4-hydroxy-3-methylbenzonitrile

103264-03-5

15777-70-5

1. Dissolve 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane in an ice bath, and slowly and dropwise add a dichloromethane solution (5 mL) of acetyl chloride (2.8 mL, 26 mmol). After 2 hours of reaction, the reaction mixture was concentrated under reduced pressure. The residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.9 g of 4-bromo-2-methylphenyl acetate as a light brown oil (quantitative yield). 2. 4-Bromo-2-methylphenyl acetate (6.9 g, 30 mmol) was dissolved in 75 mL of anhydrous dimethylacetamide, zinc cyanide (3 g, 25.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol) were added. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, 300 mL of cold water was added. The precipitate was filtered, washed with water and dried over air. Purification by silica gel column chromatography (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which cured on standing. 3. 4-Cyano-2-methylphenyl acetate (5.2 g, 29.7 mmol) was dissolved in 75 mL of methanol and an aqueous solution (25 mL) of potassium carbonate (30 mmol, 4.15 g) was added. After stirring for 30 min at room temperature, the mixture was concentrated under reduced pressure and treated with 1N sulfuric acid. The precipitate was filtered, washed with water and dried to give 3.1 g of 4-hydroxy-3-methylbenzonitrile as a white solid (78% yield). 4. 4-Hydroxy-3-methylbenzonitrile (3.1 g, 23.3 mmol) was dissolved in 60 mL of anhydrous acetonitrile, cooled to -30 °C, and nitronium tetrafluoroborate (3.4 g, 25.6 mmol) was added in batches. After 60 min of reaction, 100 mL of water was added and diluted. The light yellow precipitate was filtered, washed with water and dried to give 3.9 g of 4-hydroxy-3-methyl-5-nitrobenzonitrile (94% yield). 5. Convert 4-hydroxy-3-methyl-5-nitrobenzonitrile to the target product according to the method for the preparation of 3-fluoro-2-nitrophenyl trifluoromethanesulfonate.