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Method for synthesizing alpha-amino ketone derivatives

An amino ketone and derivative technology, applied in the field of organic synthesis, can solve the problems of complex preparation of methylene azetidine, complex preparation of starting materials, limited substrate scope, etc., and achieves reaction regioselectivity and The effect of high chemical selectivity, improved atom utilization, and high atom utilization

Active Publication Date: 2018-12-28
ZHENGZHOU UNIVERSITY OF LIGHT INDUSTRY
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

The currently reported methods for the synthesis of α-aminoketone derivatives include: Cope rearrangement, Neber rearrangement, intermolecular aldehyde-imine cross-coupling reaction, Dakin-West and other reactions, but these methods often have the following problems: Complicated raw material preparation, harsh reaction conditions, limited substrate range
[0009] Although this method can prepare α-amino ketone derivatives, the preparation of methylene azetidine used is complicated, the range of substrates is very narrow, and only tertiary amide products can be obtained
In view of the presence of phosphine ligands, the reaction requires strict anaerobic conditions, which limits its application

Method used

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  • Method for synthesizing alpha-amino ketone derivatives
  • Method for synthesizing alpha-amino ketone derivatives
  • Method for synthesizing alpha-amino ketone derivatives

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] The reaction synthesis steps and product structural formula of the present embodiment are as follows:

[0084]

[0085] The specific operation steps of this embodiment are as follows:

[0086] Add Pd(OAc) to the reaction vessel 2 (2.8mg, 0.0125mmol), chloro[1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] silver (6.6mg, 10mol%), DMAP (1equiv), Li 2 CO 3 (1equiv), carboxylic acid compound 1a (25.1mg, 0.125mmol), 2H-aziridine compound 2a (24.2mg, 0.125mmol), dioxane (2mL), heated to 110°C, and reacted for 18 hours. The reaction solution was cooled to room temperature, and after the solvent was removed under reduced pressure, the corresponding α-aminoketone derivative (3aa) was separated by column chromatography, and its structure was determined by NMR and high-resolution mass spectrometry, see figure 2 , image 3 and Figure 10 As shown, the yield can reach 92%.

[0087] The NMR data of the α-aminoketone derivative 3aa obtained in this embodiment are as follow...

Embodiment 2

[0090] The reaction synthesis steps and product structural formula of the present embodiment are as follows:

[0091]

[0092] The specific operation steps of this embodiment are as follows:

[0093] Add Pd(OAc) to the reaction vessel 2 (2.8mg, 0.0125mmol), chloro[1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] silver (6.6mg, 10mol%), DMAP (1equiv), Li 2 CO 3 (1equiv), carboxylic acid compound 1a (251.3mg, 1.25mmol), 2H-aziridine compound 2a (241.6mg, 1.25mmol), dioxane (2mL), heated to 110°C, and reacted for 18 hours. The reaction solution was cooled to room temperature, and after the solvent was removed under reduced pressure, the corresponding α-aminoketone derivative (3aa) was separated by column chromatography, and its structure was determined by NMR and high-resolution mass spectrometry, see figure 2 , image 3 and Figure 10 As shown, the yield can reach up to 30%.

Embodiment 3

[0095] The reaction synthesis steps and product structural formula of the present embodiment are as follows:

[0096]

[0097] The specific operation steps of this embodiment are as follows:

[0098] Add Pd(OAc) to the reaction vessel 2 (2.8mg, 0.0125mmol), chloro[1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] silver (6.6mg, 10mol%), DMAP (1equiv), Li 2 CO 3 (1equiv), carboxylic acid compound 1a (20.1mg, 0.1mmol), 2H-aziridine compound 2a (24.6mg, 0.125mmol), dioxane (2mL), heated to 110°C, and reacted for 18 hours. The reaction liquid was cooled to room temperature, and after the solvent was removed under reduced pressure, the corresponding α-amino ketone derivative (3aa) was obtained by column chromatography separation. Mass spectrometry was used to determine its structure, see figure 2 , image 3 and Figure 10 As shown, the yield can reach up to 85%.

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Abstract

The invention discloses a method for synthesizing alpha-amino ketone derivatives. The method is characterized in that a series of alpha-amino ketone derivatives are obtained by providing a mixed reaction system containing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent, enabling the mixed reaction system to react at 80 to 110 DEG C for 12 to 18 hours, and promoting carboxylic acid to carry out nucleophilic addition reaction and intramolecularly ring-opening rearrangement reaction on imine by using palladium. According to the method disclosed by the invention, the nucleophilic addition and ring-opening rearrangement cascade reaction of carboxylic acid carried out on the 2H-aziridine are achieved for the first time, and further the alpha-amino ketone derivatives are successfully constructed in one step. The method has the advantages of stability and insensitivity to water and air, simple operation, mild reaction conditions, high reaction efficiency,wide application range of substrates, high atomic utilization rate and high selectivity and chemical selectivity of reactive regions; the prepared alpha-amino ketone derivatives have a novel structure and potential application value.

Description

technical field [0001] The present invention relates to a method for synthesizing α-aminoketone derivatives, in particular to a method for synthesizing α-aminoketone derivatives by using Pd to catalyze the nucleophilic addition and ring-opening rearrangement of carboxylic acid and 2H-aziridine The new method belongs to the field of organic synthesis technology. Background technique [0002] α-Aminoketone derivatives are very important structural units and are widely used in the fields of medicine and natural products. As an important synthetic intermediate, α-aminoketone can be used to synthesize various heterocyclic compounds, such as imidazole, oxazole, thiazole and other fine chemicals. The currently reported methods for the synthesis of α-aminoketone derivatives include: Cope rearrangement, Neber rearrangement, intermolecular aldehyde-imine cross-coupling reaction, Dakin-West and other reactions, but these methods often have the following problems: The preparation of r...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/76C07C233/31C07D333/38
CPCC07C231/02C07C233/31C07C233/76C07D333/38
Inventor 徐粉刘春森靳清贤宋媛媛耿鹏飞
Owner ZHENGZHOU UNIVERSITY OF LIGHT INDUSTRY
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