1-Bromo-4-fluorobenzene → 8-Benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol

HRID 1913086Notes

Reaction equation

HRID 1913086 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(OCC)C>[CH2:14]([N:21]1[CH:22]2[CH2:28][CH2:27][CH:26]1[CH2:25][C:24]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)([OH:29])[CH2:23]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

6

Reactant 4

HCID 99931-Bromo-4-fluorobenzeneHCID 14798Sodium HydroxideHCID 1198468-Benzyl-8-azabicyclo(3.2.1)octan-3-oneHCID 178418339Butyllithium

Product 1

HCID 130912278-Benzyl-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent3×

Conditions

Temperature
-35 °C

Procedure

1-Bromo-4-fluoro-benzene (22.7 g) dissolved in diethylether (100 mL) is added to a solution of n-butyllithium (1.7 mol/L in pentane, 86.8 mL) in diethylether (200 mL) cooled to −35° C. The combined solutions are stirred at −35-−40° C. for 1 h, before 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (22.5 g) dissolved in diethylether (150 mL) is added quickly. The solution is warmed to −10° C. within 1 h and then quenched by the addition of aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, the combined extracts are washed with brine, and then 4 M hydrochloric acid is added to the extract phase. The organic phase is separated from the aqueous phase and an oily precipitation formed after the addition. The oily and aqueous phase are basified with 4 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and the solvent is evaporated to give the title compound.

Workup

  1. additionis added quickly
  2. temperatureThe solution is warmed to −10° C. within 1 h
  3. customquenched by the addition of aqueous NH4Cl solution
  4. extractionThe resulting mixture is extracted with ethyl acetate
  5. washthe combined extracts are washed with brine
  6. addition4 M hydrochloric acid is added to the extract phase
  7. customThe organic phase is separated from the aqueous phase
  8. customan oily precipitation
  9. customformed
  10. additionafter the addition
  11. extractionthe resulting mixture is extracted with ethyl acetate
  12. dry with materialThe organic extracts are dried (Na2SO4)
  13. customthe solvent is evaporated

Sources & evidence

ORD record
ord-14bd33d6e3dd415684579f52ff02fc25
Source dataset
uspto-grants-2013_12
Patent number
US08609690B2

Reaction notes

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