Synthesis
General procedure for the synthesis of 4-fluoro-2-nitrobenzaldehyde from 2-nitro-4-fluorotoluene: To a stirred solution of 15 mL of anhydrous N,N-dimethylformamide containing 4-fluoro-2-nitrotoluene (1a) (1.0 g, 6.45 mmol) was added pyrrolidine (0.69 g, 9.70 mmol) and N,N-dimethylformamide dimethyl acetal (1.54 g, 12.92 mmol). The resulting reaction mixture was stirred at 125 °C for 6 h and then poured into 20 mL of water. The product was extracted with ethyl acetate three times (20 mL x 3). The combined organic layers were washed sequentially with 30 mL of water and 30 mL of brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a dark red oil. The oily material was dissolved in 20 mL of THF/water (1:1, v/v) and the resulting solution was treated with sodium periodate (4.13 g, 19.3 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight and filtered through diatomaceous earth. The filtrate was diluted with 10 mL of water and extracted with ethyl acetate three times (15 mL x 3). The combined organic layers were washed sequentially with 25 mL of water and 25 mL of brine, then dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a dark oil, which was further purified by silica gel column chromatography (petroleum ether/ethyl acetate, 6:1) to give 4-fluoro-2-nitrobenzaldehyde (2a) (0.69 g, 4.08 mmol, 63%) as a yellow solid [23].
References
[1] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 426 - 437
[2] Journal of medicinal chemistry, 1963, vol. 6, p. 716 - 719
[3] Journal of the Chemical Society, 1962, p. 2825 - 2827
[4] Collection of Czechoslovak Chemical Communications, 1960, vol. 25, p. 784 - 796
[5] Organic Letters, 2011, vol. 13, # 6, p. 1418 - 1421
