The general procedure for the synthesis of 2,6-dimethyl-4-cyanopyridine from zinc cyanide and 4-bromo-2,6-dimethylpyridine is as follows:
Scheme 4, Step A: Zinc cyanide (3.82 g, 31.9 mmol) was added to a solution of DMF (40 mL) containing 4-bromo-2,6-dimethylpyridine (5.09 g, 26.5 mmol) under nitrogen protection. After degassing the stirred suspension by nitrogen bubbling for 15 min, tetrakis(triphenylphosphine)palladium(0) (1.54 g, 1.33 mmol) was added. The reaction mixture was heated at 120 °C for 5.5 h, subsequently cooled to room temperature and diluted with EtOAc (150 mL). The solids were removed by filtration through filter paper and the filter cake was washed with EtOAc (50 mL). The organic filtrate and washings were combined and washed sequentially with 15% aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl. The organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure to give a light yellow solid. The crude product was purified by rapid chromatography on silica gel with a gradient ratio of hexane/ethyl acetate (9:1 to 1:1) as eluent. The purified chromatographic fractions were combined and concentrated under reduced pressure to give 2,6-dimethyl-4-cyanopyridine (2.79 g, 77% yield).
1H NMR (CDCl3): δ 2.61 (s, 6H), 7.21 (s, 2H).
