反应 #159120

反应方程式

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

收率 68.4%

溶剂

H2O

acetone

DCM

DCM

DCM

反应条件

后处理

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
   洗涤a rinse with DCM (10 mL)
6. 6
   其他The 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
   萃取the aqueous phase was extracted 3× with EtOAc
9. 9
   干燥The combined organics were dried over MgSO4
10. 10
    过滤filtered
11. 11
    浓缩concentrated
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
    其他then quenched with 100 mL saturated aqueous Na2S2O3
15. 15
    workup.ADDITIONThe entire contents of the flask was poured into H2O
16. 16
    萃取the aqueous layer was extracted 3× with DCM
17. 17
    干燥The combined organics were dried over MgSO4
18. 18
    过滤filtered
19. 19
    浓缩concentrated
20. 20
    其他The resulting residue was purified by silica column chromatography (10% to 25% EtOAc/hexane)

实验过程

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%).

来源