1-Bromo-2-fluorobenzene → N-[(2-fluorophenyl)methyl]-1-methylpiperidin-4-amine

HRID 1591868Notes

Reaction equation

HRID 1591868 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[CH2:12][CH2:11]1

Participants

7

Reactant 4

HCID 612591-Bromo-2-fluorobenzeneHCID 5663231-Methyl-4-(methylamino)piperidineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxide

Product 1

HCID 781972N-[(2-fluorophenyl)methyl]-1-methylpiperidin-4-amineYield 24.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

Mix 1-bromo-2-fluorobenzene (3.50 g), 1-methyl-4-(methylamino)piperidine (2.56 g), Pd2(dba)3 (0.366 g), racemic BINAP (0.498 g) and sodium t-butoxide (2.70 g) in toluene (40 mL) and heat at reflux for two days. Filter through a Celite bed, partition between dichloromethane and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (35 g), using a gradient of dichloromethane-2M NH3 in methanol to give 1.1 g of the title intermediate.

Workup

  1. temperatureheat
  2. temperatureat reflux for two days
  3. filtrationFilter through a Celite bed
  4. custompartition between dichloromethane and saturated aqueous NaCl
  5. dry with materialdry over anhydrous sodium sulfate
  6. customevaporate
  7. custompurify on a silica gel column (35 g)

Sources & evidence

ORD record
ord-ed42423fa7b04b4780788b7b9c1e24f5
Source dataset
uspto-grants-2007_11
Patent number
US07291632B2

Reaction notes

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