Water-soluble self-assembled thiourea ligand as well as preparation method and application thereof

Abstract

The invention discloses a water-soluble self-assembled thiourea ligand as well as a preparation method and application thereof, and compared with the prior art, the water-soluble self-assembled thiourea ligand has the following advantages that hydrophilic functionalization and substituent groups of the thiourea ligand are redesigned, and a functionalized benzene ring is incorporated into two carbons of five-membered annular thiourea, so that the water-soluble self-assembled thiourea ligand is obtained; according to the present invention, by introducing the functional aryl group into the five-membered ring thiourea and introducing the carboxylic acid functional alkyl group to the two nitrogen atoms of the five-membered ring thiourea, the steric hindrance and the polarity of the possible modification sites of the five-membered ring thiourea structure are increased; and the water-soluble catalyst is self-assembled by combining with the ligand and the metal, so that the catalytic activity is improved, and the catalyst is convenient to recycle.

Description

Technical Field

[0001] The invention relates to the technical field of ligands, and in particular to a water-soluble self-assembling thiourea ligand and a preparation method and application thereof. Background Art

[0002] Palladium-catalyzed acylation Suzuki coupling reaction is an important method in modern organic synthesis. The commonly used ligands in this reaction include organic phosphine ligands, nitrogen-containing ligands (including diamine ligands, bipyridine ligands, oxazole ligands, etc.), NHC (N-heterocyclic carbenes) ligands, etc., and certain research results have been achieved in recent years. However, organic phosphine ligands are sensitive to air and water, and are easily oxidized to lose coordination ability and produce oxidation and decomposition residues, which not only affects the catalytic activity of transition metal catalysts, but also severely limits the recovery and cyclic catalysis of water-soluble phosphine ligand-transition metal complexes. Therefore, the reaction catalyzed by the organic phosphine-metal complex generally needs to be carried out under an inert gas. It can be seen that the synthesis and use of phosphine ligands not only need to avoid oxygen, but also the synthesis and use of phosphine ligand reagents are highly toxic, the conditions are harsh, and the operation is complicated. In addition, the water-soluble phosphine ligand transition metal complex is not stable enough, and the phosphine ligand is easily left in the product after oxidation and decomposition, which limits the recycling and reuse of the ligand. These defects not only directly raise the cost, but also require additional purification steps to remove impurities in the product, thereby greatly limiting the application of water-soluble phosphine ligands in organic synthesis. The advantage of water-soluble nitrogen-containing ligands being more stable than phosphine ligands in air makes them more attractive when applied to aerobic catalytic conditions. Diamine skeletons, bipyridine skeletons, oxazole skeletons and other ligands are functionalized by sulfonates, carboxylates, quaternary ammonium salts, phosphates and carbohydrates to achieve hydrophilic catalytic coupling reactions, but the synthesis steps of nitrogen-containing ligands are complicated, the conditions are harsh, and the stability is still relatively poor, which limits its development and application. Water-soluble NHC (N-heterocyclic carbenes) ligands have been rapidly developed due to their very stable properties to air, water and heat and their high catalytic activity, and there are relatively many experimental studies on catalyst recovery. The coupling reaction of water-soluble NHC ligands and transition metal complex catalysis has also achieved certain results, but there are also some problems that need to be solved urgently: there are few ligands with high activity and high stability, and there is a lack of quantitative data on the water solubility and toxicity of NHC ligands. In particular, the lack of toxicity research will directly affect the application of NHC ligands in the pharmaceutical industry. In short, the high price of palladium homogeneous catalysts (including metal palladium and most ligands) and the defect of easy residue in the product have greatly hindered their commercial application. Traditional palladium homogeneous catalysts cannot be reused because they are difficult to separate from the product, which not only deviates from the concept of atomic economy of green chemistry, but also the residual transition metal affects the environment and reduces product quality.

[0003]

[0004] Palladium-catalyzed acylation Suzuki reaction

[0005] In recent years, we have noticed that more and more thiourea derivatives have been used as ligands and catalysts in the field of organometallic catalytic synthesis. Although thiourea can be used as a good ligand for transition metals, most of the catalytic systems are not recyclable, and the reported thiourea ligand-transition metal and catalytic reaction types are relatively few. Since thiourea is very stable to heat, air and water, and can even catalyze oxidation reactions, it can be seen that it has great potential in catalyzing recyclable coupling reactions. However, there are few related studies. In order to investigate the effect of thiourea structure on the catalytic activity of metal complexes and the application of different catalytic processes, it is necessary to synthesize thiourea compounds with more structures. Water-soluble thiourea ligands are based on ligand design to transform fat-soluble thiourea ligands into water-soluble thiourea ligands, which can be dissolved, reacted and easily recycled in the aqueous phase. In recent years, water-soluble ligands and transition metal complex catalytic coupling reactions have developed rapidly and made certain progress, but the quantitative data of water solubility and toxicity of ligands need further research, and the expansion of catalytic systems (including low-toxic, high-activity, easily recyclable ligand libraries and metal types) also needs to be further deepened. We hope to explore the field of recyclable catalytic coupling reactions in water phase through the study of the rational design of recyclable water-soluble self-assembled thiourea ligands, and further expand it to other transition metals and catalytic reactions in the future. These results will play an increasingly important role in the development of energy-saving, efficient and environmentally friendly synthesis processes. In summary, as palladium-catalyzed coupling reactions are widely used in the synthesis of chemical raw materials, fine chemicals, drugs and their key intermediates, it is of great research significance to rationally design and synthesize functionalized ligands and develop recyclable and recyclable water-soluble palladium complexes in water phase for efficient and green catalytic coupling reactions.

[0006] Water-soluble transition metal complexes catalyze coupling reactions, which are in urgent need of further exploration in terms of ligand design (type, position, quantity, new activation mode, etc. of water-soluble functional groups introduced), catalytic reaction expansion, catalyst toxicity, water solubility, and catalyst recovery and circulation mode. The present invention intends to start from the study of the acylation Suzuki coupling reaction catalyzed by a large sterically hindered self-assembled water-soluble thiourea palladium complex, in the hope of further enriching the field of recyclable water-soluble homogeneous catalyst ligand design, expanding the scope of application of the catalytic strategy of "water-soluble self-assembled catalyst", and enriching the thiourea compound library and the water-soluble self-assembled catalyst library. Summary of the invention

[0007] The purpose of the present invention is to provide a water-soluble self-assembling thiourea ligand, which combines the design concepts of water-soluble thiourea and self-assembling thiourea, fully utilizes the advantages of the two thiourea ligand designs, and achieves the purpose of improving catalytic reaction efficiency, facilitating catalyst recovery, reducing catalyst residues in products and improving product quality.

[0008] To achieve the above object, the present invention provides a water-soluble self-assembling thiourea ligand, the structural formula of which is as follows:

[0009]

[0010] Wherein, n is a natural number.

[0011] The second object of the present invention is to provide a method for preparing a water-soluble self-assembling thiourea ligand, the preparation method specifically comprising the following steps:

[0012] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction;

[0013] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0014] S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B;

[0015] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring once and then removing tetrahydrofuran by rotary evaporation, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH, stirring twice until the reaction is completed, filtering, washing, and drying to obtain a water-soluble self-assembled thiourea ligand;

[0016] Among them, the structural formula of reactant A is: The structural formula of product A is: The structural formula of intermediate product B is: Wherein, n is a natural number, and R1 is alkyl.

[0017] Preferably, in step S1, the molar ratio of reactant A to reactant B is 1:(4-6).

[0018] Preferably, in step S1, the structural formula of reactant B is as follows:

[0019]

[0020] Wherein, X is selected from one of Br, Cl, and I, R1 is alkyl, and n is a natural number.

[0021] Preferably, in step S1, the molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the heating and stirring temperature is 80-180°C, and the heating and stirring time is 5-8h.

[0022] Preferably, in step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(2-4), and the molar ratio of product A to thiophosgene is 1:(2-4).

[0023] Preferably, in step S4, the molar ratio of the intermediate product B to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.

[0024] Preferably, in step S4, the first stirring time is 22-26 hours, and the second stirring time is 20-40 minutes.

[0025] The third object of the present invention is to provide an application of a water-soluble self-assembled thiourea ligand, which comprises applying the water-soluble self-assembled thiourea ligand to a cyclic palladium-catalyzed Suzuki reaction.

[0026] Preferably, the application specifically comprises the following steps: at room temperature and in air, a water-soluble self-assembled thiourea ligand, PdCl2, arylphenylboronic acid, potassium carbonate, aryl acid chloride and toluene are added into a round-bottom flask containing a stirring bar, the mixture is stirred in the round-bottom flask at 25°C or 100°C until the reaction is completed, ethyl acetate and water are added and stirred, the organic layers are separated and combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation and subjected to silica gel flash column chromatography to obtain a cross-coupling product.

[0027] The catalytic acylation Suzuki reaction in which the water-soluble self-assembled thiourea participates is carried out in water. After the reaction is completed, the organic solvent extracts the product into the organic layer. The novel water-soluble self-assembled thiourea catalyst containing the hydrophilic self-assembled structure in the water layer can not only be directly added to the reaction raw materials without separation, but also can realize the recycling of the water-soluble self-assembled thiourea ligand by simply adjusting the base and acid. When the reaction aqueous phase system is in an alkaline environment, the water-soluble self-assembled thiourea and the metal catalyst self-assembled assembly are dissolved in water, and the separation of the product only requires the addition of an organic solvent to extract the product into the organic layer. The water layer is then acidified to precipitate the self-assembled thiourea ligand solid containing the carboxyl functional group structure. The advantages of the present invention are that the water-soluble self-assembled thiourea catalyst solid can be recovered by simple acid adjustment and filtration, which not only conveniently realizes the recycling and reuse of the ligand and reduces the synthesis cost, but also utilizes the polarity and water solubility difference between the ligand (large polarity) and the reaction raw materials and products (small polarity) to simply and efficiently realize the separation from the reaction raw materials and products, reduces the residue of the ligand as an impurity in the product, and directly improves the purity of the product. More importantly, the water-soluble self-assembled thiourea recovered from the previous round of catalytic reaction can be conveniently used for the next round of catalytic acylation Suzuki reaction by adding reaction raw materials and solvents, thus laying a good foundation for achieving highly selective, easy-to-recover, low-toxic and efficient catalytic acylation Suzuki reaction, and providing the pharmaceutical industry with green and efficient excellent catalysts.

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] 1. The present invention redesigns the hydrophilic functionalization and substituents of the thiourea ligand, incorporates a functionalized benzene ring (the benzene ring substituent can be a large sterically hindered hydrocarbon group, or a large polar carboxyl group) on the two carbon atoms of the five-membered cyclic thiourea, and introduces a functionalized carboxylic acid functionalized hydrocarbon group on the two nitrogen atoms of the five-membered cyclic thiourea. Through these two technical adjustments, the present invention increases the steric hindrance and polarity of the possible modification sites of the five-membered cyclic thiourea structure. Because according to the data feedback design ideas obtained from previous studies, we believe that the focus of the design of water-soluble thiourea ligands is to take into account the electronic effect and steric effect, and balance the relationship between the water solubility and catalytic activity of the ligand structure (generally speaking, the water solubility of hydrophilic ligands is too low to affect the recovery of the catalyst, and the water solubility is too high to affect the activity of the catalyst). The present invention achieves better water solubility control of the hydrophilic group (large polarity is conducive to improving the ligand catalyst recovery rate) through the two design adjustments of incorporating functionalized aromatic groups and introducing carboxylic acid functionalized hydrocarbon groups on the thiourea skeleton, and combines the ligand and metal to self-assemble into a water-soluble catalyst, thereby improving the catalytic activity and facilitating the recovery of the catalyst;

[0030] 2. The first step reaction of the synthesis of the water-soluble self-assembling thiourea ligand of the present invention has milder conditions, which is conducive to reducing the occurrence of side reactions and improving the purity of the product. Due to the use of carboxylic acid functionalized hydrocarbon side chains, the synthesis of the water-soluble thiourea ligand of the present invention is efficient and simple, and the conditions are mild. The aromatic amine only needs to react with the halogenated functionalized carboxylic acid ester side chain and then use thiophosgene to close the ring to form thiourea, and finally hydrolyze, and the target product carboxyl side chain functionalized water-soluble cyclic thiourea is obtained by a three-step method. No strict anhydrous and oxygen-free operation is required, and no additional reduction operation is required. Most of the methods for preparing thiourea by the inventor previously required the use of dangerous reagents such as borane and lithium aluminum hydride for reduction reaction, involving strict anhydrous and oxygen-free operation and cumbersome and dangerous post-processing processes. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below.

[0032] The first aspect of the specific implementation of the present invention provides a water-soluble self-assembling thiourea ligand, the structural formula of which is as follows:

[0033]

[0034] Wherein, n is a natural number.

[0035] The second aspect of the specific embodiment of the present invention is to provide a method for preparing a water-soluble self-assembling thiourea ligand, which specifically comprises the following steps:

[0036] S1. Mix reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide, and heat and stir in an oil bath for reaction, wherein the molar ratio of reactant A to reactant B is 1:(4-6), the molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the temperature of heating and stirring is 80-180°C, and the heating and stirring time is 5-8h; S2. After the reaction is completed, cool the reaction solution to room temperature, add ethyl acetate and water, separate the organic layer, extract the water layer with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, chromatogram and evaporate to dryness by rotary evaporator to obtain product A;

[0037] S3, after mixing product A with a tetrahydrofuran solution of anhydrous sodium carbonate, adding a tetrahydrofuran solution of thiophosgene, stirring after completion of the dropwise addition and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and washing the organic layer with saturated brine in turn, drying over anhydrous sodium sulfate, and finally concentrating by rotary evaporation and chromatography to obtain an intermediate product B, wherein the molar ratio of product A to anhydrous sodium carbonate is 1:(2-4), and the molar ratio of product A to thiophosgene is 1:(2-4);

[0038] S4, mixing the intermediate product B with sodium hydroxide at a molar ratio of 1:(8-12), adding water and tetrahydrofuran, stirring for 22-26 hours, and then removing the tetrahydrofuran by rotary evaporation, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH to 1, stirring for a second time for 20-40 minutes until the reaction is completed, and then filtering, washing, and drying to obtain a water-soluble self-assembled thiourea ligand;

[0039] Among them, the structural formula of reactant A is: The structural formula of product A is: The structural formula of intermediate product B is: Wherein, n is a natural number, and R1 is alkyl.

[0040] In a specific implementation case, the structural formula of reactant B is as follows:

[0041]

[0042] Wherein, X is selected from one of Br, Cl, and I, R1 is alkyl, and n is a natural number.

[0043] The third object of the specific embodiment of the present invention is to provide an application of a water-soluble self-assembled thiourea ligand, which includes applying the water-soluble self-assembled thiourea ligand to a recyclable palladium-catalyzed Suzuki reaction.

[0044] In a specific implementation case, the application specifically includes the following steps: at room temperature and in air, a water-soluble self-assembled thiourea ligand, PdCl2, arylphenylboronic acid, potassium carbonate, aryl acid chloride and toluene are added to a round-bottom flask containing a stirring bar, the mixture is stirred in the round-bottom flask at 25°C or 100°C until the reaction is completed, ethyl acetate and water are added and stirred, the organic layers are separated and combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation and subjected to silica gel flash column chromatography to obtain a cross-coupling product.

[0045] The following is a full description with reference to specific embodiments.

[0046] Example 1

[0047] This embodiment provides a water-soluble self-assembling thiourea ligand, the structural formula of which is:

[0048]

[0049] Prepared by the following preparation method:

[0050] S1. 3,3'-diaminobenzidine (2.14g, 10mmol), ethyl 3-bromopropionate (9.05g, 50mmol), diisopropylethylamine (6.5g, 50mmol) and tetrabutylammonium iodide (37mg, 0.1mmol) were mixed in a round-bottom flask, heated and stirred at 130°C in an oil bath for 6 hours to stop the reaction. After the reaction solution was cooled to room temperature, 30ml of ethyl acetate and 30ml of water were added and stirred, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (30ml x 2), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel rapid column chromatography (eluent: petroleum ether: ethyl acetate = 3:1), and evaporated to dryness by rotary evaporator to obtain 4.61g (product A) of a yellow oily tetracarboxylic acid ester-substituted diaminobenzidine intermediate crude product, with a yield of 75%. The crude product was directly used in the next step without further purification. The reaction formula is as follows:

[0051]

[0052] S2. In a fume hood, in a round-bottom flask containing a 20 ml tetrahydrofuran containing a tetracarboxylic acid ester-substituted diaminobenzidine intermediate crude product (4.61 g, 7.5 mmol) and anhydrous sodium carbonate (2.385 g, 22.5 mmol), very slowly drip a 30 ml tetrahydrofuran solution containing thiophosgene (2.588 g, 22.5 mmol) under stirring at room temperature. The addition was completed in about 12 hours, and stirring was continued at room temperature for 12 hours. The tetrahydrofuran was removed by rotary evaporation, and 40 ml ethyl acetate and 40 ml water were added and stirred. The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel rapid column chromatography (eluent: petroleum ether: ethyl acetate = 3:1). The light yellow solid 2.41 g (intermediate product B) was evaporated to dryness by rotary evaporator, with a yield of 46%. The reaction formula is as follows:

[0053]

[0054] S3, the intermediate product B (1.341g, 2.26mmol) and sodium hydroxide (904mg, 22.6mmol) were mixed in a round-bottom flask, water (20mL) and tetrahydrofuran (20mL) were added, and the mixture was stirred at room temperature for 24 hours, and tetrahydrofuran was removed by rotary evaporation. Under ice bath cooling and stirring, hydrochloric acid was carefully added dropwise, and the pH was adjusted to 1. A large amount of white solid precipitated in the solution, and stirring was continued in the ice bath for 30 minutes. The white solid obtained by suction filtration was washed with water (15ml x 3), and dried to obtain 1.8g of light yellow solid, with a yield of 89%. The reaction formula is as follows:

[0055]

[0056] The intermediate product B and the final product obtained in Example 1 were tested for performance, and the test results were as follows:

[0057] Intermediate product B: Pale yellow solid; melting point: 110–111°C.

[0058] 1 H NMR(400MHz, CDCl3) δ7.50(d,J=1.4Hz,2H),7.48–7.43(m,2H),7.39(d,J=8.3Hz,2H),4.61(dt,J=15.2 ,6.9Hz,8H),4.10(dq,J=11.6,7.1Hz,8H),2.95(td,J=6.9,3.5Hz,8H),1.20(dt,J=17.3,7.1Hz,12H).

[0059] 13 C NMR (100MHz, DMSO) δ171.2,171.1,169.4,136.4,132.5,131.4,122.6,109.8,108.2,61.2,61.1,40.8,40.7,32.6,14.4,14.3.

[0060] Final product:

[0061]

[0062] Pale yellow solid; melting point: 273–275°C.

[0063] 1 H NMR (400MHz, DMSO) δ12.48(s,4H),7.87(s,2H),7.76–7.52(m,4H),4.53(dt,J=21.6,7.1Hz,8H),2.78(dd,J=14.1,7.0Hz,8H).

[0064] 13 C NMR (100MHz, DMSO) δ172.0,171.8,168.0,135.1,131.8,130.5,121.9,109.9,108.1,40.1,31.9.

[0065] Example 2

[0066] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:4, and the rest is the same as Example 1 and will not be repeated here.

[0067] Example 3

[0068] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:6, and the rest is the same as that in the example, which will not be repeated here.

[0069] Example 4

[0070] The only difference from Example 1 is that in this example, reactant B is The rest is the same as Example 1 and will not be described again here.

[0071] Example 5

[0072] The only difference from Example 1 is that in this example, reactant B is The rest is the same as Example 1 and will not be described again here.

[0073] The water-soluble self-assembled thiourea ligand prepared in Example 1 was applied to the cyclic catalytic Suzuki reaction, as follows:

[0074] At room temperature, in air, add water-soluble self-assembled thiourea ligand (0.5mol%, 1.5mg), PdCl2(CH3CN)2 (0.5mol%, 0.7mg), arylbenzeneboronic acid (0.5mmol), potassium carbonate (104mg, 0.75mmol), aryl acid chloride (0.75mmol) and toluene (2mL) into a round-bottom flask containing a stirring bar. Stir the mixture in a round-bottom flask at 25°C or 100°C until the reaction is complete. Add ethyl acetate (10mL) and water (10mL) and stir, separate the organic layer, and extract the aqueous layer with ethyl acetate (2×10mL) and retain it. Combine the organic layers, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and obtain the cross-coupling product by silica gel flash column chromatography. The coupling product is then 1 H NMR and 13 C NMR detection showed that the data obtained were consistent with those of the acylated Suzuki reaction product reported in the literature.

[0075] Recovery and catalytic reaction of water-soluble self-assembled thiourea ligand: The water layer retained after post-treatment was stirred under ice bath cooling, and hydrochloric acid was carefully added to adjust the pH to 1. A large amount of white solid precipitated in the solution, and stirring was continued in the ice bath for 30 minutes. The white solid obtained by filtration was washed with water (10ml x 3), and dried to obtain 1.5mg of white solid. The same reaction starting materials PdCl2(CH3CN)2 (0.5mol%, 0.7mg), arylphenylboronic acid (0.5mmol), potassium carbonate (104mg, 0.75mmol), aryl acyl chloride (0.75mmol) and toluene (2mL) were added again to start the next round of cyclic catalytic reaction. After six cycles of catalysis, the recovery and catalytic activity of the new water-soluble thiourea ligand palladium catalyst did not decrease significantly.

[0076] It can be seen from the above results that the catalytic acylation Suzuki reaction in which the water-soluble self-assembled thiourea participates is carried out in water. After the reaction is completed, the organic solvent extracts the product into the organic layer. The new water-soluble self-assembled thiourea catalyst containing a hydrophilic self-assembled structure in the water layer can not only be directly added to the reaction raw materials without separation, but also can be recycled by simply adjusting the base and acid to achieve the recovery of the water-soluble self-assembled thiourea ligand. When the reaction aqueous phase system is in an alkaline environment, the water-soluble self-assembled thiourea and the metal catalyst self-assembled assembly are dissolved in water, and the separation of the product only requires the addition of an organic solvent to extract the product into the organic layer. The water layer is then acidified to precipitate the self-assembled thiourea ligand solid containing a carboxyl functional group structure. The advantages of the present invention are that the water-soluble self-assembled thiourea catalyst solid can be recovered by simple acid adjustment and filtration, which not only conveniently realizes the recycling and reuse of the ligand and reduces the synthesis cost, but also utilizes the polarity and water solubility differences between the ligand (large polarity) and the reaction raw materials and products (small polarity) to simply and efficiently achieve separation from the reaction raw materials and products, reducing the residue of the ligand as an impurity in the product, and directly improving the purity of the product. More importantly, the water-soluble self-assembled thiourea recovered from the previous round of catalytic reaction can be conveniently used for the next round of catalytic acylation Suzuki reaction by adding reaction raw materials and solvents, thus laying a good foundation for achieving highly selective, easy-to-recover, low-toxic and efficient catalytic acylation Suzuki reaction, and providing the pharmaceutical industry with green and efficient excellent catalysts.

[0077] Although the disclosure is disclosed as above, the protection scope of the disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the disclosure, and these changes and modifications will fall within the protection scope of the present invention.

Claims

1. A water-soluble self-assembling thiourea ligand, It is characterized in that The structural formula is as follows: Wherein, n is a natural number.

2. A method for preparing the water-soluble self-assembling thiourea ligand as claimed in claim 1, It is characterized in that The preparation method specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath to react; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B; S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring once and then removing tetrahydrofuran by rotary evaporation, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH, stirring twice until the reaction is completed, filtering, washing, and drying to obtain a water-soluble self-assembled thiourea ligand; Among them, the structural formula of reactant A is: The structural formula of product A is: The structural formula of intermediate product B is: Where n is a natural number, R 1 It is alkyl.

3. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In step S1, the molar ratio of reactant A to reactant B is 1:(4-6).

4. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In step S1, the structural formula of reactant B is as follows: Wherein, X is selected from one of Br, Cl, and I, and R 1 is alkyl, and n is a natural number.

5. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In the step S1, the molar ratio of reactant A to diisopropylethylamine is 1:(4-6), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.06), the heating and stirring temperature is 80-180° C., and the heating and stirring time is 5-8 h.

6. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(2-4), and the molar ratio of product A to thiophosgene is 1:(2-4).

7. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In step S4, the molar ratio of the intermediate product B to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.

8. The method for preparing the water-soluble self-assembling thiourea ligand according to claim 2, It is characterized in that In step S4, the first stirring time is 22-26 hours, and the second stirring time is 20-40 minutes.

9. Application of a water-soluble self-assembling thiourea ligand, Features: The application comprises applying the water-soluble self-assembled thiourea ligand described in claim 1 to a cyclic palladium-catalyzed Suzuki reaction.

10. Use of the water-soluble self-assembling thiourea ligand according to claim 9, It is characterized in that The application specifically comprises the following steps: at room temperature, in air, water-soluble self-assembled thiourea ligands, PdCl 2 , arylboronic acid, potassium carbonate, aryl acyl chloride and toluene are added into a round-bottom flask with a stirring bar, and the mixture is stirred at 25°C or 100°C in the round-bottom flask until the reaction is completed. Ethyl acetate and water are added and stirred, and the organic layers are separated and combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel flash column chromatography to obtain the cross-coupling product.

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