Benzyl 6-oxa-3-azabicyclo(3.1.0)hexane-3-carboxylate → benzyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylate

HRID 877676Notes

Reaction equation

HRID 877676 reaction equation
[CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[Cu](C#N)[C:18]#N.C[Mg]Br>C1COCC1>[OH:6][C@H:5]1[C@H:1]([CH3:18])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1

Participants

5

Reactant 3

HCID 22147363Benzyl 6-oxa-3-azabicyclo(3.1.0)hexane-3-carboxylateHCID 178418260HCID 178418260, compoundHCID 178418573HCID 178418573, compound

Product 1

HCID 58277775benzyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylateYield 89.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

To solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (9.6 g, 43.8 mmol) in THF (150 mL) was added copper cyanide (3.92 g, 43.8 mmol) and the resulting suspension was cooled to −20° C. with dry ice-ice-water-acetone bath. Methylmagnesium bromide (3 M in diethylether) (29.2 mL, 88 mmol) was added via syringe dropwise and the resulting mixture was stirred at this temperature for 1 h. At this time, TLC analysis of the resulting slurry (after quenching an aliquot with MeOH) indicated total comsumption of substrate to give a single, more polar component. At this time, the reaction was carefully quenched at −20° C. by a slow dropwise addition of 50 mL of sat. aq. ammonium chloride. The cooling bath was removed and the mixture was allowed to stir vigorously for 1 h while warming to rt. Solid was removed by vacuum filtration through Celite and the filter cake was rinsed with dichloromethane (80 mL×3). The resulting two layers of the filtrate were separated and the aqueous portion was extracted with dichloromethane (80 mL). The combined organic portions were washed with brine and dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (9.2 g, 39.1 mmol, 89% yield). HPLC (method B) retention time=2.64 min. and LCMS (m+1)=236.2.

Workup

  1. customAt this time, TLC analysis of the resulting slurry (after quenching an aliquot with MeOH)
  2. customto give a single, more polar component
  3. customAt this time, the reaction was carefully quenched at −20° C. by a slow dropwise addition of 50 mL of sat. aq. ammonium chloride
  4. customThe cooling bath was removed
  5. stirringto stir vigorously for 1 h
  6. temperaturewhile warming to rt
  7. customSolid was removed by vacuum filtration through Celite
  8. washthe filter cake was rinsed with dichloromethane (80 mL×3)
  9. customThe resulting two layers of the filtrate were separated
  10. extractionthe aqueous portion was extracted with dichloromethane (80 mL)
  11. washThe combined organic portions were washed with brine
  12. dry with materialdried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-98240e8fc5a5442e89615e0818411a33
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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