Ammonium Chloride → (+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-methyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one

HRID 1837993Notes

Reaction equation

HRID 1837993 reaction equation
Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Mg].[CH:9]([C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10].[NH4+].[Cl-]>C1COCC1>[OH:10][C@H:9]([C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1)[C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 698312-Bromo-5-methylthiopheneHCID 5462224MagnesiumHCID 13825985(-)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one2×

Product 1

HCID 59066458(+/-)-(4R*,5R*)-5-[(1S*)-hydroxy(5-methyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-oneYield 52%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A portion (1 mL) of a solution of 2-bromo-5-methylthiophene (0.56 mL, 5.5 mmol) in THF (20 mL) was added to Mg turnings (135 mg, 5.5 mmol). The mixture was gently heated until the magnesium started to be consumed. The remaining thiophene solution was added in 1 mL increments to maintain a constant gentle reflux. After the addition was complete, the solution was heated at the reflux temperature for 3 min, then was allowed to cool to room temperature. To a −78° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 190 mg, 1 mmol) in THF (7.5 mL) was slowly added the freshly prepared Grignard reagent and the reaction mixture was allowed to warm to room temperature. After 2 h a saturated NH4Cl solution was added and the mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (100% EtOAc) to give (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-methyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one (156 mg, 52%) as a white powder: mp 185-188° C.

Workup

  1. customto be consumed
  2. additionThe remaining thiophene solution was added in 1 mL increments
  3. temperatureto maintain a constant gentle reflux
  4. additionAfter the addition
  5. temperaturethe solution was heated at the reflux temperature for 3 min
  6. temperatureto warm to room temperature
  7. extractionthe mixture was extracted with EtOAc
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by flash chromatography (100% EtOAc)

Sources & evidence

ORD record
ord-bd5add4999274a2bbf0eecfe44b9713e
Source dataset
uspto-grants-2004_08
Patent number
US06784167B2

Reaction notes

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