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

Participants

Reaction Conditions

Reaction Steps

A fresh solution of lithium diisopropylamide was made by adding n-butyllithium (0.855 mL, 2.14 mmol) to a stirred mixture of diisopropylamine (0.299 mL, 2.14 mmol) in THF (10 mL) at 0° C. After stirring for 30 min., the lithium diisopropylamide solution was added to a solution of (E)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.200 g, 1.068 mmol) in THF (25 mL) at 0° C. over 10 min., during which time the reaction mixture became orange in color. The reaction mixture was stirred for an additional 20 min., and then methyl 5-(1-methylcyclopropyl)-4-(trifluoromethyl)isoxazole-3-carboxylate (Preparation 4E, 0.177 g, 0.712 mmol) in THF (1 mL) was added. The resulting reaction mixture was stirred for 30 min. at 0° C., quenched with 1N aqueous hydrochloric acid (10 mL), and concentrated under reduced pressure. The crude residue was dissolved in toluene (10 mL), p-toluenesulfonic acid monohydrate (0.271 g, 1.424 mmol) was added, and the mixture was heated at 110° C. for 45 min. The reaction mixture was concentrated using methanol to azeotrope off the toluene solvent. The crude residue was taken up in ethyl acetate (25 mL), stirred, and filtered. The filtrate was concentrated to give 0.442 g of the crude product which was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane. Fractions containing the product were combined and concentrated to give 3-(5-(1-methylcyclopropyl)-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.043 g, 16%) as a yellow solid. The product had an HPLC ret. time=4.35 min. (condition B); LC/MS M+1=387.12; 1H NMR (500 MHz, CDCl3) δ ppm 0.79-0.93 (m, 2H), 1.02-1.16 (m, 2H), 1.42 (s, 3H), 2.75-3.12 (m, 4H), 5.26 (dd, J=11.37 Hz, 1H), 5.79 (dd, J=17.48 Hz, 1H), 6.44-6.89 (m, 1H), 7.29 (s, 1H), 7.43 (m, 1H), and 7.88 (d, J=8.05 Hz, 1H).

Provenance & Evidence