Propargyl bromide → 3-(5,5-Dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yloxy)propan-1-ol

Temperature

23 °C

A flask was charged with aluminum (4.1 g of aluminum foil cut into 50 mg pieces, 152 mmol) and mercuric chloride (0.27 g, 1 mmol). The flask was sealed with a septum, flushed with argon, and anhydrous THF (300 mL) was added. Propargyl bromide (80% in toluene, 16.9 mL, 152 mmol) was added via syringe slowly and the resulting mixture was stirred for 30 minutes at 23° C. then warmed to 55° C.-60° C. and stirred an additional 2 hours. A second flask was charged with a 1:2 inseparable mixture of the 4-(2-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one and 2-phenyl [1,3]dioxane (15.5 g). Anhydrous THF (150 mL) was added and the solution was cooled to −78° C. The solution of the propargyl aluminum solution was transferred to the ketone solution via cannula. The resulting solution was allowed to warm to 23° C. over a period of 75 minutes then stirred overnight. The reaction was quenched by carefully pouring into an aqueous saturated solution of ammonium chloride (500 mL). The mixture was diluted with diethyl ether (500 mL) and the layers were separated. The aqueous layer was washed with diethyl ether (250 mL) and the organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-(5,5-dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yloxy)propan-1-ol as an orange oil (15.0 g) that was used without purification.

1. customThe flask was sealed with a septum
2. customflushed with argon, and anhydrous THF (300 mL)
3. additionwas added
4. temperaturethen warmed to 55° C.-60° C.
5. stirringstirred an additional 2 hours
6. temperaturethe solution was cooled to −78° C
7. temperatureto warm to 23° C. over a period of 75 minutes
8. stirringthen stirred overnight
9. customThe reaction was quenched
10. additionby carefully pouring into an aqueous saturated solution of ammonium chloride (500 mL)
11. additionThe mixture was diluted with diethyl ether (500 mL)
12. customthe layers were separated
13. washThe aqueous layer was washed with diethyl ether (250 mL)
14. dry with materialdried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo

ORD record

ord-cc9ae70990d74f809af008a7b20cfd43

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08268859B2