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Method for asymmetrically constructing C-S and C-O bond bifunctionalization by one-pot method

An asymmetric, C-S technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problem of low product stability, achieve the effect of simple synthesis method, simple structure, and shorten the synthesis cycle

Active Publication Date: 2020-06-02
QINGDAO UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The purpose of the present invention is to overcome the asymmetric difunctionalization of α-keto ester derivatives that cannot be synthesized with high stereoselectivity for the C-O bond at the β position and the C-S bond at the γ position, As well as the defects of low product stability, it provides a one-pot method for the asymmetric construction of C-S and C-O bond difunctionalization

Method used

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  • Method for asymmetrically constructing C-S and C-O bond bifunctionalization by one-pot method
  • Method for asymmetrically constructing C-S and C-O bond bifunctionalization by one-pot method
  • Method for asymmetrically constructing C-S and C-O bond bifunctionalization by one-pot method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The reaction equation is as follows:

[0058]

[0059] Add compound 1a (60mmol), 2a (50mmol) and catalyst Cat.1a (0.5mmol) into the reactor, add 500mL of dichloromethane, stir at -40°C for 6 hours, warm up to room temperature, without further treatment, and then Join Na 3 PO 4 (100mmol) and 3 (100mmol), stirring was continued for 12 hours at room temperature. After the reaction was completed, the reaction solvent was spin-dried, and the pure 4a was obtained by column chromatography with a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 1:1. 4a was obtained in 67% yield with 97% enantioselectivity and 1:4 diastereoselectivity.

[0060] 4a NMR data are as follows:

[0061] 1 H NMR (500MHz, CDCl 3 ): δ7.49(d, J=8.5Hz, 2H), 7.35(d, J=8.0Hz, 2H), 5.27(d, J=11.0Hz, 1H), 5.14(d, J=7.5Hz, 1H ),4.75(s,1H),4.14(d,J=11.0Hz,1H),4.00–3.95(m,1H),3.92(s,3H),3.22-3.11(m,2H),2.53–2.44( m,2H),1.89(s,3H),1.42(s,9H),1.32-1.26(m,2H),1.21(d,J=6.0Hz,2H),1.05...

Embodiment 2

[0064] The reaction equation is as follows:

[0065]

[0066] Add compound 1b (60mmol), 2a (50mmol) and catalyst Cat.1b (0.5mmol) into the reactor, add 500mL of dichloromethane, stir at -40°C for 6 hours, warm up to room temperature, without further treatment, and then Join Na 3 PO 4 (100mmol) and 3 (100mmol), stirring was continued for 12 hours at room temperature. After the reaction was completed, the reaction solvent was spin-dried, and the pure 4b was obtained by column chromatography with a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 1:1. The yield of 4b was 59% with 92% enantioselectivity and 1:4 diastereoselectivity.

[0067] 4b NMR data are as follows:

[0068] 1 H NMR (500MHz, CDCl 3 ):δ7.46-7.44(m,2H),7.05(t,J=8.5Hz,2H),5.25(d,J=11.0Hz,1H),5.14(d,J=7.0Hz,1H),4.75 (s,1H),4.16(d,J=11.0Hz,1H),4.00–3.96(m,1H),3.92(s,3H),3.23–3.07(m,2H),2.54–2.44(m,2H ),1.89(s,3H),1.42(s,9H),1.29-1.22(m,2H),1.20-1.15(m,2H),1.06(s,3H),0.94(s,3H),0.89(...

Embodiment 3

[0071] The reaction equation is as follows:

[0072]

[0073] Add compound 1c (60mmol), 2a (50mmol) and catalyst Cat.1a (0.5mmol) into the reactor, add 500mL of dichloromethane, stir at -40°C for 6 hours, warm up to room temperature, without further treatment, and then Join Na 3 PO 4 (100mmol) and 3 (100mmol), stirring was continued for 12 hours at room temperature. After the reaction was completed, the reaction solvent was spin-dried, and the pure 4c was obtained by column chromatography with a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 1:1. The yield of 4c was 58% with 90% enantioselectivity and 1:4 diastereoselectivity.

[0074] 4c NMR data are as follows:

[0075] 1 H NMR (500MHz, CDCl 3 ): δ7.67(d, J=7.0Hz, 1H), 7.57(d, J=8.0Hz, 1H), 7.35(t, J=7.5Hz, 1H), 7.14(t, J=7.0Hz, 1H ),5.36(d,J=8.5Hz,1H),5.16(d,J=6.5Hz,1H),4.95(d,J=9.5Hz,1H),4.78(s,1H),4.00–3.95(m ,1H),3.91(s,3H),3.24(s,2H),2.58–2.47(m,2H),1.89(s,3H),1.41(s,9H),1.31–1.26(m,2...

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Abstract

The invention discloses a method for preparing an alpha-keto ester derivative by one-pot asymmetric construction of C-S and C-O bond bifunctionalization, and belongs to the technical field of organicsynthesis. The method comprises the following steps: in the presence of chiral aromatic amide, reacting N-protected cysteamine with beta,gamma-unsaturated alpha-keto ester to complete a direct Michaeladdition reaction, adding sodium phosphate and an oxygen ammonium salt, continuously carrying out the reaction without treatment to generate an asymmetric bifunctional product alpha-keto ester with beta-C-O bond and gamma-C-S bond. The method of the invention has the characteristics of being scientific, reasonable, environmentally friendly, simple in synthesis method, high in target compound yield, high in stereoselectivity and the like.

Description

technical field [0001] The invention discloses a preparation method of an asymmetric difunctional α-keto ester derivative with a C-O bond at a β position and a C-S bond at a γ position, which belongs to the technical field of organic synthesis. Background technique [0002] β,γ-unsaturated α-ketoesters are an important class of intermediates in organic synthesis, which can be catalyzed by chiral metal Lewis acids, organic small molecule catalysis and other strategies to achieve γ-position functionalization reactions. However, compared with a large number of reported γ-position functionalization reactions, there are relatively few studies on β-position and γ-position difunctionalization reactions, which are generally completed by cycloaddition reactions (Chem.Rev.2013, 113, 5924-5988). The main reason why α-ketoesters are difficult to functionalize at the β-position is that the strong nucleophilicity of the enol oxyanion can participate in the reaction, thereby greatly inhib...

Claims

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Application Information

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IPC IPC(8): C07D211/94
CPCC07D211/94C07B2200/07Y02P20/55
Inventor 吕健王满李明
Owner QINGDAO UNIV OF SCI & TECH