阅读说明：本技术 有机硼化合物的制备方法以及β-羟基有机硼化合物的制备方法 (Process for producing organoboron compound and process for producing beta-hydroxyorganoboron compound ) 是由 李博解 闻武 朱磊 魏鹏任 李伟 汪连生 于 2019-08-28 设计创作，主要内容包括：本发明涉及化合物合成技术领域,具体涉及一种有机硼化合物的制备方法以及β-羟基有机硼化合物的制备方法。本发明以温和的条件实现底物的硼加成,制备出含有不同取代基的Morita-Baylis-Hillman有机硼化合物。方法易行,操作简便,该制备方法以壳聚糖固载铜为催化剂,联硼酸频那醇酯(B<Sub>2</Sub>(pin)<Sub>2</Sub>)为反应试剂,在水中反应即可达到很高的反应活性。催化剂用量低且可回收使用,反应结束后易于分离,无金属残留,适合大规模生产。(The invention relates to the technical field of compound synthesis, in particular to a preparation method of an organic boron compound and a preparation method of a beta-hydroxyl organic boron compound. The invention realizes the boron addition of a substrate under mild conditions to prepare the Morita-Baylis-Hillman organoboron compound containing different substituents. The preparation method is easy and convenient to operate, and takes chitosan solid-supported copper as a catalyst and the diboron pinacol ester (B) 2 (pin) 2 ) The reaction reagent can reach high reaction activity after reaction in water. The catalyst is low in dosage and can be recycledThe catalyst is easy to separate after the reaction is finished, has no metal residue, and is suitable for large-scale production.)

1. A process for producing an organoboron compound, characterized by comprising the steps of: reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water and room temperature to obtain an organic boron compound II;

wherein:

the structural formula of the compound I isThe R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the structural general formula of the organoboron compound II isWherein, the R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the catalyst is a functionalized chitosan immobilized copper catalyst.

2. The process for producing an organoboron compound according to claim 1, wherein:

the R group of the compound I is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketo group, a p-methylphenylketonic group, a p-methoxyphenylketo group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the R group of the organic boron compound II is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketo group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide.

3. A method for preparing a beta-hydroxyorganoboron compound, comprising the steps of:

1) reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water and room temperature to obtain an organic boron compound II;

2) reacting the organoboron compound II obtained in the step 1) with sodium perborate hydrate to obtain an organoboron compound III with beta-hydroxyl;

wherein:

the structural formula of the compound I isThe R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the structural formula of the compound II isWherein the R group is a benzophenone group, a p-halophenonyl group, a p-methylphenonyl group,A p-methoxyphenoyl group, an acyl group, an ester group or a cyano group;

the structural general formula of the beta-hydroxyorganoboron compound III isWherein the R group is a phenylketo group, a p-halophenonyl group, a p-methylphenonyl group, a p-methoxyphenonyl group, an acyl group, an ester group or a cyano group

The catalyst is a functionalized chitosan immobilized copper catalyst.

4. The process for producing a β -hydroxyorganoboron compound according to claim 3, characterized in that:

the R group of the compound I is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketo group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the R group of the organic boron compound II is a phenyl ketone group, a p-fluorophenyl ketone group, a p-chlorophenyl ketone group, a p-methylphenyl ketone group, a p-methoxyphenyl ketone group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the R group of the beta-hydroxyorganoboron compound III is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketonic group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide.

5. The method for producing a β -hydroxyorganoboron compound of claim 3 or 4, wherein the functionalized chitosan supported copper catalyst is a chitosan supported copper sulfate catalyst.

Technical Field

The invention relates to the technical field of compound synthesis, in particular to a preparation method of an organoboron compound and a preparation method of a beta-hydroxyl organoboron compound.

Background

The organic boron compound is an important intermediate and is widely applied to synthesis of natural products and drug molecules, and because a C-B bond can be simply and conveniently converted into C-O, C-N and C-C bonds, the Morita-Baylis-Hillman organic boron compound simultaneously has allyl and alpha, beta-unsaturated carbonyl structures, and is a convenient and efficient intermediate compound for synthesizing multi-substituted functionalized drug molecules. Compared with a method using a compound with protected hydroxyl as a reaction raw material in the literature, the method reduces the synthesis steps and is more direct and convenient to react. In addition, in the literature (org. chem. front.,2017,4,1220-1223), t-butanol which is expensive is used as a solvent, strong base (lithium t-butoxide) is added, and the metal catalyst is a homogeneous catalyst, so that the content is high and the residual amount is difficult to remove. The inventor loads metal chloride on chitosan as a catalyst, and researches show that the catalyst has a very good catalytic effect when used for synthesizing a Morita-Baylis-Hillman organic boron compound, avoids using strong base with high pollution, reduces the content of the catalyst by more than 10 times, can be recycled, has no metal residue, and uses pure water as a reaction solvent, and is more environment-friendly in reaction.

The chitosan is a natural alkaline polysaccharide, has biological functionality, biocompatibility, low toxicity, biodegradability and almost no anaphylactic effect, has the characteristics of large distribution amount, rich resources, simplicity and easy obtainment in China, has good chelating capacity on metals, and can be used as a catalyst and an initiator for reactions such as hydrogenation, oxidative coupling, ring-opening polymerization, alkene monomer polymerization, esterification, etherification and the like.

The conversion of organoboron compounds to beta-hydroxy compounds is a very important application field, because the beta-hydroxy structure widely exists in the structure of natural products, if the strategy of 'one-pot method' is adopted, the boron addition of substrates is firstly realized, and then the substrates are continuously converted into the beta-hydroxy compounds without separation, so the synthesis steps of the natural products are simplified, and the method has very important application value. In addition, the organic boron compound itself has a wide range of practical uses such as an initiator of polymerization, an antioxidant, a bactericide, a neutron-capturing agent, a therapeutic agent for brain tumor, an anticancer agent, and the like.

Disclosure of Invention

The invention aims to provide a method for preparing an organic boron compound by catalyzing chitosan supported copper. The invention realizes the boron addition of a substrate under mild conditions to prepare the Morita-Baylis-Hillman organoboron compound containing different substituents. The preparation method is easy and convenient to operate, and takes chitosan solid-supported copper as a catalyst and the diboron pinacol ester (B)₂(pin)₂) The reaction reagent can achieve high reaction activity in water. The catalyst has low consumption, can be recycled, is easy to separate after the reaction is finished, has no metal residue, and is suitable for large-scale production.

The invention also aims to provide a method for preparing the organic boron compound by catalyzing chitosan supported copper to synthesize the beta-hydroxy compound. After the organoboron compound is prepared by boron addition, the functional group conversion is directly realized, and the functional molecular beta-hydroxy compound is prepared by a one-pot method, so that the method has more practical application value.

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

the organic boron compound II has the following structural general formula:

wherein, the R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group.

The organoboron compound II provided by the technical scheme can be used as an initiator, an antioxidant, a bactericide or a neutron capture agent of polymerization reaction.

Specifically, the R group is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketonic group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group.

The invention also provides a preparation method of the organoboron compound II, which comprises the following steps: reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water and room temperature to obtain an organic boron compound II;

wherein:

the structural formula of the compound I isThe R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the catalyst is a functionalized chitosan immobilized copper catalyst.

Specifically, the R group is phenylketonic group, p-fluorophenylketonic group, p-chlorophenylketonic group, p-methylphenylketonic group, p-methoxyphenylketonic group, acetyl group, carbomethoxy group, carbethoxy group or cyano group;

the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide.

The technical concept of the technical scheme is as follows: a method for preparing organic boron compound by Chitosan-supported Copper catalysis comprises the steps of using Chitosan-supported Copper (CS @ Cu) as a catalyst, and using the Chitosan-supported Copper catalyst (CS @ Cu) as Chitosan-supported Copper hydroxide (CS @ Cu (OH))₂) Chitosan-supported copper oxide (CS @ CuO), chitosan-supported copper cyanide (CS @ CuCN), chitosan-supported copper sulfate (CS @ CuSO)₄) Chitosan-immobilized copper chloride (CS @ CuCl)₂) Chitosan-immobilized copper fluoride (CS @ CuF)₂) And chitosan-immobilized copper bromide (CS @ CuBr)₂). Biboric acid pinacol ester (B)₂(pin)₂) (chemical Agents of national medicine Co.) isA reagent, water as a solvent and sodium perborate tetrahydrate (Aldrich) as an oxidant are used for selectively carrying out boron addition reaction on substrates containing different substituents respectively, and then preparing the-hydroxyl compound through continuous oxidation reaction.

Under the catalysis of chitosan supported copper (CS @ Cu), a substrate and diboron pinacol ester (B)₂(pin)₂The structure is shown by the chemical reaction equation) are adsorbed on the catalyst surface and are close to each other. Copper and diboron pinacol ester form a composite metal complex, and the addition is carried out on a substrate. The boron group connected with copper is transferred to a substrate in a six-membered ring transition state, and the direct boron addition process is selectively completed by 1,4 to prepare the organic boron compound. After the reaction is finished, the chitosan supported copper (CS @ Cu) catalyst is recovered through simple filtering operation, sodium perborate is added into the residual reaction system, and the organic boron compound is directly oxidized into the hydroxyl compound. When the starting material is-unsaturated carbonyl compound I, preparing organic boron compound II, wherein the chemical reaction equation is as follows:

an organoboron compound II of the formula:

in the compound II, R¹The groups are defined identically and are phenylketonic group, p-fluorophenylketonic group, p-chlorobenzophenone group, p-methylbenzophenone group, p-methoxybenzophenone group, p-fluorophenylketonic group, acetyl group, carbomethoxy group, carboethoxy group or cyano group;

specifically, the method for preparing the organic boron compound II by catalyzing chitosan supported copper comprises the following steps:

A. adding chitosan-supported copper catalyst (CS @ Cu) into a 2.5mL reaction tube, adding 2.0mL water, and stirring at room temperature (20-25 ℃, the same below) for 1 hour; the chitosan-immobilized copper catalyst (CS @ Cu) is chitosan-immobilized copper hydroxide (CS @ Cu (OH)₂) Chitosan-supported copper oxide (CS @ CuO), chitosan-supported copper cyanide (CS @ CuCN), and chitosan-supported copper sulfate (CS @ CuSO)₄) Chitosan-immobilized copper chloride (CS @ CuCl)₂) Chitosan-immobilized copper fluoride (CS @ CuF)₂) And chitosan-immobilized copper bromide (CS @ CuBr)₂) More preferably chitosan-supported copper sulfate (CS @ CuSO)₄) (ii) a The dosage of the chitosan-supported copper catalyst (CS @ Cu) is 5mg, 10mg and 15mg, and more preferably 5 mg; the ratio of the mass of the starting material I to the milliliter number of the solvent water is 0.1;

B. respectively and continuously and sequentially adding the starting material I and the diboron pinacol ester (B) into the system obtained in the step A₂(pin)₂) (ii) a The pinacol ester diborate B₂(pin)₂The amount of substance to starting material I is 1.2 to 2.0, more preferably 1.2;

C. the whole reaction system is stirred at room temperature for reaction; the reaction time is 10-14 hours;

D. after completion of the reaction, the whole reaction system was filtered and washed with 3mL of tetrahydrofuran. And (3) carrying out rotary evaporation and concentration on the filtrate, carrying out column chromatography on the residue by using ethyl acetate/petroleum ether mixed solvents with different proportions, and separating and purifying to obtain a target product II. The proportion of the ethyl acetate/petroleum ether mixed solvent is selected according to different product polarities, and silica gel is used as a stationary phase for column chromatography.

The invention also provides a beta-hydroxy organoboron compound III, which has the following structural general formula:

wherein, the R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group.

Specifically, the R group is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketonic group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group.

The beta-hydroxyorganoboron compound III provided by the technical scheme can be used for preparing medicines for treating brain tumors or anticancer medicines.

The invention also provides a preparation method of the beta-hydroxyorganoboron compound III, which comprises the following steps:

1) reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water and room temperature to obtain an organic boron compound II;

2) reacting the organoboron compound II obtained in the step 1) with sodium perborate hydrate to obtain an organoboron compound III with beta-hydroxyl;

wherein:

the structural formula of the compound I isThe R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the structural formula of the compound II isWherein, the R group is a phenyl ketone group, a p-halogen phenyl ketone group, a p-methyl phenyl ketone group, a p-methoxy phenyl ketone group, an acyl group, an ester group or a cyano group;

the catalyst is a functionalized chitosan immobilized copper catalyst.

Specifically, the method comprises the following steps:

the R group of the compound I is a phenylketonic group, a p-fluorophenylketonic group, a p-chlorophenylketo group, a p-methylphenylketonic group, a p-methoxyphenylketonic group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the R group of the organic boron compound II is a phenyl ketone group, a p-fluorophenyl ketone group, a p-chlorophenyl ketone group, a p-methylphenyl ketone group, a p-methoxyphenyl ketone group, an acetyl group, a carbomethoxy group, an carbethoxy group or a cyano group;

the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide.

Specifically, the application of the organic boron compound II prepared by catalysis of chitosan supported copper in the synthesis of the beta-hydroxy compound III has the chemical reaction formula:

the R groups in the compounds I, II and III in the above reaction equations are defined identically and are phenyl keton group, p-fluorophenyl keton group, p-chlorophenyl keton group, p-methylphenyl keton group, p-methoxyphenyl keton group, p-fluorophenyl keton group, acetyl group, carbomethoxy group, carbethoxy group or cyano group;

specifically, the method comprises the following steps:

A. adding chitosan supported copper sulfate catalyst (CS @ CuSO) into a 2.5mL reaction tube₄) Adding 2.0mL of water; the chitosan-supported copper sulfate catalyst (CS @ CuSO)₄) The dosage of the composition is 5 mg; the ratio of the amount of the starting material I to the amount of solvent water in milliliters is 0.1;

B. to the above system, the starting material I and the pinacol ester diborate (B) were continuously added in this order₂(pin)₂) (ii) a The mass ratio of the pinacol diboron the starting material I is 1.2;

C. the whole reaction system is stirred at room temperature for reaction; the reaction time is 11-13 hours;

D. after completion of the reaction, the whole reaction system was filtered and washed with 3mL of tetrahydrofuran. 244mg of sodium perborate tetrahydrate was added directly to the residue, and the whole was stirred at room temperature for 3 to 5 hours.

E. To the above system was added ethyl acetate (3 mL) to dilute the solution, the solution was extracted with ethyl acetate (3X 10mL), the organic phase was separated, and anhydrous sodium sulfate (Na) was added₂SO₄) Drying, filtering and rotary evaporating to remove solvent. And purifying the residue by column chromatography with ethyl acetate/petroleum ether mixed solvent in different proportions to obtain III, wherein the column chromatography adopts silica gel as a stationary phase.

Compared with the prior art, the invention has the following advantages and effects:

1. the method is easy to implement, simple and convenient to operate, rich in raw material source and low in cost, such as chitosan, copper hydroxide and the like, and the method is beneficial to application of the method in actual production;

2. the method can realize higher conversion number of reactants only by using lower catalyst dosage;

3. the method has mild reaction conditions, takes water as a solvent, performs reaction at room temperature, and is simple and easy to operate;

4. the method has wide applicability, can be suitable for various substrates of different types, and successfully prepares the corresponding target compound.

5. In the method, the whole reaction system is heterogeneous, and the catalyst can be conveniently removed by filtration after the reaction is finished;

the chitosan immobilized copper sulfate catalyst can be recycled, and the catalytic reaction is carried out without activity loss. The recycling experimental data are as follows: taking I-1 as a raw material to generate a product III-1 as an example, after the reaction is finished, the chitosan-supported copper sulfate catalyst (CS @ CuSO) is recovered by filtration₄) Directly used in the next reaction, and the step is repeated five times to obtain the target products with the yields of respectively>99％,>99％, 98％,96％,>99 percent, proves that the catalyst has almost no loss of activity and can be recycled.

Detailed Description

The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.

When the initial raw material is an alpha, beta-unsaturated carbonyl compound I, preparing an organic boron compound II, and further converting the organic boron compound II into a beta-hydroxyl compound III;