tert-Butyl cyanoacetate → HCID 178451100, compound

HRID 1091632Notes

Reaction equation

HRID 1091632 reaction equation
[C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1>C1COCC1>[C:1]([C:3](=[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][NH:23]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]

Participants

5

Reactant 3

HCID 70693tert-Butyl cyanoacetateHCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 57426343Lithium bis(trimethylsilyl)amide

Product 1

HCID 178451100HCID 178451100, compoundYield 82%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

tert-Butyl 2-cyanoacetate (97.45 g, 690 mmol) was dissolved in anhydrous THF (1 L), and cooled on an ice-bath for 90 min with stirring under nitrogen. A 1M solution of lithium hexamethyldisilazane in THF (690 mL, 690 mmol) was added dropwise. The mixture was stirred for an additional 1 hr, then 2-chloro-4-trifluoromethylpyrimidin (105 g, 590 mmol) was added dropwise. The mixture was then heated to 50° C. for 3 hr with stirring under nitrogen, allowed to cool, and the solvent removed under reduced pressure. Hydrochloric acid (1N) was added to the residue to achieve a pH of 1-2. The precipitated solids were collected by filtration and dried under vacuum to give tert-butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (135 g, 82% yield) as a bright yellow solid, >98% pure by LC/MS. tert-Butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (48 g; 166 mmol) was suspended in 4M hydrogen chloride in dioxane (415 mL, 1.66 mol) and the mixture stirred at room temperature for 6 hr, then concentrated under reduced pressure to give 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31 g, 100% yield) as an orange oil, >98% pure by LC/MS. To a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31.0 g; 166 mmol) in absolute ethanol (800 mL) was added potassium O-ethylxanthate (26.6 g; 166 mmol) followed by potassium carbonate (45.8 g; 332 mmol). The mixture was heated to 100° C. for 3 hr, cooled to room temperature, iodomethane (47.1 g; 332 mmol) added dropwise, and 1N hydrochloric acid (2 L) added. The resulting mixture was extracted with DCM (1.5 L), and the DCM layer was washed twice with brine (1 L each). The solvent was removed under reduced pressure to give 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (36 g, 75% yield) as a light brown solid, >95% pure by LC/MS.

Workup

  1. temperaturecooled on an ice-bath for 90 min
  2. stirringThe mixture was stirred for an additional 1 hr
  3. stirringwith stirring under nitrogen
  4. temperatureto cool
  5. customthe solvent removed under reduced pressure
  6. additionHydrochloric acid (1N) was added to the residue
  7. filtrationThe precipitated solids were collected by filtration
  8. customdried under vacuum

Sources & evidence

ORD record
ord-e50f36769c744438af9f73bbc6e238b3
Source dataset
uspto-grants-2012_03
Patent number
US08129396B2

Reaction notes

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