3-Dimethylaminoacrylonitrile → Ethyl 5-cyano-2-(difluoromethyl)nicotinate

HRID 1469795Notes

Reaction equation

HRID 1469795 reaction equation
C(O/[CH:4]=[C:5](/[C:11](=O)[CH:12]([F:14])[F:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C[N:17](C)/[CH:18]=[CH:19]/[C:20]#[N:21]>CN(C=O)C>[C:20]([C:19]1[CH:18]=[N:17][C:11]([CH:12]([F:13])[F:14])=[C:5]([CH:4]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:21]

Participants

4

Reactant 2

HCID 53247353-DimethylaminoacrylonitrileHCID 44185486HCID 44185486, compound

Product 1

HCID 71059720Ethyl 5-cyano-2-(difluoromethyl)nicotinateYield 23.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of cyanoacetic acid (2.0 g, 23.53 mmol) in 1,4-dioxane (10 mL) was added N,N-dimethylformamide dimethylacetal (3.35 g, 28.23 mmol) and the reaction mixture was heated at 80° C. for 4 h. Then the reaction mixture was concentrated, diluted with Et2O and filtered through a pad of silica. The filtrate was concentrated to afford 2.37 g of (E)-3-(dimethylamino)acrylonitrile which was taken to the next step without further purification. To a solution of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (5.5 g, 24.77 mmol) in DMF (15 mL) at 65° C. was added (E)-3-(dimethylamino)acrylonitrile (2.37 g, 24.77 mmol) dropwise and the reaction mixture was heated at the same temperature for 5 h. Then NH4OAc (2.86 g, 37.15 mmol) was added to the reaction mixture and heating was continued for 12 h. Then the reaction mixture was quenched with water at rt and was extracted with Et2O. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.3 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.60 (s, 1H), 7.62-7.26 (t, J=54 Hz, 1H), 4.51-4.44 (q, J=7.2 Hz, 2H), 1.46-1.42 (t, J=7.2 Hz, 3H); MS [M+H]+: 227.38.

Workup

  1. customwas taken to the next step without further purification
  2. temperaturethe reaction mixture was heated at the same temperature for 5 h
  3. temperatureheating
  4. customThen the reaction mixture was quenched with water at rt
  5. extractionwas extracted with Et2O
  6. customThe organic layer was separated
  7. customdried
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-637d4d17a6d04afa86dbcc9c7cc1dabc
Source dataset
uspto-grants-2015_04
Patent number
US09006257B2

Reaction notes

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