Phthalimide → (2S,3R)-Benzyl 2-((1,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate

HRID 60887Notes

Reaction equation

HRID 60887 reaction equation
O[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(CCCC)(CCCC)CCCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:51]1(=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[NH:52]1>C1COCC1.CCOCC>[O:61]=[C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[N:52]1[CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]

Participants

7

Reactant 4

HCID 6809PhthalimideHCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 117731459(2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate

Product 1

HCID 117731460(2S,3R)-Benzyl 2-((1,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylateYield 89.1%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (4.61 g, 17.5 mmol) and n-Bu3P (10.6 g, 52.4 mmol) in anhydrous THF (150 mL) was added 1,1′-(azodicarbonyl)dipiperidine (ADDP; 8.83 g, 35.0 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 30 min. To the reaction mixture was then added isoindoline-1,3-dione (3.09 g, 21.0 mmol), followed by heating at reflux for 20 h. After this time, the reaction mixture was cooled to rt, diluted with Et2O (100 mL), and further cooled with an ice/water bath. The resulting mixture was filtered and the filter cake was washed with Et2O (40 mL). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8). The material obtained from the chromatography was triturated with hexanes/CH2Cl2 (5:1) and solids removed by filtration. Concentration of the filtrate afforded the title compound as a colorless oil (6.12 g, 89%). ESI MS (M+H) 393.

Workup

  1. temperatureby heating
  2. temperatureat reflux for 20 h
  3. temperatureAfter this time, the reaction mixture was cooled to rt
  4. temperaturefurther cooled with an ice/water bath
  5. filtrationThe resulting mixture was filtered
  6. washthe filter cake was washed with Et2O (40 mL)
  7. concentrationThe combined filtrate was concentrated under reduced pressure
  8. customThe resulting residue was purified by flash column chromatography on silica gel eluting with hexanes/CH2Cl2/EtOAc (50:48:2) to hexanes/CH2Cl2/EtOAc (50:42:8)
  9. customThe material obtained from the chromatography
  10. customwas triturated with hexanes/CH2Cl2 (5:1) and solids
  11. customremoved by filtration

Sources & evidence

ORD record
ord-0e90db3d29484f4599d3c7bae161eb34
Source dataset
uspto-grants-2016_09
Patent number
US09440982B2

Reaction notes

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