Heterocycle-containing thiourea ligand as well as preparation method and application thereof

Abstract

The invention discloses a heterocyclic ring-containing thiourea ligand and a preparation method and application thereof, and compared with the prior art, the heterocyclic ring-containing thiourea ligand has the following advantages: selection and optimization of a monothiourea skeleton: on the basis of early-stage work, the monothiourea skeleton is still kept in a ring shape, which is a precondition for keeping high activity and stability; on the basis that monothiourea and five-membered ring chain hydrocarbon skeleton structures are reserved, a previous N-connected benzene ring side chain is assumed to be further studied and optimized into an aliphatic carboxylic acid side chain, a functionalized aromatic ring is combined on a five-membered ring chain hydrocarbon skeleton, and the water solubility of thiourea ligand molecules is changed by changing the structure of the novel thiourea ligand, so that the water solubility of the thiourea ligand molecules is improved. The steric hindrance and the electronic effect can generate controllable influence on the catalytic efficiency and the recoverability of the thiourea ligand.

Description

Technical Field

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

[0002] The palladium-catalyzed acylation Suzuki coupling reaction (as shown below) 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. 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 efficient and green catalytic coupling reactions in coordination with metal palladium. Summary of the invention

[0006] The purpose of the present invention is to provide a heterocyclic thiourea ligand, which can not only give full play to the low toxicity and stability of the thiourea skeleton, but also develop a new catalyst containing a pyridine hydrocarbon side chain with high catalytic activity.

[0007] In order to achieve the above object, the present invention provides a heterocyclic thiourea ligand, the structural formula of which is as follows:

[0008]

[0009] Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

[0010] The present invention has the following two advances: 1. Selection and optimization of the monothiourea skeleton: Based on the previous work, the monothiourea skeleton is still kept in a cyclic shape, which is a prerequisite for maintaining high activity and stability. On the basis of retaining the monothiourea and five-membered ring chain hydrocarbon skeleton structure, it is envisaged to further study and optimize the previous N-connected benzene ring side chain into a fatty carboxylic acid side chain, and combine a functionalized aromatic ring on the five-membered ring chain hydrocarbon skeleton. The structural changes of the above new thiourea ligands will change the water solubility, steric hindrance and electronic effect of the thiourea ligand molecule, and produce a controllable influence on the catalytic efficiency and recyclability of the thiourea ligand.

[0011] 2. Side chain of ligand substituent, regulation of steric effect and electronic effect: Large steric functional groups and electron-donating groups contribute to the improvement of ligand catalyst activity, which has been fully confirmed in previous work. We designed and added new side chains of benzyl and pyridine-containing hydrocarbon side chains to the thiourea side chain. The complexation of pyridine and transition metal can regulate the coordination of thiourea and transition metal. Aromatic ring system design is applied to the five-membered ring chain hydrocarbon skeleton ring of thiourea (not limited to benzene ring, but also other aromatic systems such as naphthalene ring). The substituted hydrocarbon groups on the aromatic ring system are designed as large steric groups or large steric and polar groups, which can regulate the electronic effect and lipid-water partition coefficient while increasing the steric hindrance.

[0012] The second object of the present invention is to provide a method for preparing a heterocyclic thiourea ligand, the preparation method specifically comprising the following steps:

[0013] S1. After reactant A, reactant B, N,N-diisopropylethylamine and acetonitrile are mixed in a round-bottom flask, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction;

[0014] S2. After the reaction is completed, ethyl acetate and water are added to separate the organic layer, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the layers are dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0015] S3, after mixing product A, 2-vinylpyridine and glacial acetic acid, heating and stirring in an oil bath to react, after the reaction is completed, adding ethyl acetate and water, separating the organic layer, extracting the aqueous layer with ethyl acetate, combining the organic layers, and drying over anhydrous sodium sulfate, concentrating by rotary evaporation, chromatographically and evaporating to dryness on a rotary evaporator to obtain an intermediate product B;

[0016] S4, after the intermediate product B is mixed with a tetrahydrofuran solution of anhydrous sodium carbonate, a tetrahydrofuran solution of thiophosgene is added, and after the dropwise addition is completed, the tetrahydrofuran is removed by stirring and rotary evaporation, and then ethyl acetate and water are added and stirred, and the organic layer is washed with saturated brine in sequence, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain a heterocyclic thiourea ligand;

[0017] Among them, the structural formula of reactant A is: The structural formula of product A is: The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

[0018] Preferably, in step S1, the molar ratio of reactant A to reactant B is 1:(1-2).

[0019] Preferably, in step S1, the structural formula of reactant B is selected from one of (1)-(13):

[0020]

[0021]

[0022] Wherein, X is selected from one of Br and Cl, R 2 One selected from H, Alkyl, OMe and CO2R.

[0023] Preferably, in step S1, the molar ratio of reactant A to N,N-diisopropylethylamine is 1:(1-2), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.02), the heating and stirring temperature is 20-30°C, and the heating and stirring time is 20-26h.

[0024] Preferably, in step S3, the molar ratio of product A to 2-vinylpyridine is 1:(1-2), and the molar ratio of product A to glacial acetic acid is 1:(1-2).

[0025] Preferably, in step S3, the temperature of the oil bath is 100-140° C., and the time is 1-3 hours.

[0026] Preferably, in step S4, the molar ratio of the intermediate product B to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of the intermediate product B to thiophosgene is 1:(1-2).

[0027] The third object of the present invention is to provide an application of a heterocyclic thiourea ligand, which comprises applying the heterocyclic thiourea ligand to catalyze the acylation Suzuki reaction.

[0028] Preferably, the application specifically comprises the following steps: at room temperature and in air, a heterocyclic thiourea ligand, PdCl2, arylphenylboronic acid, potassium carbonate, aryl acyl chloride and toluene are added into a round-bottom flask containing a stirrer, 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.

[0029] Compared with the defects of water-soluble organic phosphine ligands that are sensitive to air and water, easily oxidized and lose coordination ability, and produce oxidation and decomposition residues, the heterocyclic thiourea ligand of the present invention is very stable to air, water, and heat. The acylation Suzuki reaction catalyzed by it can be carried out in the aqueous phase. The separation of the product and the catalyst only requires the addition of a small amount of organic solvent for extraction. There will be no catalyst residue or loss in the extraction organic solvent. After the product is concentrated by vacuum distillation, the extraction organic solvent can be very conveniently used for the next cycle of catalytic reaction. The new thiourea containing pyridine hydrocarbon side chain and the metal palladium complex are dissolved in the aqueous phase, and the reaction raw materials are continuously added to start the next catalytic cycle. Therefore, the entire catalytic reaction system, ligand synthesis and catalytic cycle of the present invention have a series of advantages such as economy, greenness, safety, and environmental protection.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] 1. Selecting low-toxic thiourea skeleton as the basic structural framework of the catalyst is beneficial to reduce the residual ligand impurities in the product and avoid the toxicity and other side effects caused by them:

[0032] Compared with traditional NHC ligands, heterocyclic thiourea ligands and their metal complexes not only have the advantages of easy availability of raw materials, simple synthesis, high catalytic activity, and extremely stable to air, water, and heat, but also thiourea and its derivatives have long been used as drugs or active pharmaceutical intermediates, and there are a large number of literature reports on their physicochemical properties, biological activities, toxicity tests, and toxicological properties. However, there are few reports on the biological activity and toxicity tests of NHC structure compounds. Therefore, thiourea structures with clearer biological activity and toxicological properties as ligands will have more advantages than NHC structure compounds with unknown toxicological properties in future industrial large-scale catalytic reactions. In summary, the toxicity and safety of the catalyst in future applications are considered from the top-level design in the design of the ligand structure, and the selection of a thiourea ligand skeleton with stable properties and clearer biological activity for self-assembly modification to obtain a new type of recyclable nanoreactor catalytic system that conforms to the development trend of green chemistry is the core innovation of the invention.

[0033] 2. The design innovation of heterocyclic thiourea ligands is conducive to simplifying the synthesis method and improving the synthesis efficiency of the ligand and the catalytic reaction efficiency:

[0034] The present invention optimizes the design of multiple sites of the catalyst structure. Since there are many sites modified on the aromatic ring of the benzyl side chain, the solubility of the ligand can be regulated by introducing fat-soluble or water-soluble substituted benzyl according to the need of the water-soluble nature of the ligand. Therefore, we can freely adjust to obtain fat-soluble or water-soluble thiourea in which the new heterocyclic side chain participates in the coordination. And on the basis of the second-generation water-soluble thiourea ligand that we have successfully prepared in the early stage, we have conducted a comprehensive exploration of the thiourea ligand structure. The advantages of converting thiourea into water-soluble thiourea are mainly: making the thiourea ligand recyclable and reducing the residual ligand in the product to reduce the transition metal residue, directly improving the product quality and safety. After the catalytic acylation Suzuki reaction in which the water-soluble thiourea participates is completed, only a small amount of organic solvent needs to be added to extract the product into the organic layer. This new water-soluble catalyst containing a hydrophilic structure can extract the organic matter by a simple organic solvent to complete product extraction and purification. Because the catalyst is highly water-soluble, it will not cause the catalyst to be lost or remain in the product when dissolved in water. Because the water layer contains water-soluble thiourea ligands and transition metal palladium complexes, the catalyst can be recovered and recycled by utilizing the alkalinity of the pyridine side chain or the acidity of the carboxylic acid group of the benzyl side chain. This lays a good foundation for achieving highly selective, easy-to-recover, low-toxic and efficient catalysis of other coupling reactions, and provides green and efficient catalysts for the pharmaceutical industry. DETAILED DESCRIPTION

[0035] 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.

[0036] The first aspect of the specific implementation of the present invention provides a heterocyclic thiourea ligand, the structural formula of which is as follows:

[0037]

[0038] Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

[0039] A second aspect of the specific implementation of the present invention provides a method for preparing a heterocyclic thiourea ligand, the preparation method specifically comprising the following steps:

[0040] S1. After reactant A, reactant B, N,N-diisopropylethylamine and acetonitrile are mixed in a round-bottom flask, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction, wherein the molar ratio of reactant A to reactant B is 1:(1-2), the molar ratio of reactant A to N,N-diisopropylethylamine is 1:(1-2), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.02), the heating and stirring temperature is 20-30°C, and the heating and stirring time is 20-26h;

[0041] S2. After the reaction is completed, ethyl acetate and water are added to separate the organic layer, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the layers are dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0042] S3, after mixing product A, 2-vinylpyridine and glacial acetic acid, heating and stirring in an oil bath to react, after the reaction is completed, 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 dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed and evaporated to dryness using a rotary evaporator to obtain an intermediate product B, the molar ratio of product A to 2-vinylpyridine is 1:(1-2), the molar ratio of product A to glacial acetic acid is 1:(1-2), the temperature of the oil bath is 100-140°C, and the time is 1-3h;

[0043] S4, after mixing the intermediate product B 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 a heterocyclic thiourea ligand, wherein the molar ratio of the intermediate product B to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of the intermediate product B to thiophosgene is 1:(1-2);

[0044] Among them, the structural formula of reactant A is: The structural formula of product A is: The structural formula of intermediate product B is:

[0045] Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

[0046] In a specific implementation case, in step S1, the structural formula of reactant B is selected from one of (1)-(13):

[0047]

[0048] Wherein, X is selected from one of Br and Cl, R 2 One selected from H, Alkyl, OMe and CO2R.

[0049] The third aspect of the specific embodiment of the present invention is to provide an application of a heterocyclic thiourea ligand, which includes applying the heterocyclic thiourea ligand to catalyze the acylation Suzuki reaction.

[0050] In a specific implementation case, the application specifically includes the following steps: at room temperature and in air, a heterocyclic thiourea ligand, PdCl2, arylphenylboronic acid, potassium carbonate, aryl acyl 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.

[0051] The following is a full description with reference to specific embodiments.

[0052] Example 1

[0053] This embodiment provides a heterocyclic thiourea ligand, the structural formula of which is:

[0054]

[0055] Prepared by the following preparation method:

[0056] S1. Mix 4,5-dimethyl-o-phenylenediamine (2.724 g, 20 mmol), 2,4,6-trimethylbenzyl chloride (3.373 g, 20 mmol), N,N-diisopropylethylamine (3.23 g, 25 mmol) and 30 mL of acetonitrile in a round-bottom flask, add tetrabutylammonium iodide (92 mg, 0.25 mmol), stir in an oil bath at 25°C for 24 hours to stop the reaction. Add 50 ml of ethyl acetate and 100 ml of water to the reaction solution and stir, separate the organic layer, extract the aqueous layer with ethyl acetate (50 ml x 2), combine the organic layers, dry over anhydrous sodium sulfate, concentrate by rotary evaporation, and perform silica gel rapid column chromatography (eluent: petroleum ether: ethyl acetate = 10:1). Evaporate to dryness on a rotary evaporator to obtain a pale yellow oily crude product of 4,5-dimethyl-o-phenylenediamine monosubstituted product (4.562 g), with a yield of 85%. The crude product was directly used in the next step without further purification. The reaction formula is as follows:

[0057]

[0058] S2. In a fume hood, at room temperature, crude monosubstituted 4,5-dimethyl-o-phenylenediamine (805.2 mg, 3 mmol), 2-vinylpyridine (378.5 mg, 3.6 mmol) and glacial acetic acid (217 mg, 3.6 mmol) were mixed in a round-bottom flask, stirred at 120°C in an oil bath for 2 hours, and the reaction was stopped. 20 ml of ethyl acetate and 20 ml of water were added to the reaction solution and stirred, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (20 ml x 2), and 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). The crude product of 4,5-dimethyl-o-phenylenediamine disubstituted was obtained as a pale yellow oily substance (806.8 mg) with a yield of 72%. The crude product was directly used in the next step without further purification. The reaction formula is as follows:

[0059]

[0060] S3. In a fume hood, in a round-bottom flask containing 30 ml of tetrahydrofuran containing crude 4,5-dimethyl-o-phenylenediamine (1.12 g, 3 mmol) and anhydrous sodium carbonate (382 mg, 3.6 mmol), very slowly drip a 10 ml solution of tetrahydrofuran containing thiophosgene (414 mg, 3.6 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 30 ml of ethyl acetate and 30 ml of water were added and stirred. The organic layer was washed with saturated brine (10 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 847.8 mg was obtained by rotary evaporation, with a yield of 68%. The reaction formula is as follows:

[0061]

[0062] The final product obtained in Example 1 was tested for performance, and the test results are as follows:

[0063] Final product:

[0064]

[0065] Pale yellow solid; melting point: 191-192℃

[0066] 1H NMR(400MHz, CDCl3)δ8.60(dd,J=4.8,0.7Hz,1H),7.55(td,J=7.7,1.4Hz,1H),7.24–7.09(m,2H),6.87(s,2H),6.83(s,1H ),6.12(s,1H),5.57(s,2H),4.76–4.66(m,2H),3.35(t,J=7.4Hz,2H),2.29(s,3H),2.23(s,6H),2.17(s,3H),2.02(s,3H).

[0067] 13 C NMR (100MHz, CDCl3) δ168.2,158.2,149.0,137.7,137.6,136.9,131.3,131.1,130.3,12 9.9,129.5,128.6,124.2,121.8,110.7,109.7,45.5,44.8,36.1,20.9,20.3,20.2,19.9.

[0068] Example 2

[0069] The only difference from Example 1 is that the structural formula of reactant A in this example is:

[0070] The rest is the same as Example 1 and will not be described again here.

[0071] The final product obtained in this embodiment was tested for performance, and the test results are as follows:

[0072] Final product:

[0073]

[0074] Pale yellow solid; melting point: 137-138℃

[0075] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=4.2Hz,1H),7.55(t,J=7.2Hz,1H),7.21(d,J=7.7Hz,1H),7.19–7.11(m,1H) ,7.06(s,2H),6.79(s,1H),5.93(s,1H),5.60(s,2H),4.77–4.65(m,2H),3.34(t,J=7.4Hz,2H),3.26(dt,J=

[0076] 13.5, 6.8Hz, 2H), 2.92 (hept, J=6.9Hz, 1H), 2.14 (s, 3H), 1.95 (s, 3H), 1.28 (d, J=6.9Hz, 6H), 1.10 (s, 12H).

[0077] 13 C NMR (100MHz, CDCl3) δ167.8,158.2,149.6,148.7,137.0,131.0,130.8,130.3,130.2,12 6.2,124.2,121.9,121.4,111.5,109.5,44.8,44.2,36.1,34.3,29.7,24.1,19.9,19.8.

[0078] Example 3

[0079] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:1.2, and the rest is the same as in the example, which will not be repeated here.

[0080] Example 4

[0081] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:2, and the rest is the same as that in the example, which will not be repeated here.

[0082] Example 5

[0083] 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.

[0084] Example 6

[0085] 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.

[0086] The heterocyclic thiourea ligand prepared in Example 1 was applied to catalyze the acylation Suzuki reaction, as follows:

[0087] At room temperature, in air, add heterocyclic thiourea ligand (0.5 mol%), PdCl2(CH3CN)2 (0.5 mol%, 0.7 mg), arylbenzene boronic acid (0.5 mmol), potassium carbonate (104 mg, 0.75 mmol), aryl acid chloride (0.75 mmol) and toluene (2 mL) into a round-bottom flask containing a stirrer. Stir the mixture in a round-bottom flask at 25°C or 100°C until the reaction is complete, add ethyl acetate (10 mL) and water (10 mL) and stir, separate the organic layer, extract the aqueous layer with ethyl acetate (2×10 mL) 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.

[0088] From the above results, it can be seen that compared with the defects of water-soluble organic phosphine ligands that are sensitive to air and water, easily oxidized and lose coordination ability, and produce oxidation and decomposition residues, the heterocyclic thiourea ligand of the present invention is very stable to air, water, and heat, and the acylation Suzuki reaction catalyzed by it can be carried out in the aqueous phase. The separation of the product and the catalyst only requires the addition of a small amount of organic solvent for extraction. There will be no catalyst residue or loss in the extraction organic solvent. After the product is concentrated by vacuum distillation, the extraction organic solvent can be very conveniently used for the next cycle of catalytic reaction. The new thiourea containing pyridine hydrocarbon side chain and the metal palladium complex are dissolved in the aqueous phase, and the reaction raw materials are continuously added to start the next catalytic cycle. Therefore, the entire catalytic reaction system of the present invention, ligand synthesis and catalytic cycle have a series of advantages such as economy, greenness, safety, and environmental protection.

[0089] 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 heterocyclic thiourea ligand, characterized in that: The structural formula is as follows: Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

2. A method for preparing a heterocyclic thiourea ligand according to claim 1, characterized in that: The preparation method specifically comprises the following steps: S1. After reactant A, reactant B, N,N-diisopropylethylamine and acetonitrile are mixed in a round-bottom flask, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction; S2. After the reaction is completed, ethyl acetate and water are added to separate the organic layer, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the layers are dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, after mixing product A, 2-vinylpyridine and glacial acetic acid, heating and stirring in an oil bath to react, after the reaction is completed, adding ethyl acetate and water, separating the organic layer, extracting the aqueous layer with ethyl acetate, combining the organic layers, and drying over anhydrous sodium sulfate, concentrating by rotary evaporation, chromatographically and evaporating to dryness on a rotary evaporator to obtain an intermediate product B; S4, after the intermediate product B is mixed with a tetrahydrofuran solution of anhydrous sodium carbonate, a tetrahydrofuran solution of thiophosgene is added, and after the dropwise addition is completed, the tetrahydrofuran is removed by stirring and rotary evaporation, and then ethyl acetate and water are added and stirred, and the organic layer is washed with saturated brine in sequence, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain a heterocyclic 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: Among them, R 1 is selected from one of H, Alkyl, OMe and CO2R, R 2 One selected from H, Alkyl, OMe and CO2R.

3. The method for preparing a heterocyclic thiourea ligand according to claim 2, wherein: In step S1, the molar ratio of reactant A to reactant B is 1:(1-2).

4. The method for preparing a heterocyclic thiourea ligand according to claim 2, characterized in that: In step S1, the structural formula of reactant B is selected from one of (1)-(13): Wherein, X is selected from one of Br and Cl, R 2 One selected from H, Alkyl, OMe and CO2R.

5. The method for preparing a heterocyclic thiourea ligand according to claim 2, characterized in that: In the step S1, the molar ratio of reactant A to N,N-diisopropylethylamine is 1:(1-2), the molar ratio of reactant A to tetrabutylammonium iodide is 1:(0.01-0.02), the heating and stirring temperature is 20-30° C., and the heating and stirring time is 20-26 h.

6. The method for preparing a heterocyclic thiourea ligand according to claim 2, characterized in that: In step S3, the molar ratio of product A to 2-vinylpyridine is 1:(1-2), and the molar ratio of product A to glacial acetic acid is 1:(1-2).

7. The method for preparing a heterocyclic thiourea ligand according to claim 2, characterized in that: In step S3, the temperature of the oil bath is 100-140° C., and the time is 1-3 hours.

8. The method for preparing a heterocyclic thiourea ligand according to claim 2, characterized in that: In the step S4, the molar ratio of the intermediate product B to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of the intermediate product B to thiophosgene is 1:(1-2).

9. An application of a heterocyclic thiourea ligand, characterized in that: The application comprises applying the heterocyclic thiourea ligand according to claim 1 to catalyze the acylation Suzuki reaction.

10. The use of the heterocyclic thiourea ligand according to claim 9, characterized in that: The application specifically comprises the following steps: at room temperature and in air, a heterocyclic thiourea ligand, PdCl2, arylphenylboronic acid, potassium carbonate, aryl acyl chloride and toluene are added into a round-bottom flask containing a stirrer, 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 with anhydrous sodium sulfate, concentrated by rotary evaporation and subjected to silica gel rapid column chromatography to obtain a cross-coupling product.

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