Diisopropylamine → 3-(4-Isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole

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Reaction Conditions

Reaction Steps

To a heat gun dried 50 mL 2-necked flask was added butyllithium (1.406 mL, 3.51 mmol) followed by 2 mL of anhydrous THF under a nitrogen atmosphere. The flask was cooled to 0° C. and diisopropylamine (0.49 mL, 3.51 mmol) was added dropwise over a period of 1 min. The contents were stirred at 0° C. for 15 min. To the LDA solution, 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.219 g, 1.171 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. The orange-red solution was stirred at 0° C. for 25 min. Isopropyl 4-isopropoxy-2-(trifluoromethyl)benzoate (Preparation 17A, 0.340 g, 1.171 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to yield a dark oil. To this oil was added toluene (5.00 mL). The contents were sonicated for 2 min. and p-toluenesulfonic acid monohydrate (0.446 g, 2.343 mmol) was added at room temperature. The contents were heated at 110° C. for 25 min. The reaction mixture was concentrated and partitioned between dichloromethane (15 mL) and saturated aqueous sodium bicarbonate (10 mL). The dichloromethane layer was dried over sodium sulfate, concentrated, and subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.225 g, 0.563 mmol, 48% yield) as an oil. LC/MS M+1=400.1.

Provenance & Evidence