Water → 4-(2-Ethynylpyridin-4-yloxy)-2-fluorobenzenamine

HRID 450471

Reaction equation

HRID 450471 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([Si](C)(C)C)#[CH:18].O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO.[Cu]I>[C:17]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)#[CH:18]

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 66111TrimethylsilylacetyleneHCID 594583014-(2-Chloropyridin-4-yloxy)-2-fluorobenzenamine

Product 1

HCID 598255834-(2-Ethynylpyridin-4-yloxy)-2-fluorobenzenamine

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a degassed solution of 4-(2-chloropyridin-4-yloxy)-2-fluoroaniline from Example A1 (0.801 g, 3.36 mmol) in DMF (2 mL) and TEA (2 mL) was added ethynyltrimethylsilane (0.929 ml, 6.71 mmol), trans-dichloro-bis(triphenyl phosphine) palladium(0) (0.236 g, 0.336 mmol) and copper (I) iodide (0.064 g, 0.336 mmol) and the mixture was stirred at 90° C. for 16 h. Water (60 ml) was added to the mixture, product was extracted with EtOAc (2×45 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford crude product. The product was dissolved in methanol (10 ml), K2CO3 (0.5 g) was added and the mixture was stirred at RT for 2 h. Solvent was removed, water (60 mL) and EtOAc (40 ml) were added, the layers were separated and the aqueous layer was extracted with EtOAc (1×30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated and purified by column chromatography (ethylacetate/hexanes) to afford 4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine as a thick residue (0.56 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=6.0 Hz, 1H), 6.98 (dd, J=8.0 Hz, 2.4 Hz, 1H), 6.95 (d, J=6.0 Hz, 1H), 6.87 (dd, J=6.0 Hz, 2.4 Hz, 1H), 6.81-6.73 (m, 2H), 5.20 (brs, 2H), 4.03 (s, 1H); MS (ESI) m/z: 229.1 (M+H+).

Workup

  1. extractionwas extracted with EtOAc (2×45 ml)
  2. washthe combined organics were washed with brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. customto afford crude product
  6. stirringthe mixture was stirred at RT for 2 h
  7. customSolvent was removed
  8. additionwater (60 mL) and EtOAc (40 ml) were added
  9. customthe layers were separated
  10. extractionthe aqueous layer was extracted with EtOAc (1×30 mL)
  11. washThe combined organic layer was washed with brine
  12. dry with materialdried (Na2SO4)
  13. concentrationconcentrated
  14. custompurified by column chromatography (ethylacetate/hexanes)

Sources & evidence

ORD record
ord-b56575374afe4eadbae6b62c3d7d921d
Source dataset
uspto-grants-2013_07
Patent number
US08486951B2

Linked notes

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