Benzyl 3-formylpiperidine-1-carboxylate → (R,S)-3-(1-Hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester

HRID 892246Notes

Reaction equation

HRID 892246 reaction equation
[Zn](C)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@@H:20]([OH:21])[CH3:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1

Participants

5

Reactant 2

HCID 9899653Benzyl 3-formylpiperidine-1-carboxylateHCID 178477796HCID 178477796, compound

Product 1

HCID 60072571(R,S)-3-(1-Hydroxyethyl)-piperidine-1-carboxylic acid benzyl esterYield 51%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 13 prepared according to Example 11, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15 (0.162 g, 51%). HLPC analysis of the product presented in the Figures. 1H NMR (CDCl3, 300 MHz) 7.43–7.31 (5H, broad s), 5.16 (2H, s), 4.30–3.60 (2H, broad m), 3.63 (1H, dq, J=6.4, 6.4 Hz), 3.30–2.70 (2H, broad s), 2.15–1.90 (1H, broad s), 1.84–1.72 (1H, m), 1.76–1.56 (1H, m), 1.58–1.36 (2H, m), 1.23 (3H, d, J=6.4 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.81, 137.04, 128.61, 128.08, 127.93, 68.35, 67.19, 46.61, 45.02, 43.25, 27.08, 24.37, 20.95 ppm. LRMS m/z 263.68 (M+, C15H21NO3, requires 263.15. Protocol 2

Workup

  1. distillationfreshly distilled from sodium/benzophenone (2.43 mL)
  2. additionwas added to catalyst 13
  3. customprepared
  4. temperaturethe reaction was warmed to −30° C.
  5. stirringstirred overnight
  6. customThe reaction was then quenched at −30° C. with saturated aqueous NH4Cl
  7. additionEt2O was added
  8. filtrationthe reaction was filtered through Celite wet with Et2O
  9. dry with materialThe reaction was dried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. custompurified

Sources & evidence

ORD record
ord-a06f970c02e84831bb7dea43a88c56cc
Source dataset
uspto-grants-2006_02
Patent number
US07005524B2

Reaction notes

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