Hexane → 4-[2-(Hydroxyethyl)phenyl]-1-benzylpiperidin-4-ol

HRID 1182727Notes

Reaction equation

HRID 1182727 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C([Li])CCC.CCCCCC.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][OH:10])([OH:35])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1

Participants

6

Reactant 4

HCID 8058HexaneHCID 192201-Benzyl-4-piperidoneHCID 27340892-(2-Bromophenyl)ethan-1-olHCID 178418339Butyllithium

Product 1

HCID 673640824-[2-(Hydroxyethyl)phenyl]-1-benzylpiperidin-4-olYield 76.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2-bromophenyl ethyl alcohol (1.9 g, 9.6 mmol) in tetrahydrofuran (25 ml) was added 1.6 M n-butyl lithium solution in n-hexane (14 ml, 23 mmol) at −60° C. After stirring for 30 min a solution of 1-benzyl-4-piperidone (2.6 g, 14 mmol) in tetrahydrofuran (10 ml) was added over a period of 15 min at −40° C. The cooling bath was removed and the reaction mixture was stirred for 72 h at room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution (30 ml). Basification to pH 11 with 2 M aqueous sodium carbonate solution (50 ml) was followed by extraction with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Volatile impurities were removed by kugelrohrdistillation at 170° C. and 1-2 mbar. Flash chromatography of the residual crude product with dichloromethane/methanol as eluent gave the title compound (2.3 g, 53%) as dark brown oil. MS m/e: 312 (M+H+).

Workup

  1. additionwas added over a period of 15 min at −40° C
  2. customThe cooling bath was removed
  3. customThe mixture was quenched with saturated aqueous ammonium chloride solution (30 ml)
  4. extractionBasification to pH 11 with 2 M aqueous sodium carbonate solution (50 ml) was followed by extraction with three 100-ml portions of tert-butyl methyl ether
  5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customVolatile impurities were removed by kugelrohrdistillation at 170° C.

Sources & evidence

ORD record
ord-682b2b783aaf4d218349f37e0ea82639
Source dataset
uspto-grants-2014_03
Patent number
US08664216B2

Reaction notes

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