Sodium hydride → Tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 1778462Notes

Reaction equation

HRID 1778462 reaction equation
[CH2:1]([O:8][CH:9]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[C:19]([O:18][C:16]([N:11]1[CH:10]2[CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH:12]1[CH2:14][O:24][CH2:23]2)=[O:17])([CH3:21])([CH3:20])[CH3:22]

Participants

4

Reactant 2

HCID 24758Sodium hydrideHCID 45141853tert-butyl (2R,5R)-3-benzyloxy-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 66582731Tert-butyl 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylateYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of tert-butyl (2R,5R)-3-benzyloxy-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1.15 g, 3.4 mmol) in THF (50 mL) was added NaH (60%, 0.409 g, 10.2 mmol). The mixture was stirred at room temperature for 30 minutes and cooled to 0° C. A solution of p-TsCl (0.65 g, 3.4 mmol) in THF (5 mL) was slowly added to the mixture. The reaction mixture was then stirred at room temperature for 12 hours and quenched by sat. NH4Cl solution (20 mL). The mixture was concentrated in vacuo, and the residue was taken up with water and EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4. The organic solvent was removed in vacuo to give the crude product, which was purified by flash chromatography on silica gel to give 6-benzyloxy-3-oxa-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (716 mg, 66%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): 7.35-7.27 (m, 5H), 4.59-4.43 (m, 2H), 4.38-4.07 (m, 3H), 3.73-3.56 (m, 3H), 3.47 (t, 1H, J=9.8 Hz), 2.27 (m, 1H), 1.96 (m, 1H), 1.48 (s, 4.5H), 1.44 (s, 4.5H).

Workup

  1. temperaturecooled to 0° C
  2. stirringThe reaction mixture was then stirred at room temperature for 12 hours
  3. customquenched by sat. NH4Cl solution (20 mL)
  4. concentrationThe mixture was concentrated in vacuo
  5. customThe organic layer was separated
  6. extractionthe aqueous phase was extracted with EtOAc
  7. washThe combined organic phases were washed with water and brine
  8. dry with materialdried over Na2SO4
  9. customThe organic solvent was removed in vacuo
  10. customto give the crude product, which
  11. customwas purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-5bb802857f554029bf6fe5dc216c78ad
Source dataset
uspto-grants-2016_02
Patent number
US09266904B2

Reaction notes

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