tert-Butyl 4-oxopiperidine-1-carboxylate → Tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

HRID 1675024Notes

Reaction equation

HRID 1675024 reaction equation
C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 27344145-Bromo-2-chloropyridineHCID 178418339Butyllithium

Product 1

HCID 86638078Tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylateYield 51.2%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

n-Butyl lithium (1.6M in hexanes, 6.50 mL, 10.39 mmol) was added dropwise to 5-bromo-2-chloropyridine (2.0 g, 10.39 mmol) in ether (30 mL) cooled to −78° C. over a period of 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes then a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.66 g, 8.31 mmol) in ether (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature then quenched with ammonium chloride solution (50 mL) and extracted with EtOAc. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and concentrated by evaporation, then purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (1.33 g, 41%) as a cream solid.

Workup

  1. temperatureto warm slowly to room temperature
  2. customthen quenched with ammonium chloride solution (50 mL)
  3. extractionextracted with EtOAc
  4. washThe extract was washed sequentially with water and saturated brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated by evaporation
  7. custompurified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane
  8. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-27306ecc6fe54c01bca764dce78b1af2
Source dataset
uspto-grants-2011_08
Patent number
US08003649B2

Reaction notes

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