Sulfuric Acid → 7-Methoxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole

Participants

Reaction Conditions

Reaction Steps

To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 2, 0.328 g, 1.715 mmol) in 3 mL of THF, cooled to 0° C. was added butyllithium (1.372 mL, 3.43 mmol) dropwise over a period of 3 min. The contents were stirred at 0° C. for 30 min. A solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (Intermediate 3, 0.31 g, 1.14 mmol) dissolved in 2 mL of THF was added over a period of 3 min. The pale yellow reaction mixture was allowed to come to room temperature and stirred for 20 min. To the reaction mixture was added 0.5 mL of conc. sulfuric acid dropwise over a period of 3 min. at 0° C. and the contents were allowed to come to room temperature over a period of 10 min., then stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Dioxane (5 mL) was added and the contents were heated at 100° C. for 1.5 h, and at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (25 mL) and water (10 mL). The ethyl acetate layer was washed with sat. aq. sodium bicarbonate (15 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography using hexane/ethyl acetate to yield 7-methoxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (0.125 g, 0.303 mmol, 26.5% yield) as pale yellow solid. LC/MS M+1=413.0.

Provenance & Evidence