反应详情

To a stirred solution of 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (7B, 2.1 g, 5.12 mmol), tert-butyl azetidine-3-carboxylate, AcOH (1.668 g, 7.68 mmol), and acetic acid (0.586 mL, 10.24 mmol) in anhydrous MeOH (10 mL) and anhydrous 1,2-dichloroethane (30 mL) was added titanium(IV) isopropoxide (3.05 mL, 10.24 mmol) dropwise at room temperature under nitrogen. The solution was stirred at room temperature for 1 hr before sodium triacetoxyborohydride (4.34 g, 20.47 mmol) was added in 10 portions over 3.5 hr. The mixture was stirred at room temperature for 2 hr. Saturated sodium bicarbonate (70 mL) was added slowly to make the mixture basic. After celite was added, the mixture was stirred at room temperature for 30 min and then filtered through a pad of celite. The aqueous filtrate was separated and extracted with dichloromethane (3×20 mL). The combined organic solutions were dried (sodium sulfate) and concentrated. Flash chromatography purification (120 g silica gel column, 25→70% ethyl acetate in hexanes) afforded tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (2.24 g, 4.06 mmol, 79% yield) as a yellow solid. The compound had an HPLC retention time=3.40 min (condition C); LC/MS M+1=552.1.

1. additionwas added in 10 portions over 3.5 hr
2. additionAfter celite was added
3. stirringthe mixture was stirred at room temperature for 30 min
4. filtrationfiltered through a pad of celite
5. customThe aqueous filtrate was separated
6. extractionextracted with dichloromethane (3×20 mL)
7. dry with materialThe combined organic solutions were dried (sodium sulfate)
8. concentrationconcentrated
9. customFlash chromatography purification (120 g silica gel column, 25→70% ethyl acetate in hexanes)