反应详情

温度

-100 °C

A solution of 1-bromo-2-fluorobenzene (31.1 g, 178 mmol) in a mixture of toluene (750 ml) and tetrahydrofuran (75 ml) was cooled to −100° C. Within 10 minutes a solution of n-butyllithium (1.6 M in hexane; 100 ml, 160 mmol) was added dropwise at a rate so that temperature could be maintained between −95 and −102° C. After 10 minutes stirring at −100° C. a mixture of (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (11.3 g, 88.9 mmol) and boron trifluoride diethyl etherate (25.2 g, 178 mmol) in a mixture of toluene (75 ml) and tetrahydrofuran (14 ml) was added within 3-5 minutes keeping the temperature below −94° C. The reaction mixture was stirred additional 10 minutes at −95 to −102° C. For the workup, a saturated solution of ammonium chloride (60 ml), water (100 ml) and ethyl acetate (200 ml) were added and the reaction mixture was left to warm to 0° C. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by chromatography using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole (17 g, 81% yield) was obtained as an off-white solid. MS (ISP): m/z=224.1 [M+H]+.

1. temperaturecould be maintained between −95 and −102° C
2. additionwas added within 3-5 minutes
3. customthe temperature below −94° C
4. stirringThe reaction mixture was stirred additional 10 minutes at −95 to −102° C
5. waitthe reaction mixture was left
6. temperatureto warm to 0° C
7. customThe layers were separated
8. extractionthe aqueous layer was extracted once more with ethyl acetate
9. washThe combined organic layers were washed with brine
10. dry with materialdried over sodium sulphate
11. customevaporated at reduced pressure
12. customThe crude product was purified by chromatography