Ammonium Chloride → 1-Benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-ol

HRID 1931889Notes

Reaction equation

HRID 1931889 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=2)([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 676754-Bromo-1,2-difluorobenzeneHCID 698901-Benzyl-3-pyrrolidinoneHCID 178418339Butyllithium

Product 1

HCID 671736601-Benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-olYield 38.7%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Procedure

To a solution of 1-bromo-3,4-difluorobenzene (4 g, 20.7 mmol) in dry diethyl ether (25 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 8.3 mL, 20.7 mmol). The mixture was stirred at −78° C. for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.62 g, 20.7 mmol) in dry diethyl ether (15 mL) was added drop wise. The mixture was stirred at −78° C. for 15 min and at ambient temperature for 1 h after which aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1 and 3:2 isocratic) gave the title compound (2.32 g). MS m/z (relative intensity, 70 eV) 289 (M+, 4), 198 (23), 133 (29), 132 (23), 91 (bp). The enantiomers were separated by chiral HPLC (Kromasil 5-Cellucoat, heptane/2-propanol/diethyl amine, 99:1:0.1). Yield: enantiomer E1, 0.81 g, enantiomer E2 0.835 g.

Workup

  1. additionwas added drop wise
  2. additionwas added
  3. extractionthe mixture was extracted with ethyl acetate (2×50 mL)
  4. dry with materialThe combined organic phase was dried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated
  7. customPurification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1 and 3:2 isocratic)

Sources & evidence

ORD record
ord-3fa8ea306483423692587ba757e25b1e
Source dataset
uspto-grants-2012_05
Patent number
US08188301B2

Reaction notes

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