General procedure for the synthesis of 2-chloro-4-(trifluoromethyl)nicotinonitrile and 6-chloro-4-(trifluoromethyl)nicotinonitrile from 3-cyano-4-(trifluoromethyl)pyridine 1-oxide:
1. 3-cyano-4-(trifluoromethyl)pyridine 1-oxide (10.5 g, 55.8 mmol) was mixed with phosphorus trichloride (51 mL, 558 mmol) and the reaction was heated at 110 °C for 5 hours.
2. Upon completion of the reaction, excess phosphorous trichloride was removed by distillation under reduced pressure.
3. The residue was dissolved in dichloromethane and washed sequentially with 5% potassium carbonate solution and water.
4. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to give a mixture of 2-chloro-4-(trifluoromethyl)nicotinonitrile and 6-chloro-4-(trifluoromethyl)nicotinonitrile.
5. The crude product was analyzed by 1H NMR, and the main product was determined to be 2-chloro-4-(trifluoromethyl)nicotinonitrile (ratio 7:3, 2-chloro:6-chloro).
6. The isomers were separated by fast column chromatography: the 6-chloro isomer was first eluted using a 9:1 hexane:triethylamine solvent mixture, followed by dichloromethane to obtain the target compound 2-chloro-4-(trifluoromethyl)nicotinonitrile as an orange oil (4.50 g, 38% yield).
