Application
4-Chloro-2-trifluoromethylbenzonitrile (1) is an important intermediate in the synthesis of bicalutamide. In addition, due to its multiple reaction sites, it is widely used in the preparation of pharmaceutical and chemical intermediates.
Synthesis
General procedure for the synthesis of 2-trifluoromethyl-4-chlorobenzonitrile from 2-iodo-5-chlorobenzotrifluoride and zinc cyanide: 4-chloro-1-iodo-2-trifluoromethylbenzene (1500 mg, 4.89 mmol), zinc cyanide (345 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (564 mg, 0.488 mmol), then N,N-dimethylformamide (40 mL) was added. The reaction mixture was heated at 80 °C for overnight reaction. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with toluene, washed sequentially with 2N ammonium hydroxide solution (3 times) and saturated aqueous sodium chloride solution, and the organic phase was filtered after drying and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography with hexane/dichloromethane as eluent to give 4-chloro-2-trifluoromethylbenzonitrile (630 mg, 63% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 7.81-7.78 (m, 2H), 7.67 (dd, 1H, J = 8.4, 2.4 Hz).
