Tert-butyl 4-benzyl-3-oxopiperazine-1-carboxylate → Tert-butyl 4-benzyl-4,7-diazaspiro[2.5]octane-7-carboxylate

HRID 527883Notes

Reaction equation

HRID 527883 reaction equation
[CH3:1][CH2:2][Mg+].[Br-].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][C:14]2([CH2:2][CH2:1]2)[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]

Participants

5

Reactant 2

HCID 10891590Tert-butyl 4-benzyl-3-oxopiperazine-1-carboxylateHCID 178461630HCID 178461630, compound2×

Product 1

HCID 66888528Tert-butyl 4-benzyl-4,7-diazaspiro[2.5]octane-7-carboxylateYield 58%

Reagents, catalysts & solvents 2

HCID 178460666HCID 178460666, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

To EtMgBr (344 mL) in THF cooled to −78° C. was added Ti(OiPr)4 (39 g, 137.93 mmol), followed by commercially available 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (40 g, 137.93 mmol) and the resultant reaction mixture was heated to reflux for 1 h. After cooling the reaction mixture to 5° C., another portion of EtMgBr (344 ml) and Ti(OiPr)4 (39 g, 137.93 mmol) was added. The mixture was stirred for 16 h at RT. The reaction mixture was quenched with NH4Cl solution and stirred for 15 min and filtered through a celite bed and washed with EtOAc. The aqueous layer was again extracted with EtOAc (3×). The combined EtOAc layers were washed with water and dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography to afforded the title compound as a solid (24 g, 58%).

Workup

  1. customthe resultant reaction mixture
  2. temperaturewas heated
  3. temperatureto reflux for 1 h
  4. customThe reaction mixture was quenched with NH4Cl solution
  5. stirringstirred for 15 min
  6. filtrationfiltered through a celite bed
  7. washwashed with EtOAc
  8. extractionThe aqueous layer was again extracted with EtOAc (3×)
  9. washThe combined EtOAc layers were washed with water
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated under reduced pressure
  12. customPurification by column chromatography

Sources & evidence

ORD record
ord-ed5b0737bf8a4f69b4c0b0dce7670889
Source dataset
uspto-grants-2016_05
Patent number
US09346809B2

Reaction notes

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