Methyl morpholine oxide → 3-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

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Reaction Steps

To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.06 g, 2.60 mmol) in chloroform (1 mL) and THF (15 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.807 mL, 3.89 mmol) and osmium tetroxide in water (0.317 mL, 0.052 mmol) at room temperature. The solution was stirred at room temperature overnight. More N-methylmorpholine-N-oxide in water (0.40 mL) was added. The mixture was stirred at room temperature for 2 hr before sodium periodate (0.666 g, 3.11 mmol) in water (4 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hr. Water (30 mL) was added and the mixture was concentrated to remove THF. The solid was filtered, washed with water (1 mL), and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde as a yellow solid. The filtrate was extracted with dichloromethane (3×6 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give a yellow liquid. This liquid was combined with the yellow solid obtained above with dichloromethane (5 mL), THF (5 mL), and methanol (7 mL). The suspension obtained was treated with sodium borohydride (0.147 g, 3.89 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 1 hr before water (10 mL) and saturated aqueous ammonium chloride solution (5 mL) were added. The mixture was concentrated to remove organic solvents. The solid was filtered, washed with water (2×2 mL), and crystallized in methanol to give (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (500 mg, 1.213 mmol, 46.7% yield) as a yellow solid. The filtrate was extracted with dichloromethane (3×10 mL). The dichloromethane extracts were dried over sodium sulfate and combined with the mother liquor from the crystallization. Purification using silica gel chromatography (20 to 100% dichloromethane in heptane and then 20→100% ethyl acetate in heptane) afforded an additional crop of (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (205 mg, 0.497 mmol, 19.15% yield) as a yellow solid. LC/MS M+1=413.1.

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