Potassium Carbonate → 2,4-Difluoro-3-(pyridin-3-yl)aniline

HRID 1061775Notes

Reaction equation

HRID 1061775 reaction equation
Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:3]1[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 6428513-(Diethylboryl)pyridineHCID 137327463-Bromo-2,4-difluoroaniline

Product 1

HCID 137730352,4-Difluoro-3-(pyridin-3-yl)anilineYield 7%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 3-bromo-2,4-difluorophenylamine (prepared according to the procedure described in EP-A-0184384) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 mL) and water (50 mL) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 mL), extracted with ethyl acetate (300 mL), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) on a gradient of ethyl acetate (10-50%) afforded 2,4-difluoro-3-(pyridin-3-yl)phenylamine as a cream-coloured solid (5.8 g, 7%): δH (400 MHz, CDCl3) 3.69 (2H, br), 6.72-6.88 (2H, m), 7.39 (1H, dd, J 8 and 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5 and 1), 8.72 (1H, s).

Workup

  1. customprepared
  2. customwas degassed with nitrogen for 15 min
  3. temperaturethe reaction was heated
  4. temperatureat reflux for 4 days
  5. customthe majority of the tetrahydrofuran removed on a rotary evaporator
  6. additionThe residue was diluted with water (250 mL)
  7. extractionextracted with ethyl acetate (300 mL)
  8. washthe organics were washed with water, brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered and pre-adsorbed onto silica
  11. customPurification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) on a gradient of ethyl acetate (10-50%)

Sources & evidence

ORD record
ord-816f7f5389bf40d6ac3daefec96b2ccb
Source dataset
uspto-grants-2005_11
Patent number
US06960598B2

Reaction notes

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