The general procedure for the synthesis of 5-chloro-3-cyanomethylpyridine from 3,5-dichloropyridine and cuprous cyanide was as follows: 3,5-dichloropyridine (4.23 g, 28.6 mmol), cuprous cyanide (CuCN, 3.07 g, 34.3 mmol), and argon-bubbled N-methylpyrrolidone (NMP, 8 mL) were placed in a 40 mL scintillation vial. The reaction system was flushed with argon for 1 min, quickly capped, and the reaction was stirred at 210 °C for 3 h under argon protection. Upon completion of the reaction, the dark brown easily stirred solution was cooled slightly and subsequently poured into concentrated ammonia (NH4OH, 50 mL) under ice bath conditions with vigorous stirring for 5 min. Dichloromethane (DCM, 50 mL) was added and the bilayer mixture was stirred for an additional 5 minutes and filtered. The lower dark amber colored organic layer was retained and the dark blue aqueous layer was extracted with DCM (2 × 50 mL). All organic layers were combined and washed sequentially with NH4OH (1 × 30 mL) and 4M NaCl solution (1 × 30 mL), then dried with anhydrous sodium sulfate (Na2SO4) and concentrated to give an amber-colored oily material containing a large amount of NMP. The residue was separated by rapid chromatography on silica gel (column: 90 mm × 6 mm; eluent: 6:1 hexane/ethyl acetate; fractions of 100 mL were collected; fractions 15-19 were combined) and rotary evaporated at 40 °C to ultimately yield 5-chloro-3-cyanomethylpyridine as bright white microcrystals (891 mg, 22% yield).
