Diisopropylamine → 3-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence