Ethyl Acetate → 2-{4-[(S)-3-(2-Methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-malonic acid diethyl ester

HRID 1617814Notes

Reaction equation

HRID 1617814 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[NH4+].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>C(OCC)(=O)CC(OCC)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:34]([O:33][C:30](=[O:32])[CH:31]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1)[C:30]([O:33][CH2:34][CH3:35])=[O:32])[CH3:35]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 67015671(S)-3-(4-Bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one

Product 1

HCID 666662372-{4-[(S)-3-(2-Methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-malonic acid diethyl esterYield 71%

Reagents, catalysts & solvents 3

HCID 27342152-(Di-tert-butylphosphino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 7761Diethyl MalonateSolvent

Conditions

Temperature
135 °C

Procedure

To a solution of (S)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (600 mg) in diethyl malonate (11 mL) were added sodium hydride (124 mg), tris(dibenzylideneacetone)dipalladium(0) (81.4 mg) and 2-(di-tert-butylphosphino)biphenyl (26.5 mg) at room temperature. The reaction mixture was stirred at 135° C. for 1½ h. A saturated aq. solution of ammonium chloride and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% to 70% ethyl acetate in n-heptane) to yield the title compound as a light yellow oil (514 mg, 71%), MS (ESI+): m/z=474.3 ([M+H]+).

Workup

  1. customthe phases were separated
  2. extractionthe inorganic one was extracted with ethyl acetate (2×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by flash chromatography on silica gel (10% to 70% ethyl acetate in n-heptane)

Sources & evidence

ORD record
ord-825b05b5c387424f913bcdf51f5af3eb
Source dataset
uspto-grants-2014_07
Patent number
US08765730B2

Reaction notes

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