Lithium Hydroxide → 3-(2-Methyl-6-trifluoromethylpyridin-3-yl)acrylic acid

HRID 2265989

Reaction equation

HRID 2265989 reaction equation
[CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C[O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[OH-]>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]=[CH:17][C:16]([OH:37])=[O:15])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1

Participants

8

Reactant 3

HCID 3939Lithium HydroxideHCID 17453Acetic acid, 2-(triphenylphosphoranylidene)-, methyl esterHCID 288753222-Methyl-6-(trifluoromethyl)nicotinaldehyde

Product 1

HCID 685099343-(2-Methyl-6-trifluoromethylpyridin-3-yl)acrylic acidYield 56.4%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde (440 mg, 2.32 mmol) in toluene (10 mL) was added methyl(triphenylphosphoranylidene)acetate (855 mg, 2.56 mmol). The mixture was heated at 110° C. for overnight, cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (EtOAc/hexanes=1/4) to 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid methyl ester (376 mg, 65.9%) as a mixture of cis- and trans-isomers (cis-/trans-=1/10). To a solution of the ester (376 mg, 1.53 mmol) in THF (5 mL) was added 1 N LiOH (2.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The aqueous layer was then separated, acidified to pH 4 with 3 N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexanes to give 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (trans-isomer, 200 mg, 56.4%) as solid.

Workup

  1. temperaturecooled to room temperature
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe crude residue was purified by column chromatography (EtOAc/hexanes=1/4) to 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid methyl ester (376 mg, 65.9%) as a mixture of cis- and trans-isomers (cis-/trans-=1/10)
  6. concentrationconcentrated under reduced pressure
  7. additionThe residue was diluted with EtOAc and water
  8. customThe aqueous layer was then separated
  9. extractionextracted with EtOAc
  10. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified by recrystallization from EtOAc/hexanes

Sources & evidence

ORD record
ord-fa660f3412014cf2b5aba7ee167985f1
Source dataset
uspto-grants-2010_12
Patent number
US07858621B2

Linked notes

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