Phosphoryl chloride (1.5 eq.) was slowly added dropwise to anhydrous N,N-dimethylformamide (10 mL) at 0 °C with continuous stirring for 10 minutes. Subsequently, a solution of anhydrous N,N-dimethylformamide (5 mL) of 4-fluoroindole (1 eq.) was added dropwise to the mixture. The reaction system was warmed up to 45°C and the reaction was continued with stirring for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and the pH was adjusted to 9-10 with 1 M sodium hydroxide solution. next, the resulting suspension was heated to 60 °C and subsequently cooled to room temperature. Deionized water was added to the cooled mixture, and the precipitate was collected by filtration and washed with plenty of deionized water. Finally, the precipitate was air-dried overnight at room temperature to obtain the target product 4-fluoro-indole-3-carbaldehyde.
4-Fluoro-1H-indole-3-carboxaldehyde (Intermediate 2a) was synthesized from phosphoryl chloride (2.1 mL, 22.2 mmol), 4-fluoroindole (2.0 g, 14.8 mmol) and N,N-dimethylformamide following the general procedure described above. The product was a beige solid with a yield of 1.76 g in 77%; melting point 170-172 °C (literature value 182-187 °C); thin-layer chromatography Rf=0.2 (unfolding reagent: hexane/ethyl acetate=2:1); nuclear magnetic resonance hydrogen spectroscopy (400 MHz, acetone-d6): δ=7.02 (td, J=9.5,3 Hz, 1H, H-6), 7.29 (td J=8,5Hz, 1H, H-7), 7.45 (d, J=8Hz, 1H, H-5), 8.23 (s, 1H, H-2), 10.21 (d, J=2Hz, 1H, CHO) ppm; NMR Carbon Spectrum (100MHz, acetone-d6): δ=108.8 (d, J=20Hz), 115.5 (d, J= 20 Hz), 119.4 (d, J=5 Hz), 125.6 (d, J=8 Hz), 135.1, 141.5, 157.2, 159.6, 185.2 ppm; mass spectrum (+ESI): m/z calculated value C9H7FNO+ 164.0506, measured value 163.7540 [MH+].
