Cyanoacetic acid → 4-(4-Chlorophenyl)-3-oxobutanenitrile

HRID 1644637Notes

Reaction equation

HRID 1644637 reaction equation
C([Mg]Cl)(C)C.[C:6]([CH2:8][C:9]([OH:11])=O)#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]C(O)=O)=[CH:15][CH:14]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1.C(O)(=O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:9](=[O:11])[CH2:8][C:6]#[N:7])=[CH:15][CH:14]=1

Participants

8

Reactant 4

HCID 9740Cyanoacetic acidHCID 15880(4-Chlorophenyl)acetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 178418918HCID 178418918, compound

Product 1

HCID 509888474-(4-Chlorophenyl)-3-oxobutanenitrileYield 60.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent2×HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Isopropylmagnesium chloride (24.6 mL, 2 M solution in THF, 50 mmol, 5 equiv) was added to a −78° C. solution of cyanoacetic acid (2.52 g, 29.6 mmol, 2.96 equiv) in 80 mL of anhydrous tetrahydrofuran. After 1 h, a solution of 4-chlorophenylacetic acid (1.7 g, 10 mmol, 1.0 equiv) and N,N-carbonyldiimidazole (1.93 g, 11.9 mmol, 1.19 equiv) in 20 mL of anhydrous tetrahydrofuran was added to the reaction mixture, and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was poured into 300 mL of water. The mixture was adjusted to pH 4 with glacial acetic acid. Gas evolution was evident during addition of the acetic acid. The mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via automated flash chromatography (80 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a white solid (1.17 g, 57%).

Workup

  1. waitAfter 16 h
  2. extractionThe mixture was extracted with ethyl acetate (4×100 mL)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified

Sources & evidence

ORD record
ord-527460c810f34e41aba4b6bf383679a0
Source dataset
uspto-grants-2012_02
Patent number
US08124610B2

Reaction notes

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