反应详情

温度

83 °C

Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution. Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetate/heptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.

1. customequipped with a large blade mechanical stirrer
2. customthe temperature below 40° C
3. temperatureincrease
4. stirringStir for 6 h
5. temperatureat reflux
6. temperatureCool the resulting mixture to room temperature
7. customquenched carefully with water (450 mL)
8. filtrationFilter the solid
9. washwash with heptane
10. customdry under vacuum