1-Bromo-4-phenylmethoxybenzene → 1-Benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl)piperidine

HRID 2381130Notes

Reaction equation

HRID 2381130 reaction equation
C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Participants

5

Reactant 3

HCID 1388351-Bromo-4-phenylmethoxybenzeneHCID 643496Benzyl 4-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 218398431-Benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl)piperidineYield 37.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (1.6M in hexane, 42.9 ml, 107.18 mmol) was added dropwise to 1-(benzyloxy)-4-bromobenzene (28.2 g, 107.18 mmol, CAS 6793-92-6) in THF (367 ml) at −78° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at −78° C. for 1 hour then benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in THF (122 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was evaporated to dryness and quenched with saturated ammonium chloride (50 mL), then then extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford crude product. The crude product was further purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford benzyl 4-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-1-carboxylate (13.49 g, 30.1%) as a gum.

Workup

  1. stirringThe resulting mixture was stirred at −78° C. for 10 minutes
  2. temperatureto warm to room temperature
  3. stirringstirred for 16 hours
  4. customThe reaction mixture was evaporated to dryness
  5. customquenched with saturated ammonium chloride (50 mL)
  6. extractionextracted with EtOAc (500 mL)
  7. dry with materialThe organic layer was dried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customto afford crude product
  11. customThe crude product was purified by flash silica chromatography, elution gradient 1 to 100% EtOAc in isohexane
  12. customPure fractions were evaporated to dryness
  13. customto afford crude product
  14. customThe crude product was further purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM
  15. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-f994f1f70fe9449a832f161e28f465d3
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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