[Synthesis]
Preparation of Example G-1. First, isoquinoline-6-carboxylic acid was prepared by adding a solution (51.4 g, 0.189 mmol) of (4-bromobenzyl)-(2,2-diethoxyethyl)amine (synthesized from 4-bromobenzaldehyde) to ice-cooled, concentrated sulfuric acid (20 g) according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983). -6-carboxylic acid. Subsequently, this solution was added to the solution prepared by adding phosphorus pentoxide (40 g) to ice-cold concentrated sulfuric acid (360 g) and stirred at 160°C for 2 hours. Upon completion of the reaction, the reaction solution was gradually cooled to 0°C, filtered through a diatomaceous earth pad and the filtrate was neutralized with sodium carbonate. The solution was further filtered through a diatomaceous earth pad and the filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to afford 6-bromoisoquinoline (482 mg, 1.2%) as an orange oil.
Next, zinc cyanide (431 mg, 3.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) were added to an N,N-dimethylformamide (3.8 mL) solution of 6-bromoisoquinoline (382 mg, 1.84 mmol) under nitrogen atmosphere. The mixture was stirred at 100°C for 1 hour. Subsequently, tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) was added again and the mixture was continued to be stirred at 100°C for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding ethyl acetate and water. The organic layer was washed with water and dried with anhydrous magnesium sulfate. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate) afforded isoquinoline-6-carbonitrile (234 mg, 83%) as a yellow solid.
Finally, isoquinoline-6-carbonitrile (51 mg, 0.331 mmol) was dissolved in diethylene glycol (1.0 mL), potassium hydroxide (9 mg, 0.166 mmol) was added, and the reaction was then stirred for 3 h at 160 °C. The reaction was completed with the addition of potassium hydroxide (9 mg, 0.166 mmol). After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with hydrochloric acid, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and then the solvent was evaporated. Water was added to the residue and the precipitated solid was collected, washed with water and dried under vacuum to give 6-cyanoisoquinoline (12 mg, 21%) as a yellow solid. |