Ethanol → Ethyl 5-fluoropyridine-2-carboxylate

HRID 592272Notes

Reaction equation

HRID 592272 reaction equation
[C:1]([O-:4])(=[O:3])[CH3:2].[Na+].BrC1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[C]=O.[CH2:16](O)[CH3:17]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:2]([C:1]([O:4][CH2:16][CH3:17])=[O:3])=[N:8][CH:9]=1

Participants

7

Reactant 4

HCID 702EthanolHCID 517045Sodium AcetateHCID 27831712-Bromo-5-fluoropyridineHCID 178418416HCID 178418416, compound3×

Product 1

HCID 10986675Ethyl 5-fluoropyridine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
90 °C

Procedure

To a degassed solution of ethyl alcohol (400 mL) in a Parr steel bomb was added sodium acetate (43.3 g, 528 mmol), 2-bromo-5-fluoropyridine (20 g, 114 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.27 g, 4.09 mmol) and palladium acetate (204 mg, 0.91 mmol). The vessel was put under nitrogen and sealed with Parr top. The atmosphere was displaced with carbon monoxide gas and the pressure was adjusted to 300 psi. The mixture was heated to 90° C. After 3 h, the pressure dropped to below 100 psi. The vessel was cooled to ambient temperature and the reaction was repressurized with carbon monoxide to 300 psi. The vessel was heated to 90° C. for an additional 4 h. The vessel was cooled to ambient temperature and the remaining carbon monoxide was vented. The mixture was concentrated to half of the volume. Ethyl acetate (500 mL) and water (300 mL) were added. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound. MS 170.0 (M+1).

Workup

  1. customsealed with Parr top
  2. additionthe pressure dropped to below 100 psi
  3. temperatureThe vessel was cooled to ambient temperature
  4. temperatureThe vessel was heated to 90° C. for an additional 4 h
  5. temperatureThe vessel was cooled to ambient temperature
  6. concentrationThe mixture was concentrated to half of the volume
  7. additionEthyl acetate (500 mL) and water (300 mL) were added
  8. customThe organic layer was isolated
  9. extractionthe aqueous layer was extracted with ethyl acetate (2×)
  10. washThe combined organic extracts were washed with brine
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-ebf9ebeab4304b57bb933af0b9344e85
Source dataset
uspto-grants-2016_01
Patent number
US09238647B2

Reaction notes

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