CN-115141135-B - Preparation method of oxindole-acetic acid compound containing 3-chiral quaternary carbon center

CN115141135BCN 115141135 BCN115141135 BCN 115141135BCN-115141135-B

Abstract

The invention discloses a preparation method of an oxindole-acetic acid compound containing a 3-position chiral quaternary carbon center, which belongs to the technical field of organic synthesis and specifically comprises the following steps of adding a catalyst, a ligand, alkali and a reducing agent into a reaction container, adding a reaction substrate and a solvent in a CO 2 atmosphere, stirring at room temperature for reaction for 0.1-96 hours, then acidizing, and separating and purifying a reaction product to obtain the oxindole-acetic acid compound containing the 3-position chiral quaternary carbon center. The transition metal catalytic CO 2 based on the reduction system participates in the carbon-carboxylation reaction of olefin, realizes the efficient construction of the oxindole-acetic acid compound containing the 3-chiral quaternary carbon center for the first time, and has the advantages of wide range of reaction substrates, good selectivity, good functional group compatibility, mild reaction conditions, low cost and the like.

Inventors

YU DAGANG
ZHOU WENJUN
CHEN XIAOWANG
YUE JUNPING
WANG KUAI
GUI YONGYUAN
NIU YANAN
LIU JIE
Ran Chuankun
KONG WANGQING

Assignees

四川大学
四川大学

Dates

Publication Date: 20260421
Application Date: 20210329
Priority Date: 20210329

Claims (3)

1. The preparation method of the oxindole-acetic acid compound containing the 3-chiral quaternary carbon center is characterized by comprising the following steps: Adding a catalyst, a ligand, alkali and a reducing agent into a reaction container, adding a reaction substrate and a solvent in a CO 2 atmosphere, stirring at room temperature for reacting for 0.1-96 hours, then acidizing, and separating and purifying a reaction product to obtain an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center, wherein the molar ratio of the reaction substrate to the catalyst to the ligand to the alkali to the reducing agent is 1:0.001-0.30:0.002-0.60:1-4:1-4; The reaction substrate is an enamide bridged aryl (quasi) halide, and the structural general formula is shown as follows: Wherein X is chlorine, bromine or triflate, R 1 and R 2 are alkyl; The catalyst is ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel acetylacetonate or bis- (1, 5-cyclooctadiene) nickel; The ligand is 、、、、、 ; The solvent is N, N-dimethylformamide and dimethyl sulfoxide; The alkali is lithium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate or potassium phosphate; The reducing agent is zinc or manganese.
2. The method for preparing the indole-acetic acid compound containing the 3-chiral quaternary carbon center according to claim 1, wherein the molar ratio of the reaction substrate to the catalyst to the ligand to the alkali to the reducing agent is 1:0.05-0.15:0.15-0.30:2:2, and the reaction time is 48-96 hours.
3. The method for preparing an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center according to claim 1, wherein magnesium chloride is added together when a catalyst, a ligand, a base and a reducing agent are added into a reaction vessel, and the molar ratio of the magnesium chloride to a reaction substrate is 1-4:1.

Description

Preparation method of oxindole-acetic acid compound containing 3-chiral quaternary carbon center Technical Field The invention relates to the technical field of organic synthesis, in particular to a preparation method of an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center. Background Indoline and oxindole structures containing chiral quaternary carbon centers are widely found in natural products. The alkaloid has excellent physiological activity, such as anti-tumor, antiviral, anxiolytic, antiinflammatory, blood pressure lowering, fever relieving, pain relieving, and cathepsin inhibiting effects. Therefore, efficient construction of such structures is receiving a great deal of attention in the fields of organic chemistry, pharmaceutical chemistry and biochemistry. The oxindole-acetic acid compound containing 3-site chiral quaternary carbon center is an important synthesis precursor of a large class of alkaloids, and the efficient construction of the compound can promote the rapid synthesis of (spiro) heterocycle fused indole alkaloids and enrich a molecular library thereof, thereby providing a material basis for researching the physiological properties of the molecules in the fields of pharmaceutical chemistry and biochemistry. The traditional synthesis method of the oxindole-acetic acid compound containing the 3-chiral quaternary carbon center has larger limitation, has the defects of complicated steps, needs to use toxic CO gas or a highly toxic cyano compound as a carboxyl source, needs to use noble metal and the like, and has the direct and efficient chiral synthesis of the molecules which is difficult to realize. Therefore, the exploration of the high-efficiency chiral synthesis of the molecules has important academic significance and application value. Carbon dioxide is used as a cheap and easily available carbon resource with no toxicity, regeneration and rich reserves. In recent years, great attention has been paid to the fields of materials and chemistry and chemical engineering. Therefore, the development of efficient CO 2 conversion processes is also of great academic interest and potential industrial value. Recently, the use of CO 2 in carboxylic acid construction has received high attention from organic chemists. Among these, the participation of CO 2 in the functionalization reaction of unsaturated hydrocarbons is an important pathway for the construction of carboxylic acid products. Furthermore, CO 2 can simultaneously introduce two carbon functional groups when participating in carbon-carboxyl difunctional reaction of olefin, and is a convenient way for quickly constructing polysubstituted complex carboxylic acid. However, to date, transition metal catalyzed CO 2 has been rarely reported to be involved in the carbon-carboxylation of olefins. Transition metal-catalyzed CO 2 based on a reduction system is not reported to participate in the carbon-carboxylation reaction of olefins, and asymmetric carbon-carboxylation reaction is a difficult problem. Therefore, using CO 2 to replace the expensive and toxic carboxyl source (CO or cyano), it is needed in the art to provide a method for the efficient synthesis of optically pure oxindole-acetic acid compounds by developing a novel asymmetric carbon-carboxylation reaction of olefins in which CO 2 participates. Disclosure of Invention Aiming at the defects or shortcomings of the prior art, the invention aims to provide a preparation method of an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center, which can effectively solve the problems of complicated steps, use of toxic CO gas or a virulent cyano compound as a carboxyl source in the existing preparation method, and has the advantages of high yield, high selectivity, mild reaction conditions, low toxicity of a reaction reagent, low cost and the like. In order to achieve the above purpose, the invention adopts the following technical scheme: the invention provides a preparation method of an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center, which specifically comprises the following steps: Adding a catalyst, a ligand, alkali and a reducing agent into a reaction container, adding a reaction substrate and a solvent under the atmosphere of CO 2, stirring at room temperature for reacting for 0.1-96 h, then acidizing, and separating and purifying a reaction product to obtain an oxindole-acetic acid compound containing a 3-chiral quaternary carbon center, wherein the molar ratio of the reaction substrate to the catalyst to the ligand to the alkali to the reducing agent is 1:0.001-0.30:0.002-0.60:1-4:1-4; the reaction substrate is an enamide bridged aryl (quasi) halide, and the structural general formula is shown as follows: Wherein X is chlorine, bromine or trifluoro methanesulfonate, and R 1 and R 2 are both alkyl. On the basis of the technical scheme, the invention can be improved as follows. Further, the molar ratio of the re