Citric Acid → 2-(4-Fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile

HRID 8223

Reaction equation

HRID 8223 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].ClC1C=CC(S[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=2)=[O:30])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[N:32]=2)[C:9]#[N:10])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 68016Benzeneacetonitrile, 4-fluoro-HCID 3251421Potassium bis(trimethylsilyl)amideHCID 41561066-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) ester

Product 1

HCID 219926412-(4-Fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrileYield 66%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4-fluorophenylacetonitrile (0.12 mL, 1.0 mmol) in dry tetrahydrofuran (2 mL) is treated dropwise with potassium bis(trimethylsilyl)amide (0.5 M toluene, 3.0 mL, 1.5 mmol) at 0° C. under an atmosphere of nitrogen. The mixture is stirred 10 min then 6-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) ester is added all at once. The mixture is allowed to warn to room temperature then warmed to reflux for 10 min, at which time the reaction is complete by TLC (methylene chloride). The mixture is allowed to cool then poured into 10% citric acid and extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated in vacuo. The residue is purified on a silica gel cartridge prepared with hexane then eluted with methylene chloride to yield 204 mg (66%) 2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile. MS ES− m/z 307 (M−1).

Workup

  1. customto warn to room temperature
  2. temperaturethen warmed
  3. temperatureto reflux for 10 min, at which time the reaction
  4. temperatureto cool
  5. extractionextracted into methylene chloride
  6. dry with materialThe methylene chloride solution is dried over magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe residue is purified on a silica gel cartridge
  9. customprepared with hexane
  10. washthen eluted with methylene chloride

Sources & evidence

ORD record
ord-93bcccec9d1e4801a4fde7f976f24c31
Source dataset
uspto-grants-2006_08
Patent number
US07087626B2

Linked notes

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