Reaktion #159120

Reaktionsgleichung

N-methylmorpholine-N-oxide

4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester

CH2I2

TFA

Diethyl zinc

hexane

→

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester

Ausbeute 68.4%

Lösungsmittel

H2O

acetone

DCM

DCM

DCM

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONcontaining a stir bar
2. 2
   workup.ADDITIONwas added dropwise by addition funnel over 22 minutes
3. 3
   workup.ADDITIONwas added slowly over 4 minutes
4. 4
   workup.ADDITIONwas added by cannula
5. 5
   Waschena rinse with DCM (10 mL)
6. 6
   SonstigeThe reaction was quenched by addition of 100 mL saturated aqueous NH4Cl
7. 7
   workup.ADDITIONThe entire contents of the flask were poured into saturated aqueous NaHCO3
8. 8
   Extraktionthe aqueous phase was extracted 3× with EtOAc
9. 9
   TrocknenThe combined organics were dried over MgSO4
10. 10
    Filtrationfiltered
11. 11
    Einengenconcentrated
12. 12
    workup.DISSOLUTIONThe residue was dissolved in THF (100 mL)
13. 13
    workup.STIRRINGThe reaction mixture was stirred 7 hours at room temperature
14. 14
    Sonstigethen quenched with 100 mL saturated aqueous Na2S2O3
15. 15
    workup.ADDITIONThe entire contents of the flask was poured into H2O
16. 16
    Extraktionthe aqueous layer was extracted 3× with DCM
17. 17
    TrocknenThe combined organics were dried over MgSO4
18. 18
    Filtrationfiltered
19. 19
    Einengenconcentrated
20. 20
    SonstigeThe resulting residue was purified by silica column chromatography (10% to 25% EtOAc/hexane)

Vorschrift

Diethyl zinc (1.0 M in hexane (118 mL, 118 mmol) was added to a 3-neck round bottom flask containing a stir bar, DCM (120 mL) and equipped with an addition funnel and an Argon inlet adaptor. The solution was cooled to 0° C. before TFA (9.5 mL, 118 mmol) in DCM (40 mL) was added dropwise by addition funnel over 22 minutes. 20 minutes after completion of the addition, CH2I2 was added slowly over 4 minutes. 20 minutes after completion of addition, 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (8.10 g, 29.4 mmol) in DCM (30 mL) was added by cannula followed by a rinse with DCM (10 mL). 10 minutes later, the reaction mixture was warmed to room temperature and stirred for 110 hours. The reaction was quenched by addition of 100 mL saturated aqueous NH4Cl. The entire contents of the flask were poured into saturated aqueous NaHCO3 and the aqueous phase was extracted 3× with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in THF (100 mL), acetone (33 mL) and H2O (33 mL) and N-methylmorpholine-N-oxide (3.45 g, 29.41 mmol) and osmium tetroxide (4 wt % in H2O, 5 mL, 0.818 mmol) were added sequentially. The reaction mixture was stirred 7 hours at room temperature then quenched with 100 mL saturated aqueous Na2S2O3. The entire contents of the flask was poured into H2O and the aqueous layer was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica column chromatography (10% to 25% EtOAc/hexane) to provide 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (5.54 g, 65%).

Quelle