5-Fluoro-2-methylphenol

Chemical Properties

Uses

Synthesis

367-29-3

452-85-7

1. Prepare a hot sulfuric acid solution by slowly adding 7 mL of concentrated sulfuric acid to 21 mL of water. To 5-fluoro-2-methylaniline (5 g, 40 mmol) was added the above hot sulfuric acid solution. 2. The reaction mixture was cooled in an ice bath for 30 minutes, followed by the dropwise addition of a 10 mL aqueous solution of sodium nitrite (3.38 g, 48 mmol) over 10 minutes. 3. After continuous stirring at 0 °C for 45 min, the reaction mixture was diluted with 20 mL of cold water and treated with 0.3 g of urea. 4. the resulting mixture was slowly added to a pre-stirred solution of 11 mL of concentrated sulfuric acid with 10 mL of water (containing 15 g of anhydrous sodium sulfate) over a period of 10 minutes, maintaining the reaction temperature at 130 °C. the reaction was continued at 0 °C for a period of 45 minutes with continuous stirring. 5. After continuing the reaction at 130 °C for 5 minutes, the reaction was cooled to room temperature and extracted with three 100 mL dichloromethane. 6. The organic layers were combined and washed with two parts 50 mL of water and subsequently concentrated under vacuum. 7. The resulting slightly reddish oil was dissolved in 250 mL of ether and washed with three parts of 50 mL of 10% aqueous sodium hydroxide. 8. The aqueous sodium hydroxide extracts were combined and washed with two 50 mL portions of diethyl ether. 9. Acidify the basic layer with aqueous 1N HCl followed by extraction with three 100 mL dichloromethane. 10. The dichloromethane layers were combined, washed with two 50 mL portions of brine, dried over sodium sulfate, filtered and concentrated in vacuum to give a light red liquid. 11. The crude product was purified by silica gel column chromatography (eluent: hexane solution of 10% ethyl acetate) to give 5 g of 5-fluoro-2-methylphenol as a light brown oil (99% yield). 12. 5-fluoro-2-methylphenol (640 mg, 5 mmol) was dissolved in 20 mL of anhydrous acetonitrile, cooled to -30 °C to -40 °C, and nitronium tetrafluoroborate (740 mg, 5.5 mmol) was added. 13. After 45 minutes of reaction, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. 14. The organic layers were combined, washed with three 25 mL water, dried over sodium sulfate and concentrated in vacuum to give a reddish crystalline solid. 15. purification by silica gel column chromatography (eluent: hexane solution of 5% ethyl acetate) to give 0.58 g of the target product as a bright yellow solid (68% yield). 16. Conversion of the target compound to the corresponding trifluoromethanesulfonate according to the method described in Example 26.

References