反応 #159120

反応方程式

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

収率 68.4%

溶媒

H2O

acetone

DCM

DCM

DCM

反応条件

後処理

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

実験手順

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%).

出典