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

HRID 48476

Reaction equation

HRID 48476 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 60072567(R,R)-3-(1-Hydroxyethyl)-piperidine-1-carboxylic acid benzyl esterYield 52%

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 14 prepared according to Example 15, 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 16 (0.167 g, 52%). HLPC analysis of the product is depicted in the Figures. 1H NMR (CDCl3, 300 MHz) 7.42-7.30 (5H, broad s), 5.15 (2H, s), 4.08 (2H, broad d, J=12.8 Hz), 3.67 (1H, dq, J=6.2, 6.2 Hz), 2.81 (1H, td, J=12.4, 3.1 Hz), 3.90-2.60 (1H, broad), 2.40-1.90 (2H, broad), 1.80-1.68 (1H, m), 1.56-1.40 (2H, m), 1.23 (3H, d, J=6.3 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.58, 137.06, 128.61, 128.07, 127.91, 69.38, 67.14, 46.94, 44.81, 43.14, 25.71, 24.95, 21.03 ppm.

Workup

  1. distillationfreshly distilled from sodium/benzophenone (2.43 mL)
  2. additionwas added to catalyst 14
  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-1f9c5fd2a0874a799e11cd44f5836117
Source dataset
uspto-grants-2004_03
Patent number
US06703508B2

Linked notes

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