反应详情

温度

110 °C

A suspension of 4-fluoro-2-methoxy-5-methyl-phenylamine (25.75 g, 0.17 mol) in 180 mL of HBr (48%, 0.9 M) in an ice bath was treated dropwise with an aq solution of sodium nitrite (12.6 g, 0.18 mol, 3.6 M). A brown gas was evolved and the temperature of the reaction was monitored so that the internal temperature did not raise above 10° C. In the meantime, a suspension of CuBr (13.1 g, 0.09 mol) in 6.5 mL of HBr (48%, 13.9 M) was heated to 110° C. Next, the solution at 0° C. was slowly poured (over a period of 20 minutes) into the stirring CuBr suspension. The combined reaction mixture was heated for 2.5 h at 110° C. After cooling to room temperature, the solution was diluted with ethyl acetate and treated with aq sulfuric acid ( 50% v/v). The organic layer was separated and was washed successively with water, sulfuric acid, water, 1.25 M NaOH, water, and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was purified via silica gel flash chromatography (5% ethyl acetate in heptane) to afford 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (17.1 g, 47%) as a clear liquid: Rf 0.70 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.34 (d, J=8.4 Hz, 1H), 6.61 (d, J=10.8 Hz, 1H), 3.85 (s, 3H), 2.18 (d, J=1.8 Hz, 3H); Anal. calcd for C8H8BrFO: C, 43.86. ; H, 3.68; Br, 36.48. Found C, 44.01; H, 3.68; Br, 36.57.

1. temperaturedid not raise above 10° C
2. customThe combined reaction mixture
3. temperaturewas heated for 2.5 h at 110° C
4. temperatureAfter cooling to room temperature
5. customThe organic layer was separated
6. washwas washed successively with water, sulfuric acid, water, 1.25 M NaOH, water, and saturated aq NaCl
7. dry with materialThe organic layer was dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customThe resulting brown oil was purified via silica gel flash chromatography (5% ethyl acetate in heptane)