Ethyl Acetate → Ethyl 3-(2-Fluoro-4-methoxyphenyl)propanoate

HRID 1508467Notes

Reaction equation

HRID 1508467 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>C1COCC1>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 24758Sodium hydrideHCID 27348732-Fluoro-4-methoxybenzaldehyde

Product 1

HCID 23083097Ethyl 3-(2-Fluoro-4-methoxyphenyl)propanoate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

An oven dried flask was charged with sodium hydride (60%) (389 mg, 9.73 mmol) and THF (25 mL) and cooled to 0° C. Triethyl phosphonoacetate (1.948 mL, 9.73 mmol) was added dropwise and the reaction was heated to 50° C. for 1 hr. The reaction was then cooled to 0° C., and 2-fluoro-4-methoxy-benzaldehyde (1000 mg, 6.49 mmol) was added via cannula in THF (4×5 mL). The reaction was then heated at reflux for 16 hours. Next, the reaction was cooled to room temperature and diluted with ethyl acetate (75 mL). The organic layer was washed with water (2×75 mL) and brine (75 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (20 mL) and 10% palladium on carbon (100 mg) was added. The reaction was placed under an atmosphere of H2 (balloon) and stirred for 4 hours. The reaction was then filtered and concentrated. Purification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes) afforded ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate. 1H NMR (CDCl3, 500 MHz) δ 7.09 (t, J=8.5 Hz, 1H), 6.60 (m, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.7 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).

Workup

  1. customAn oven dried flask
  2. temperaturethe reaction was heated to 50° C. for 1 hr
  3. temperatureThe reaction was then cooled to 0° C.
  4. temperatureThe reaction was then heated
  5. temperatureat reflux for 16 hours
  6. temperatureNext, the reaction was cooled to room temperature
  7. washThe organic layer was washed with water (2×75 mL) and brine (75 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. dissolutionThe residue was dissolved in ethanol (20 mL)
  12. addition10% palladium on carbon (100 mg) was added
  13. filtrationThe reaction was then filtered
  14. concentrationconcentrated
  15. customPurification of the residue via flash chromatography on silica gel (0 to 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c99df06e2018416b81c02651e2d6822e
Source dataset
uspto-grants-2015_12
Patent number
US09221834B2

Reaction notes

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