1-Benzyl-4-piperidone → 4-(2-Fluoro-4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinol

HRID 2093145Notes

Reaction equation

HRID 2093145 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[F:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1

Participants

5

Reactant 3

HCID 192201-Benzyl-4-piperidoneHCID 37184441-Bromo-2-fluoro-4-methoxybenzeneHCID 178418918HCID 178418918, compound

Product 1

HCID 670660104-(2-Fluoro-4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS =315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 6.66 (dd, J=8.7, 2.5 Hz, 1 H), 6.61 (dd, J=14.4, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.56 (s, 2 H), 2.77 (br d, J=10.6 Hz, 2 H), 2.54-2.48 (m, 2 H), 2.31-2.24 (m, 2 H), 1.84 (d, J=12.3 Hz, 2 H).

Workup

  1. stirringThe reaction was stirred at room temperature for 30 min
  2. stirringthe reaction was stirred at room temperature for 14 h
  3. customThe reaction was quenched with saturated NH4Cl
  4. custompartitioned between EtOAc (50 mL) and H2O (30 mL)
  5. extractionThe aqueous layer was extracted with EtOAc (3×50 mL)
  6. washthe combined extracts were washed with brine (50 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient)

Sources & evidence

ORD record
ord-2b1fb4f9a3a04ddebd8572890c0abada
Source dataset
uspto-grants-2013_05
Patent number
US08440702B2

Reaction notes

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