Chlorotrimethylsilane → 3-(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol

Temperature

0 °C

To a stirred solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (I-1, 4.03 g, 21.50 mmol) and diisopropylethylamine (6.83 mL, 39.1 mmol) in anhydrous THF (50 mL) was added TMS-Cl (2.75 mL, 21.50 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min. The previously prepared LiTMP solution was added dropwise at −78° C. under nitrogen. After the mixture was stirred at the same temperature for 30 min, a solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (I-3, 5.3 g, 19.54 mmol) in anhydrous THF (10 mL) was added dropwise at −78° C. The solution was stirred at −78° C. for 30 min and then warmed to 0° C. over 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution (25 mL) and water (20 mL). The mixture was mixed with EtOAc (50 mL), stirred at room temperature for 30 min and filtered through a pad of celite. The filtrate was separated. The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a liquid. Flash chromatography purification (330 g silica gel column, 15-30% ethyl acetate in hexanes) afforded 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (5 g, 11.73 mmol, 60.0% yield) as a yellow solid. The compound had an HPLC retention time=3.74 min (condition C); LC/MS M+1=426.9.

1. stirringAfter the mixture was stirred at the same temperature for 30 min
2. stirringThe solution was stirred at −78° C. for 30 min
3. temperaturewarmed to 0° C. over 30 min
4. customThe reaction was quenched with saturated aqueous ammonium chloride solution (25 mL) and water (20 mL)
5. additionThe mixture was mixed with EtOAc (50 mL)
6. stirringstirred at room temperature for 30 min
7. filtrationfiltered through a pad of celite
8. customThe filtrate was separated
9. extractionThe aqueous layer was extracted with EtOAc (2×25 mL)
10. washThe combined organic solutions were washed with brine (50 mL)
11. dry with materialdried over sodium sulfate
12. concentrationconcentrated
13. customto give a liquid
14. customFlash chromatography purification (330 g silica gel column, 15-30% ethyl acetate in hexanes)

ORD record

ord-91272f9665844f27bfed3dca3370b04e

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216972B2