1-Benzyl-4-piperidone → 1-Benzyl-4-(4-fluorophenyl)piperidin-4-ol

HRID 278903Notes

Reaction equation

HRID 278903 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1

Participants

4

Reactant 2

HCID 192201-Benzyl-4-piperidoneHCID 178418676HCID 178418676, compound

Product 1

HCID 100395771-Benzyl-4-(4-fluorophenyl)piperidin-4-olYield 89%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 hours and then quenched with 100.0 mL of saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et2O. The combined organic extracts were washed with brine, separated, and dried over Na2SO4. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension was heated to reflux for 8 hours. After the suspension was cooled, it was basified with 3 N NaOH solution and was extracted with Et2O (2×50 mL). The organic extracts were combined, washed with brine, and the organic layer was dried over Na2SO4. The solvent was removed in vacuo to obtain 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.

Workup

  1. customquenched with 100.0 mL of saturated NH4Cl solution
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was extracted with 100.0 mL of Et2O
  4. washThe combined organic extracts were washed with brine
  5. customseparated
  6. dry with materialdried over Na2SO4
  7. filtrationThe solution was filtered
  8. customthe solvent was removed in vacuo
  9. customto obtain a yellow oil which
  10. customwas purified

Sources & evidence

ORD record
ord-2634ba098f634730931a3b104f980b29
Source dataset
uspto-grants-2002_03
Patent number
US06362182B1

Reaction notes

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