阅读说明：本技术 一种α-芳基α-氨基酮类化合物的制备方法 (Preparation method of alpha-aryl alpha-aminoketone compound ) 是由 魏小红 张平 陈丽华 王彦斌 于 2019-10-22 设计创作，主要内容包括：本发明公开了一种α-芳基α-氨基酮类化合物的制备方法,其步骤如下：1)将α-氨基羰基化合物、芳基硼酸、催化剂、氧化剂置于反应容器中,通入氮气后加入反应溶剂,然后在20-100℃的温度下反应完全后得反应液；2)所述反应液进行萃取后得萃取液；3)所述萃取液经干燥、浓缩、柱层析分离提纯后即得α-芳基α-氨基酮类化合物。本发明采用α-氨基羰基化合物与芳基硼酸化合物制备α-芳基α-氨基酮类化合物,可一锅法得到目标产物,不仅解决了传统α-氨基酮合成原料类型单一的问题,简化了合成步骤,并且高选择性、高产率地得到了目标产物,具有操作简单、原料易得、产率高、生产成本低、产率高的优点。(The invention discloses a preparation method of an alpha-aryl alpha-aminoketone compound, which comprises the following steps: 1) placing an alpha-aminocarbonyl compound, arylboronic acid, a catalyst and an oxidant in a reaction vessel, introducing nitrogen, adding a reaction solvent, and reacting completely at the temperature of 20-100 ℃ to obtain a reaction solution; 2) extracting the reaction solution to obtain an extract; 3) and drying, concentrating, and carrying out column chromatography separation and purification on the extract liquor to obtain the alpha-aryl alpha-aminoketone compound. The invention adopts the alpha-aminocarbonyl compound and the aryl boric acid compound to prepare the alpha-aryl alpha-aminoketone compound, can obtain the target product by a one-pot method, not only solves the problem of single type of the traditional alpha-aminoketone synthesis raw material, simplifies the synthesis steps, but also obtains the target product with high selectivity and high yield, and has the advantages of simple operation, easily obtained raw material, high yield, low production cost and high yield.)

1. A preparation method of alpha-aryl alpha-aminoketone compounds is characterized by comprising the following steps:

1) adding an alpha-aminocarbonyl compound, arylboronic acid, a catalyst and an oxidant into a reaction vessel, introducing nitrogen, adding a reaction solvent, reacting at the temperature of 20-100 ℃, and obtaining a reaction solution after the reaction is completed;

2) extracting the reaction solution to obtain an extract;

3) and drying, filtering, separating and purifying by silica gel column chromatography, and performing rotary evaporation and concentration on the extract liquor to obtain the alpha-aryl alpha-aminoketone compound.

2. The method of claim 1, wherein: the reaction formula of the preparation method is as follows:

in the formula, R₁Is aryl, R₂Is aryl, R₃Is aryl or naphthalene ring radical.

3. The method of claim 1, wherein: the structural general formula (1) of the alpha-aryl alpha-aminoketone compound is as follows:

（1）

in the formula (1), R₁Is aryl, R₂Is aryl, R₃Is aryl or naphthalene ring radical.

4. The method of claim 1, wherein: the structural general formula (2) of the alpha-aminocarbonyl compound is as follows:

（2）

in the formula (2), R₁Is aryl, R₂Is an aryl group.

5. The method of claim 1, wherein: the structural general formula (3) of the aryl boric acid is as follows:

（3）

in the formula (3), R₃Is aryl or naphthalene ring radical.

6. The method of claim 1, wherein: the catalyst comprises any one of 2, 2-bipyridyl, 4-bipyridyl, triphenylphosphine, alpha-bipyridyl, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

7. The method of claim 1, wherein: the oxidant comprises any one of benzoquinone, silver oxide, silver acetate, silver carbonate, dicumyl peroxide, 2,6, 6-tetramethylpiperidine oxide, copper acetate, iodobenzene acetate and potassium peroxodisulfate.

8. The method of claim 1, wherein: the reaction solvent comprises any one of dichloroethane, acetonitrile, toluene, N-dimethylformamide, dioxane, dichloromethane, methanol, ethanol, tetrahydrofuran and trifluoroethanol.

9. The method of claim 1, wherein: the molar ratio of the alpha-aminocarbonyl compound to the arylboronic acid is from 1:1 to 1: 2; the molar ratio of the alpha-aminocarbonyl compound to the catalyst is 1:0.01-1:0.2, the molar ratio of the alpha-aminocarbonyl compound to the oxidant is 1:1-1:2, and the molar ratio of the alpha-aminocarbonyl compound to the reaction solvent is 1:30-1: 60.

10. The method of claim 1, wherein: the reaction is carried out at a temperature of 80 ℃.

Technical Field

The invention belongs to the technical field of synthesis of alpha-aminocarbonyl compounds, and particularly relates to a preparation method of an alpha-aryl alpha-aminoketone compound.

Background

Alpha-aminocarbonyl compounds are important components of natural products and also important structural units of natural products, and are widely applied to synthesis of bioactive agents, therapeutic agents, quinazolines, imidazoles, pyrazines, indoles, pyrroles and the like. At present, the reaction for synthesizing an α -aminocarbonyl compound is: the method comprises the following steps of Strecker reaction, transition metal catalyzed alpha-enamine or imido ester hydrogenation reaction, transition metal catalyzed nucleophilic addition reaction of various nucleophilic reagents to alpha-imido ester, and direct synthesis reaction of alpha-aminocarbonyl compound under the condition of Schiff base synergistic phase transfer catalyst.

Although more and more synthetic methods have been developed and applied to the synthesis of α -aminocarbonyl compounds, the following problems and challenges remain with research in this area: 1) compared with the traditional synthesis method, the synthesis method mainly adopts the modes of a Strecker reaction, a transition metal catalyzed alpha-enamine or imido hydrogenation reaction, a transition metal catalyzed nucleophilic addition reaction of various nucleophiles to alpha-imido ester, a Schiff base synergistic phase transfer catalyst condition for directly synthesizing an alpha-aminocarbonyl compound and the like, and the synthesis method with high speed, high efficiency, environmental protection and low cost is pending for further research and development; 2) the types of the substrates are single, and the substrates are mainly imine substrates; 3) in some existing synthetic methods, the catalytic system limits the range of substrates, thereby limiting further applications of these methods. The alpha-aryl alpha-aminoketones as an important compound in the alpha-aminocarbonyl compounds not only have the problems of the above synthetic methods of the alpha-aminocarbonyl compounds, but also have the problem of how to prepare the target products with high selectivity and high yield. Therefore, it is important to provide a method for preparing α -aryl α -aminoketones rapidly, efficiently and selectively.

Disclosure of Invention

The invention aims to: solves the defects of the existing alpha-aminocarbonyl compound synthesis method, and realizes the preparation of the alpha-aryl alpha-aminoketone compound with high selectivity and high yield, thereby providing the preparation method of the alpha-aryl alpha-aminoketone compound with mild reaction, low cost, small environmental pollution, simple operation and high yield.

In order to achieve the purpose, the invention adopts the following technical scheme:

a preparation method of alpha-aryl alpha-aminoketones compounds comprises the following steps:

1) adding an alpha-aminocarbonyl compound, arylboronic acid, a catalyst and an oxidant into a reaction vessel, introducing nitrogen, adding a reaction solvent, reacting at the temperature of 20-100 ℃, and obtaining a reaction solution after the reaction is completed;

2) extracting the reaction solution to obtain an extract;

3) and drying, filtering, separating and purifying by silica gel column chromatography, and performing rotary evaporation and concentration on the extract liquor to obtain the alpha-aryl alpha-aminoketone compound.

The reaction formula of the preparation method is as follows:

wherein R is₁Is aryl, R₂Is aryl, R₃Is aryl or naphthalene ring radical.

The structural general formula (1) of the alpha-aryl alpha-aminoketone compound is as follows:

（1）

in the formula (1), R₁Is aryl, R₂Is aryl, R₃Is aryl or naphthalene ring radical.

The structural general formula (2) of the alpha-aminocarbonyl compound is as follows:

（2）

in the formula (2), R₁Is aryl, R₂Is an aryl group.

The structural general formula (3) of the aryl boric acid is as follows:

（3）

wherein R is₃Aryl, naphthalene ring group.

Preferably, the α -aminocarbonyl compound comprises: n- (4-chlorophenyl) -1-phenylethanone, N- (4-fluorophenyl) -1-phenylethanone, N- (4-bromophenyl) -1-phenylethanone, N- (3-chlorophenyl) -1-phenylethanone, N- (4-methylphenyl) -1-phenylethanone, N- (3, 4-dimethylphenyl) -1-phenylethanone, N- (3, 5-dimethylphenyl) -1-phenylethanone, N- (4-chlorophenyl) -1- (4-chlorophenyl) ethanone, N- (4-chlorophenyl) -1- (4-methylphenyl) ethanone, N- (4-chlorophenyl) -1-phenylethanone, N- (4-methylphenyl) ethanone, N- (3-chlorophenyl) -1-, N-phenyl-1-phenylethanones.

Preferably, the arylboronic acid comprises: p-methylbenzeneboronic acid, p-ethylphenylboronic acid, p-isopropylphenylboronic acid, p-methoxyphenylboronic acid, m-methylbenzeneboronic acid, 3, 5-dimethylbenzeneboronic acid, 3, 4-dimethylbenzeneboronic acid, phenylboronic acid, 1-naphthylboronic acid, 3, 4-methylenephenylboronic acid, p-benzothiophene-3-boronic acid, p-dibenzothiophene-4-boronic acid, 4-fluorobenzeneboronic acid, 4-chlorobenzeneboronic acid, 4-bromobenzeneboronic acid and 4-iodophenylboronic acid.

Preferably, the catalyst is any one of 2, 2-bipyridine, 4-bipyridine, triphenylphosphine, alpha-bipyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

Preferably, the oxidizing agent is any one of benzoquinone, silver oxide, silver acetate, silver carbonate, dicumyl peroxide, 2,6, 6-tetramethylpiperidine oxide, copper acetate, iodobenzene acetate, and potassium peroxodisulfate.

Preferably, the reaction solvent is any one of dichloroethane, acetonitrile, toluene, N-dimethylformamide, dioxane, dichloromethane, methanol, ethanol, tetrahydrofuran, and trifluoroethanol.

Preferably, the molar ratio of the alpha-aminocarbonyl compound to the arylboronic acid is from 1:1 to 1: 2; the molar ratio of the alpha-aminocarbonyl compound to the catalyst is 1:0.01-1: 0.2; the molar ratio of the alpha-aminocarbonyl compound to the oxidant is 1:1-1: 2; the molar ratio of the alpha-aminocarbonyl compound to the reaction solvent is 1:30-1: 60.

Preferably, the reaction is carried out at a temperature of 80 ℃ in order to increase the yield.

Compared with the prior art, the invention has the beneficial effects that:

1) the alpha-amino carbonyl compound and the arylboronic acid are used as raw materials, the alpha-aryl alpha-aminoketone compound is synthesized under the action of the catalyst, the oxidant and the reaction solvent, and a target product can be obtained by a one-pot method;

2) the preparation method disclosed by the invention has the advantages that the required reaction temperature is lower, no pollution intermediate or product is generated in the synthesis process, the reaction condition is mild, the method is safe and environment-friendly, the method is an environment-friendly green synthesis method, the large-scale production can be realized, and the industrial application prospect is better;

3) the preparation method of the invention does not adopt metal raw materials to synthesize the alpha-alkyl alpha-aminoketone compound, achieves the aim of preparing the alpha-aryl alpha-aminoketone compound with high selectivity and high yield, and has the advantages of simple method, safety, environmental protection, high efficiency and high product yield up to 90 percent.

Drawings

FIG. 1 is a nuclear magnetic H spectrum of N- (4-chlorophenyl) -1-phenyl-2- (4-methylphenyl) ethanone;

FIG. 2 is a nuclear magnetic C spectrum of N- (4-chlorophenyl) -1-phenyl-2- (4-methylphenyl) ethanone.

Detailed Description

In order to make the objects, technical solutions and effects of the present invention clearer and more obvious, the following embodiments are further described. It should be understood that the following examples are intended to illustrate and describe the present invention and are not intended to limit the scope of the claims of the present invention.

The following examples

The raw materials are analytically pure;

the reaction solvent can be methanol, or any one of dichloroethane, acetonitrile, toluene, N-dimethylformamide, dioxane, dichloromethane, ethanol, tetrahydrofuran and trifluoroethanol;

the catalyst can be alpha, alpha-bipyridine, or any one of 2, 2-bipyridine, 4-bipyridine, triphenylphosphine, bipyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate;

the oxidant can be 2,2,6, 6-tetramethyl piperidine oxide, or any one of benzoquinone, silver oxide, silver acetate, silver carbonate, dicumyl peroxide, copper acetate, iodobenzene acetate and potassium peroxydisulfate;

the molar ratio of the alpha-aminocarbonyl compound to the arylboronic acid is 1:1-1: 2; the molar ratio of the alpha-aminocarbonyl compound to the catalyst is 1:0.01-1: 0.2; the molar ratio of the alpha-aminocarbonyl compound to the oxidant is 1:1-1: 2; the molar ratio of the alpha-aminocarbonyl compound to the reaction solvent is 1:30-1: 60.

The preparation method of the alpha-aryl alpha-aminoketone compound comprises the following steps:

1) adding alpha-aminocarbonyl compound, arylboronic acid, catalyst and oxidant into a reaction tube, introducing nitrogen, adding a reaction solvent, reacting at the temperature of 20-100 ℃ according to the following reaction formula,

wherein R is₁Is aryl, R₂Is aryl, R₃Is aryl or naphthalene ring radical.

The reaction process of the reaction is tracked by thin layer chromatography, and the tracking method is as follows:

respectively dropping a reaction liquid sample application and a raw material liquid alpha-aminocarbonyl compound sample application on a thin-layer chromatography silica gel plate by using a capillary tube, wherein the two sample applications are positioned on the same straight line, then placing the silica gel plate into a developing bottle containing a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10:1, after the plate moving is finished, placing the silica gel plate under an ultraviolet lamp for observation, and if the reaction liquid has no point which is level with the raw material liquid alpha-aminocarbonyl compound, indicating that the reaction is complete, and obtaining a reaction liquid at this moment;

2) performing reduced pressure evaporation at 40 ℃ by adopting a RE-52AA type rotary evaporator produced by Shanghai Yangrong biochemistry Co Ltd to remove the reaction solvent, adding 10mL of saturated sodium bicarbonate solution into the reaction solution, adding 3X 5mL of ethyl acetate, extracting and separating out an organic phase, and combining the organic phases to obtain an extract liquid;

3) adding anhydrous magnesium sulfate into the extract liquid to dry the extract liquid, and filtering to obtain filtrate; evaporating the filtrate at 40 deg.C under reduced pressure by using RE-52AA rotary evaporator produced by Shanghai Yangrong biochemistry Co Ltd to remove ethyl acetate to obtain concentrated solution; adding silica gel with the mass 2-3 times that of the concentrated solution into the concentrated solution for sample mixing, putting the mixed sample into a chromatographic column, adding mixed solution of petroleum ether and ethyl acetate with the volume ratio of 80:1 for elution and separation, finally collecting eluent, putting the eluent into a rotary evaporator, and concentrating at 40 ℃ to obtain the alpha-alkyl alpha-aminoketone compound.