Boron trifluoride etherate → (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate

HRID 1961403Notes

Reaction equation

HRID 1961403 reaction equation
[CH3:1][C@@:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][C:5]([CH3:8])([CH3:7])[C:4](=O)[N:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Li+].[B-](CC)(CC)CC.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][C@@:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][N:3]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]

Participants

6

Reactant 4

HCID 8000Boron trifluoride etherate2×HCID 12052Triethylsilane2×HCID 23712863Lithium triethylborohydrideHCID 29983443Methyl (2S)-1-tert-Boc-2,4,4-trimethylpyroglutamate

Product 1

HCID 68474517(S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylateYield 75.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of (S)-1-tert-butyl 2-methyl 2,4,4-trimethyl-5-oxopyrrolidine-1,2-dicarboxylate 106C (13.96 g, 48.9 mmol) in THF (100 mL) was added Super-hydride (lithium triethylboro-hydride) (58.7 mL, 58.7 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 at −78° C. The reaction mixture was warmed to 0° C. and hydrogen peroxide (15 ml) was added drop-wise at 0° C. The mixture was stirred at 0° C. for 30 min and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. After concentration, the crude product was used for the next step without purification. To a stirred solution of the crude product obtained above in CH2Cl2, was added half of triethylsilane (17.19 mL., 108 mmol) and half of BF3.OEt2 (13.64 mL., 108 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 h, then the remaining triethylsilane (17.19 mL., 108 mmol) and BF3.OEt2 (13.64 mL, 108 mmol) were added. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 solution. The reaction mixture was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by Biotage (0-30% EtOAc/Hexane, 1.5 L) to give (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate 106D (10 g, 75%) as an oil.

Workup

  1. customquenched with saturated NaHCO3 at −78° C
  2. temperatureThe reaction mixture was warmed to 0° C.
  3. additionhydrogen peroxide (15 ml) was added drop-wise at 0° C
  4. stirringThe mixture was stirred at 0° C. for 30 min
  5. extractionextracted with ethyl acetate
  6. washThe combined organic layers were washed with water and brine
  7. dry with materialdried over Na2SO4
  8. concentrationAfter concentration
  9. customthe crude product was used for the next step without purification
  10. customTo a stirred solution of the crude product obtained above in CH2Cl2
  11. stirringThe reaction mixture was stirred at −78° C. for 1 h
  12. stirringThe reaction mixture was stirred at −78° C. for 2 h
  13. customquenched with saturated NaHCO3 solution
  14. extractionThe reaction mixture was extracted with CH2Cl2
  15. washThe combined organic layers were washed with water and brine
  16. dry with materialdried over Na2SO4
  17. customThe crude product was purified by Biotage (0-30% EtOAc/Hexane, 1.5 L)

Sources & evidence

ORD record
ord-eb1228fdcb0c4a14803298450dbac595
Source dataset
uspto-grants-2013_04
Patent number
US08415340B2

Reaction notes

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