2,4-Difluoroaniline → HCID 67491765, compound

HRID 1620400Notes

Reaction equation

HRID 1620400 reaction equation
Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.[Li]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1

Participants

7

Reactant 4

HCID 97092,4-DifluoroanilineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 3028194LithiumHCID 123877376-Chloro-2-methylnicotinonitrile

Product 1

HCID 67491765HCID 67491765, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 6-chloro-2-methylnicotinonitrile (2.01 g, 13 mmol), 2,4-difluorobenzenamine (2.0 mL, 20 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.36 g, 0.40 mmol), 2-dicyclohexylphosphino-2′-(n,n-dimethylamino)biphenyl (0.31 g, 0.79 mmol, Dave-Phos) in 8.0 mL of THF at RT was treated with bis(trimethylsilyl)amino)lithium (28 mL of 1.0 M in THF solution, 28 mmol) drop wise. The mixture was heated at 50° C. in an oil bath for 0.5 h, then cooled to RT, quenched with NH4Cl and diluted with EtOAc. The mixture was filtered through a pad of Celite to remove some Pd black. The filtrate was transferred to a separatory funnel. The EtOAc layer was washed with brine, dried and concentrated. Purification of the resulting brown residue on an ISCO column (120 g, with 25-75% EtOAc in Hexanes) afforded 6-(2,4-difluorophenylamino)-2-methylnicotinonitrile afforded the title compound as a tan crystalline solid. MS (ESI, pos.ion) m/z: M+1=246.0

Workup

  1. temperaturecooled to RT
  2. customquenched with NH4Cl
  3. additiondiluted with EtOAc
  4. filtrationThe mixture was filtered through a pad of Celite
  5. customto remove some Pd black
  6. customThe filtrate was transferred to a separatory funnel
  7. washThe EtOAc layer was washed with brine
  8. customdried
  9. concentrationconcentrated
  10. customPurification of the resulting brown residue on an ISCO column (120 g, with 25-75% EtOAc in Hexanes)

Sources & evidence

ORD record
ord-e16167ab4a0447e3b7ff49d4abc60077
Source dataset
uspto-grants-2014_07
Patent number
US08772481B2

Reaction notes

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