Formaldehyde → tert-Butyl alpha-(1-Hydroxymethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate

HRID 727566Notes

Reaction equation

HRID 727566 reaction equation
[CH3:1][CH:2]([CH3:26])[CH2:3][C:4]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].[Li+].CC([N-]C(C)C)C.[CH2:35]=[O:36]>C1COCC1>[OH:36][CH2:35][CH:18]([C:4]1([CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]1=[O:17])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 2724682Lithium diisopropylamideHCID 54164883tert-Butyl 3-(2-Methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate

Product 1

HCID 19705491tert-Butyl alpha-(1-Hydroxymethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetateYield 116.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A cold (-78° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 2.00 g, 5.56 mmol) in dry THF (20 mL) is treated with the dropwise addition of LDA (3.20 mL, 6.40 mmol, 2.0N). The solution is maintained at -78° C. for 30 min and then warmed to -30° C. Gaseous formaldehyde (generated by heating 834 mg of paraformaldehyde at 160° C. to provide approximately 28 mmol) is bubbled through the enolate solution. The solution is maintained at -30° C. for 1 hour and then quenched with saturated aqueous NH4Cl (5 mL) and diluted with H2O (20 mL). The product is extracted into EtOAc (3×50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 2.52 g of a yellow solid which is purified by silica gel chromatography (100 g SG; 25% EtOAc/hexane) to give 1.43 g (83%) of the title compound as a golden oil. Another fraction containing 375 mg of a mix of both diastereomers is also recovered. Spectral data for the title compound:

Workup

  1. temperaturewarmed to -30° C
  2. temperatureThe solution is maintained at -30° C. for 1 hour
  3. customquenched with saturated aqueous NH4Cl (5 mL)
  4. additiondiluted with H2O (20 mL)
  5. extractionThe product is extracted into EtOAc (3×50 mL)
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-ecb86ded8e0e41389a9119b8c959b156
Source dataset
uspto-grants-1998_01
Patent number
US05712300

Reaction notes

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