(Trifluoromethyl)trimethylsilane → (4R)-1-((R)-1-(4-Methoxyphenyl)ethyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one

HRID 2208989Notes

Reaction equation

HRID 2208989 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([CH:17]=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)[C:39]([F:42])([F:41])[F:40]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:12][C@H:13]([CH:17]([OH:18])[C:39]([F:42])([F:41])[F:40])[CH2:14][C:15]2=[O:16])[CH3:10])=[CH:5][CH:4]=1

Participants

5

Reactant 3

HCID 552549(Trifluoromethyl)trimethylsilaneHCID 2724141Tetrabutylammonium FluorideHCID 117842859(R)-1-((R)-1-(4-Methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde

Product 1

HCID 117843277(4R)-1-((R)-1-(4-Methoxyphenyl)ethyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
-60 °C

Procedure

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carbaldehyde 1.07 (7 g, 28.31 mmol, 1.00 equiv) in toluene (100 mL), trimethyl(trifluoromethyl)silane (2.9 mL), followed by the addition of tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran) (1.53 mL) dropwise with stirring at −60° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane: methanol (200:1-80:1) to afford (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one. The diastereomers were separated by chiral HPLC (CHIRALPAK IC), and the later eluting diastereomer was collected to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one 1.29. This compound is the earlier diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).

Workup

  1. customInto a 250-mL 3-necked round-bottom flask purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. stirringThe resulting solution was stirred overnight at room temperature
  4. customquenched by the addition of 100 mL of water/ice
  5. extractionextracted with 3×300 mL of ethyl acetate
  6. washwashed with 3×300 mL of brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under vacuum
  9. washeluting with dichloromethane: methanol (200:1-80:1)

Sources & evidence

ORD record
ord-0c2d96567530479f834d56fec80b0033
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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