Hydrochloric Acid → Ethyl 4-oxo-4-(4-pyridyl)butyrate

HRID 2299731Notes

Reaction equation

HRID 2299731 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.[C:22]([O:25][C:26]([CH3:29])(C)C)(=[O:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+].Cl.[H-].[Na+].BrCC(OCC)=O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[O:21]=[C:19]([C:16]1[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=1)[CH2:1][CH2:23][C:22]([O:25][CH2:26][CH3:29])=[O:24]

Participants

13

Reactant 9

HCID 313Hydrochloric Acid2×HCID 5922Isonicotinic AcidHCID 6422Trifluoroacetic acidHCID 7748Ethyl bromoacetateHCID 10908tert-Butyl acetate2×HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 2724682Lithium diisopropylamide

Product 1

HCID 10943675Ethyl 4-oxo-4-(4-pyridyl)butyrateYield 31%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

Carbonyldiimidazole (7.25 g) was added to a solution of 4-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (80 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of lithiated tert-butyl acetate prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at −78 ° C. over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction. This oil was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil, 1.16 g) was added at 0° C., and then the reaction mixture was stirred for 10 minutes. Ethyl bromoacetate (2.88 ml) was added to the mixture, and the resultant mixture was stirred at room temperature for 24 hours, 0.1N hydrochloric acid (300 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. This oil was dissolved in toluene (120 ml), and stirred with trifluoroacetic acid (5.64 ml) at 90° C. for 6 hours. An aqueous saturated solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-oxo-4-(4-pyridyl)butyrate (2.61 g, yield 31%) from an ethyl acetate-hexane (2:1, v/v)-eluted fraction as a pale brown oil.

Workup

  1. stirringAfter stirring for 15 minutes
  2. extractionextracted with ethyl acetate
  3. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto obtain an oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction
  7. stirringthe reaction mixture was stirred for 10 minutes
  8. extractionextracted with ethyl acetate
  9. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  10. dry with materialdried (MgSO4)
  11. concentrationconcentrated
  12. customto obtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction
  13. extractionextracted with ethyl acetate
  14. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  15. dry with materialdried (MgSO4)
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-b4c626da87c942e785fcbd25d5060511
Source dataset
uspto-grants-2002_12
Patent number
US06495581B1

Reaction notes

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