1-Methylpiperazine → 4-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine

HRID 81962Notes

Reaction equation

HRID 81962 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[C:5]([O:9][C:10]([F:13])([F:12])[F:11])[CH:4]=2)[CH2:27][CH2:26]1

Participants

7

Reactant 3

HCID 531671-MethylpiperazineHCID 27793675-Bromo-2-(trifluoromethoxy)anilineHCID 178418261HCID 178418261, compound

Product 1

HCID 666783064-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamineYield 70%

Reagents, catalysts & solvents 3

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3(1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5-bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with water (1×100 mL). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder.

Workup

  1. customflushed with argon
  2. customThe flask was evacuated
  3. temperaturethe reaction refluxed for 1 h
  4. filtrationfiltered through a pad of celite
  5. concentrationThe organic phase was concentrated
  6. dissolutionthe residue dissolved in DCM (200 mL)
  7. washwashed with water (1×100 mL)
  8. dry with materialThe organic phases were dried over anhydrous Na2SO4
  9. customthe solvent evaporated in vacuo
  10. customthe crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10)

Sources & evidence

ORD record
ord-5292c3f707ea477a814529b0879a9268
Source dataset
uspto-grants-2014_09
Patent number
US08846701B2

Reaction notes

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