2-Chloro-5-fluorobenzaldehyde

Uses

2-Chloro-5-Fluorobenzaldehyde is a benzaldehyde derivative with chlorine and fluorine atom substituents at the 2 and 5 positions. It is used as a reagent in organic synthesis or chemical reactions and can be used in the preparation of immunomodulators.

Synthesis

General procedure for the synthesis of 2-chloro-5-fluorobenzaldehyde from 2-chloro-5-fluorobenzyl alcohol: 2-chloro-5-fluorobenzyl alcohol (4.00 g, 23.0 mmol) and triethylamine (4.14 ml, 29.9 mmol) were added in a 200 ml reaction flask. The mixture was cooled to -30 °C and ethyl chloroformate (2.62 ml, 27.8 mmol) was slowly added and the reaction was stirred for 10 min. Sodium borohydride (2.60 g, 68.9 mmol) was then added and stirring was continued for 5 minutes. Water (10 ml) was added and stirred for 20 minutes at room temperature. After completion of the reaction, the mixture was concentrated in vacuum and the residue was treated with chloroform and 1N aqueous hydrochloric acid. The organic layer was washed with 1N aqueous sodium hydroxide and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was washed with hexane to give 2-chloro-5-fluorobenzyl alcohol as a colorless solid. In another reaction flask, dimethyl sulfoxide (2.43 ml, 34.2 mmol) was dissolved in 50 ml of anhydrous dichloromethane at -78°C. Oxalyl chloride (1.47 ml, 17.1 mmol) was added slowly and stirred for 20 min. A solution of 2-chloro-5-fluorobenzyl alcohol dissolved in 15 ml of dichloromethane was then added. The reaction mixture was slowly warmed to -40°C and kept for 1 hour. Triethylamine (7.89 ml, 57.0 mmol) was added and the warming was continued to room temperature and treated with 0.1N aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was ground with hexane to give 2-chloro-5-fluorobenzaldehyde (1.33 g, 37% yield) as a colorless solid. Product characterization: 1H NMR (400 MHz, CDCl3) δ 7.22-7.28 (1H, m), 7.41-7.47 (1H, m), 7.58-7.64 (1H, m), 10.42 (1H, d, J = 3.2 Hz). ms (EI) m/z 158 [M]+.

References

[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 6, p. 1930 - 1949