Lithium Hexamethyldisilazide → HCID 67389092, compound

Temperature

-78 °C

A solution of lithium hexamethyldisilazide (2.4 mL of a 1.0M solution in THF, 2.4 mmol) was diluted with THF (2 mL) and cooled in a −78° C. bath. To this cold solution was added 1-(4-bromo-furan-2-yl)-ethanone (317 mg, 1.68 mmol) dropwise as a solution in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After ˜2 minutes the resulting red enolate solution was treated with a solution of 2,2-difluoro-butyric acid benzyl ester (357 mg, 1.67 mmol) in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After the completion of the addition, the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After stirring for 16 hrs at ambient temperature, the reaction was quenched by the addition of H2O (10 mL), and diluted with ether (50 mL). Phosphoric acid (2M, aqueous) was added to the mixture to bring the pH below 3. The layers were separated and the aqueous was extracted with ether (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark brown oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (224 mg, 46% yield) as a red oil. The compound exists primarily in its' enolic form. 1H-NMR (400 MHz, CDCl3): δ 14.77 (1H, br s), 7.62 (1H, s), 7.27 (2H, s), 6.45 (1H, s), 2.12 (2H, t of q, JH-H=7.6 Hz, JH-F=16.7 Hz), 1.05 (3H, t, J=7.6 Hz).

1. washrinse of the vial and syringe
2. washrinse of the vial and syringe
3. additionAfter the completion of the addition
4. customthe cooling bath was removed
5. temperatureto warm to ambient temperature
6. customthe reaction was quenched by the addition of H2O (10 mL)
7. additiondiluted with ether (50 mL)
8. additionPhosphoric acid (2M, aqueous) was added to the mixture
9. customThe layers were separated
10. extractionthe aqueous was extracted with ether (3×20 mL)
11. washThe combined organic layers were washed with brine
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customto afford a dark brown oil
16. customThe crude material was purified by flash chromatography
17. washeluting with a gradient from 0% to 30% ethyl acetate/hexane

ORD record

ord-cd5e4f75c4b24fc291979e48471bceac

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08013001B2