Reaction #76753

Reaction equation

Me2Zn

Aldehyde

3-formyl-piperidine-1-carboxylic acid benzyl ester

→

15

Yield 51.0%

(R,S)-3-(1-Hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester

Yield 51.0%

Solvents

Et2O

ethyl ether

Conditions

Workup

1. 1
   workup.DISTILLATIONfreshly distilled from sodium/benzophenone (2.43 mL)
2. 2
   workup.ADDITIONwas added to catalyst 13
3. 3
   Otherprepared
4. 4
   Temperaturethe reaction was warmed to −30° C.
5. 5
   workup.STIRRINGstirred overnight
6. 6
   OtherThe reaction was then quenched at −30° C. with saturated aqueous NH4Cl
7. 7
   workup.ADDITIONEt2O was added
8. 8
   Filtrationthe reaction was filtered through Celite wet with Et2O
9. 9
   DryingThe reaction was dried with sodium sulfate
10. 10
    Filtrationfiltered
11. 11
    Concentrationconcentrated
12. 12
    Otherpurified

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.

Source