反应详情

温度

0 °C

Sodium nitrite (359 mg, 5.2 mmol) in water (5 ml) was added dropwise to a stirred, cooled (0° C.) suspension of 3-bromo-4-trifluoromethoxyaniline (Description 19) (1.02 g, 4 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then added dropwise to a stirred, cooled (-5° C.) suspension of tin (II) chloride dihydrate (4.06 g, 18 mmol) in aqueous hydrochloric acid (37%, 10 ml). The mixture was stirred at 0° C. for 30 min., then at room temperature for 30 min. The mixture was poured into cooled (0° C.) aqueous sodium hydroxide (4M, 200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), cooled in ice and ethanolic hydrogen chloride (5M, 0.76 ml, 3.8 mmol) was added. The solvent was evaporated under reduced pressure, ethanol (50 ml) and malonaldehyde bis(dimethyl acetal) (0.63 ml, 0.62 g, 3.8 mmol) were added. The mixture was heated under reflux for 30 min., cooled and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (92:8) to give the title compound as a yellow oil (801 mg, 65%). 1H NMR (360 MHz, CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.90 (1H, d, J=2.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=8.9, 2.6 Hz), 7.39 (1H, d, J=8.9 Hz), and 6.50 (1H, dd, J=2-4, 1.8 Hz). m/z (ES+) 307, 309 (M+1).

1. temperaturecooled
2. additionadded dropwise to a stirred
3. temperaturecooled
4. stirringThe mixture was stirred at 0° C. for 30 min.
5. waitat room temperature for 30 min
6. additionThe mixture was poured
7. extractionextracted with ethyl acetate (3×100 ml)
8. washThe combined organic fractions were washed with aqueous sodium hydroxide (4M, 2×100 ml) and brine (100 ml)
9. dry with materialdried (MgSO4)
10. customevaporated under reduced pressure
11. dissolutionThe residue was dissolved in ethanol (10 ml)
12. temperaturecooled in ice
13. additionwere added
14. temperatureThe mixture was heated
15. temperatureunder reflux for 30 min.
16. temperaturecooled
17. customthe solvent was evaporated under reduced pressure
18. additionSaturated aqueous sodium hydrogen carbonate (50 ml) and water (20 ml) were added
19. extractionthe mixture was extracted with ethyl acetate (3×50 ml)
20. washThe combined organic fractions were washed with brine (50 ml)
21. dry with materialdried (MgSO4)
22. customevaporated under reduced pressure
23. customThe residue was purified by flash column chromatography on silica gel
24. washeluting with hexane/EtOAc (92:8)