反应详情

温度

0 °C

To a stirred solution of diisopropylamine (2.80 mL, 19.62 mmol) in anhydrous THF (15 mL) was added n-butyllithium (7.85 mL, 19.62 mmol) (2.5 M in hexanes) dropwise at 0° C. under a nitrogen atmosphere. The yellow cloudy solution was stirred at the same temperature for 20 min before a solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 1.705 g, 9.11 mmol) in anhydrous THF (7 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 50 min. A solution of methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate 5, 1.9 g, 7.01 mmol) in anhydrous THF (5 mL) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 70 min., quenched with saturated aqueous ammonium chloride solution (15 mL) and water (15 mL) and extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated to yield a brown foamy solid. To the solid was added anhydrous toluene (40 mL) and p-toluenesulfonic acid monohydrate (2.67 g, 14.01 mmol) and the contents were heated at 110° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the liquid was separated from the solid by decantation and washed with saturated aqueous sodium bicarbonate solution (5 mL). The left solid was stirred with dichloromethane (70 mL) and water (50 mL) for 1 hr with occasional sonication. The solid was filtered off and washed with dichloromethane (2×5 mL). The filtrate was basified with aqueous ammonia solution (2 mL). The aqueous layer was separated, combined with previous sodium bicarbonate solution wash, and extracted with dichloromethane (2×20 mL). The combined organic solutions were dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (10 to 100% dichloromethane in heptane) afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (1.07 g, 2.62 mmol, 37.4% yield) as a yellow solid. LC/MS M+1=409.4.

1. additionwas added dropwise at 0° C. under nitrogen
2. stirringThe dark red mixture was stirred at 0° C. for 70 min.
3. customquenched with saturated aqueous ammonium chloride solution (15 mL) and water (15 mL)
4. extractionextracted with ethyl acetate (2×30 mL)
5. washThe ethyl acetate extracts were washed with brine (20 mL)
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. customto yield a brown foamy solid
9. temperaturethe contents were heated at 110° C. under nitrogen for 3 h
10. temperatureThe reaction mixture was cooled to room temperature
11. customthe liquid was separated from the solid by decantation
12. washwashed with saturated aqueous sodium bicarbonate solution (5 mL)
13. stirringThe left solid was stirred with dichloromethane (70 mL) and water (50 mL) for 1 hr with occasional sonication
14. filtrationThe solid was filtered off
15. washwashed with dichloromethane (2×5 mL)
16. customThe aqueous layer was separated
17. washwash
18. extractionextracted with dichloromethane (2×20 mL)
19. dry with materialThe combined organic solutions were dried over sodium sulfate
20. concentrationconcentrated under reduced pressure