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

HRID 72834Notes

Reaction equation

HRID 72834 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 to −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 the reaction is quenched by the addition of aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, the combined extracts are washed with brine, and 4 M hydrochloric acid is added to the organic phase. The organic phase is separated from the aqueous phase and an oily precipitation formed after the addition. The oily and aqueous phase are combined and 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. customthe reaction is quenched by the addition of aqueous NH4Cl solution
  4. extractionThe resulting mixture is extracted with ethyl acetate
  5. washthe combined extracts are washed with brine, and 4 M hydrochloric acid
  6. additionis added to the organic 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-3daac1c55a1b46dd80d595152ab04052
Source dataset
uspto-grants-2014_09
Patent number
US08829027B2

Reaction notes

Loading…