous phase was extracted three times with 2-methyltetrahydrofuran (3 x 500 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (350 mL), heated to reflux to dissolve and cooled to room temperature. Ethane (480 mL) was added and the mixture was further cooled to -15 °C. The precipitated solid was collected by filtration, washed with hexane and dried under vacuum to afford the target product 3,5-difluoro-4-formylbenzoic acid (122 g, 35% yield) as a white solid. The product was characterized by 1H NMR (300 MHz, DMSO-d6): δ 7.63-7.70 (m, 2H), 10.23 (s, 1H); mass spectrum (ESI) m/z: 187.17 [M+H]+.
