2-FLUORO-6-METHOXYPHENOL

456-49-5

73943-41-6

The general procedure for the synthesis of 2-fluoro-6-methoxyphenol from m-fluoroanisole was as follows: 4.0 mL (9.4 mmol) of 2.36 M n-butyllithium solution was slowly added dropwise over a period of 1 h to 10.0 mL of anhydrous tetrahydrofuran (THF) solution containing 1.28 g (10 mmol) of m-fluoroanisole (1) according to the method of Ladd and Weinstock The reaction temperature was maintained below -65 °C and cooled using a dry ice/acetone bath. The reaction mixture was stirred at -78 °C and under nitrogen protection for 2 hours. Subsequently, 1.17 g (11 mmol) of trimethoxyborane dissolved in 2.00 mL of anhydrous THF was added dropwise over 1 h at -78 °C and stirring was continued at -78 °C for 30 min. The reaction mixture was slowly warmed to 0 °C and 0.88 mL (15 mmol) of glacial acetic acid was added, followed by the dropwise addition of 1 mL (10 mmol) of 30% hydrogen peroxide (H2O2) solution. The reaction mixture was stirred at 25 °C overnight. After completion of the reaction, the reaction solution was diluted with 10 mL of water and extracted with THF (2 × 10 mL). The organic phases were combined and washed sequentially with H2O (2 × 7 mL) and 10% brine (2 × 3 mL). The organic phase was dried with anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure to give 1.16 g (80% yield) of 2-fluoro-6-methoxyphenol. The yields of successive replicate experiments were as follows: 15.5 g of product (63% yield) was obtained from 174 mmol of feedstock; 29.7 g of product (80% yield) was obtained from 261 mmol of feedstock. The structures of the products were analyzed by 1H NMR (300 MHz, CDCl3) δ 6.82-6.63 (m, 1H), 5.51 (s, 1H), 3.90 (s, 1H); 19F NMR (282 MHz, CDCl3) δ -137.61 ppm (m, 1F); EI-MS: m/z 142 (M+), 127.