Large-steric-hindrance water-soluble thiourea ligand as well as preparation method and application thereof

Abstract

The invention discloses a large-steric-hindrance water-soluble thiourea ligand and a preparation method and application thereof, and compared with the prior art, the large-steric-hindrance water-soluble thiourea ligand has the following advantages: through two design adjustments of incorporation of a functionalized aryl group and introduction of a functionalized benzyl group, better water-soluble control and steric-hindrance control of a hydrophilic group are achieved, and the water-soluble thiourea ligand has good water solubility and steric-hindrance control performance. Benzyl halogenated hydrocarbon is high in activity and mild in reaction condition, strict anhydrous and anaerobic operation is not needed, additional reduction operation is not needed either, and in previous methods for preparing thiourea, borane, lithium aluminum hydride and other dangerous reagents need to be used for reduction reaction, so that the cost is low. The whole synthesis and post-treatment are simple, safe, green and environment-friendly, and the large-steric-hindrance water-soluble thiourea ligand can be conveniently recycled after being subjected to acid regulation.

Description

Technical Field

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

[0002] The palladium-catalyzed acylation Suzuki coupling reaction (shown in the following formula) 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] 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 research on the rational design of recyclable water-soluble thiourea ligands, and further expand it to other transition metals and catalytic reactions in the future. Then 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.

[0005] 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 Suzuki coupling reaction catalyzed by a large sterically hindered 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 homogeneous catalyst", and enriching the thiourea compound library and the water-soluble homogeneous catalyst library. Summary of the invention

[0006] The purpose of the present invention is to provide a large sterically hindered water-soluble thiourea ligand, which achieves better water solubility control and steric hindrance control of the hydrophilic group through the two design adjustments of incorporating a functionalized aromatic group and introducing a functionalized benzyl group.

[0007] To achieve the above object, the present invention provides a large sterically hindered water-soluble thiourea ligand, the structural formula of which is selected from one of I-III:

[0008]

[0009] Among them, R 1 Selected from one of H, Alkyl, OMe, and CO2H.

[0010] 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 steric hindrance hydrocarbon group, or a large polar carboxyl group) on two carbon atoms of the five-membered cyclic thiourea, and introduces a functionalized benzyl group (the substituent on the benzyl group can be a large steric hindrance hydrocarbon group, or a large polar carboxyl group) on two nitrogen atoms of the five-membered cyclic thiourea. The present invention adjusts these two technologies so that the possible modification sites of the five-membered cyclic thiourea structure have increased steric hindrance and polarity. Because the design ideas are fed back based on the data 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, the steric effect, and the balance between the water solubility of the ligand structure and the catalytic activity (generally speaking, if the water solubility of the hydrophilic ligand is too low, it will affect the recovery of the catalyst, and if the water solubility is too high, it will affect the activity of the catalyst).

[0011] The second object of the present invention is to provide a preparation method of structural formula I, which specifically comprises 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 and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I;

[0016] Among them, the structural formula of reactant A is:

[0017] The structural formula of product A is:

[0018] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0019] The third object of the present invention is to provide a preparation method of structural formula II, which specifically comprises the following steps:

[0020] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath to react;

[0021] 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;

[0022] 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;

[0023] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I; Among them, the structural formula of reactant A is:

[0024] The structural formula of product A is:

[0025] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0026] The fourth object of the present invention is to provide a preparation method of structural formula III, which specifically comprises the following steps:

[0027] S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction;

[0028] 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;

[0029] 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;

[0030] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III;

[0031] Among them, the structural formula of reactant A is:

[0032] The structural formula of product A is:

[0033] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0034] The first step of the synthesis of the large sterically hindered water-soluble thiourea ligand of the present invention is to use functionalized benzyl bromide when preparing the functionalized benzyl-substituted o-phenylenediamine intermediate, because there are more reaction sites on the benzyl group, not only can the type and number of functional groups be adjusted to adjust the water solubility and polarity of the thiourea ligand, but also a large space steric hindrance can be created through multiple transformable sites of the functionalized benzyl group, which are all conducive to the improvement of the recyclability and catalytic activity of the thiourea ligand. And because the reaction activity of benzyl bromide is higher than that of bromohydrocarbon, the first step of the reaction conditions of the synthesis of the thiourea ligand is more mild, which is conducive to reducing the generation of side reactions and improving the purity of the product. Due to the use of the functionalized benzyl side chain, 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 benzyl side chain and then use thiophosgene to close the ring to form thiourea, and finally hydrolyze, and the target product, the water-soluble cyclic thiourea with functionalized benzyl carboxylic acid side chain, is obtained by the three-step method. Benzyl halides have high activity and mild reaction conditions. They do not require strict anhydrous and oxygen-free operation or additional reduction operation. Most of the methods previously used by the inventors to prepare thiourea require the use of dangerous reagents such as borane and lithium aluminum hydride for reduction reactions, involving strict anhydrous and oxygen-free operation and cumbersome and dangerous post-processing processes. For details, please refer to the literature: Chen, W.; Li, R.; Han, B.; Li, B.-J.; Chen, Y.-C.; Wu Y.; Ding L.-S.; Yang, D. L.-S.;Chen,Y.-C.Synthesis,2006,3058-3062.Li,R.;Chen,W.;Shi,J.-Y.;Chen,L.-J.;Chen,Y.-C.;Ding L.-S.;Wei,Y.-QJ Mass Spectrom.2008,43,542–546.Chen,W.;Lu,X.-Y.;Xu,B.-H.;Yu,W.-G.;Zhou,Z.-N.;Hu,Y.

[0035] Preferably, in step S1, reactant B is selected from one of (1)-(13),

[0036]

[0037] and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(2-6).

[0038] Preferably, in step S1, the heating and stirring temperature is 80-180° C., and the heating and stirring time is 0.5-2 h.

[0039] Preferably, in step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of product A to thiophosgene is 1:(1-2).

[0040] Preferably, in step S3, the time for adding thiophosgene dropwise is 10-14 hours, and the time for stirring after the addition is 10-14 hours.

[0041] 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.

[0042] The fifth object of the present invention is to provide a method for applying a large sterically hindered water-soluble thiourea ligand to a Suzuki reaction catalyzed by aqueous recyclable palladium.

[0043] The catalytic acylation Suzuki reaction involving large steric thiourea is carried out in alkylbenzenes (toluene, xylene, trimethylbenzene, etc.). After the reaction is completed, only a small amount of water and organic solvent need to be added to extract the product into the organic layer. The reuse of the new water-soluble thiourea catalyst containing a hydrophilic structure in the water layer can be purified by simply adjusting the alkalinity (the catalyst is dissolved in water) to extract the organic matter with an organic solvent, and then the water layer is adjusted to acid to precipitate the catalyst solid containing a carboxyl functional group structure. The large steric thiourea recovered from the previous round of catalytic reaction can be conveniently used for the next round of catalytic acylation Suzuki reaction after adding reaction raw materials and solvents, thereby laying a good foundation for realizing highly selective, easy to recover, low-toxic and efficient catalytic acylation Suzuki reaction, and providing green and efficient excellent catalysts for the pharmaceutical industry.

[0044] Compared with the prior art, the present invention has the following advantages:

[0045] 1. The present invention achieves better water solubility control of hydrophilic groups (large polarity is conducive to improving the recovery rate of ligand catalysts) and steric hindrance control (large steric hindrance is conducive to improving catalytic activity) by incorporating functionalized aromatic groups and introducing functionalized benzyl groups;

[0046] 2. Benzyl halogenated hydrocarbons have high activity and mild reaction conditions. They do not require strict anhydrous and oxygen-free operation or additional reduction operation. Most of the methods for preparing thiourea by the inventors previously required the use of dangerous reagents such as borane and lithium aluminum hydride for reduction reaction, which involved strict anhydrous and oxygen-free operation and cumbersome and dangerous post-processing. The entire synthesis and post-processing are simple, safe and environmentally friendly. The large sterically hindered water-soluble thiourea ligand can be easily recovered and recycled after acid adjustment.

[0047] 3. The recovery of the water-soluble thiourea catalyst solid with large steric hindrance can be achieved through simple acid adjustment and filtration, which not only conveniently realizes the recovery 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 separate them from the reaction raw materials and products, reduces the residual ligand as an impurity in the product, and directly improves the purity of the product. DETAILED DESCRIPTION

[0048] 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.

[0049] The specific embodiment of the present invention provides a large sterically hindered water-soluble thiourea ligand, the structural formula of which is selected from one of I-III:

[0050]

[0051] Among them, R 1 Selected from one of H, Alkyl, OMe, and CO2H.

[0052] 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 steric hindrance hydrocarbon group, or a large polar carboxyl group) on two carbon atoms of the five-membered cyclic thiourea, and introduces a functionalized benzyl group (the substituent on the benzyl group can be a large steric hindrance hydrocarbon group, or a large polar carboxyl group) on two nitrogen atoms of the five-membered cyclic thiourea. The present invention adjusts these two technologies so that the possible modification sites of the five-membered cyclic thiourea structure have increased steric hindrance and polarity. Because the design ideas are fed back based on the data 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, the steric effect, and the balance between the water solubility of the ligand structure and the catalytic activity (generally speaking, if the water solubility of the hydrophilic ligand is too low, it will affect the recovery of the catalyst, and if the water solubility is too high, it will affect the activity of the catalyst).

[0053] The specific embodiment of the present invention also provides a preparation method of structural formula I, which specifically comprises the following steps:

[0054] S1, mixing reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide in a molar ratio of 1:(2-6), heating and stirring in an oil bath at 80-180°C for 0.5-2h;

[0055] 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;

[0056] S3, after mixing the product A with a tetrahydrofuran solution of anhydrous sodium carbonate in a molar ratio of 1:(1-2), adding a tetrahydrofuran solution of thiophosgene, stirring for 10-14 hours after the addition is complete, and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and washing the organic layer with saturated brine, 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 thiophosgene is 1:(1-2);

[0057] S4, mixing the intermediate product B with sodium hydroxide at a molar ratio of 1:(8-12), adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH to 1, filtering, washing, and drying after the reaction is completed to obtain a product of structural formula I;

[0058] Among them, the structural formula of reactant A is:

[0059] The structural formula of product A is:

[0060] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0061] The specific embodiment of the present invention also provides a preparation method of structural formula II, which specifically comprises the following steps:

[0062] S1, mixing reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide in a molar ratio of 1:(2-6), heating and stirring in an oil bath at 80-180°C for 0.5-2h;

[0063] 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;

[0064] S3, after mixing the product A with a tetrahydrofuran solution of anhydrous sodium carbonate in a molar ratio of 1:(1-2), adding a tetrahydrofuran solution of thiophosgene, stirring for 10-14 hours after the addition is complete, and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and washing the organic layer with saturated brine, 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 thiophosgene is 1:(1-2);

[0065] S4, mixing the intermediate product B with sodium hydroxide at a molar ratio of 1:(8-12), adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH to 1, filtering, washing and drying after the reaction is completed to obtain a product of structural formula II;

[0066] Among them, the structural formula of reactant A is:

[0067] The structural formula of product A is:

[0068] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0069] The fourth object of the present invention is to provide a preparation method of structural formula III, which specifically comprises the following steps:

[0070] S1, mixing reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide in a molar ratio of 1:(2-6), heating and stirring in an oil bath at 80-180°C for 0.5-2h;

[0071] 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;

[0072] S3, after mixing the product A with a tetrahydrofuran solution of anhydrous sodium carbonate in a molar ratio of 1:(1-2), adding a tetrahydrofuran solution of thiophosgene, stirring for 10-14 hours after the addition is complete, and removing the tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and the organic layer is washed with saturated brine in turn, and dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain an intermediate product B, wherein the molar ratio of product A to thiophosgene is 1:(1-2);

[0073] S4, mixing the intermediate product B with sodium hydroxide at a molar ratio of 1:(8-12), adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH to 1, filtering, washing and drying after the reaction is completed to obtain a product of structural formula III;

[0074] Among them, the structural formula of reactant A is:

[0075] The structural formula of product A is:

[0076] The structural formula of intermediate product B is: Among them, R 1 is selected from one of H, Alkyl, OMe, CO2H, R 2 Select one of Alkyl.

[0077] Preferably, in step S1, reactant B is selected from one of (1)-(13),

[0078]

[0079]

[0080] and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(2-6).

[0081] The fifth object of the present invention is to provide a method for applying a large sterically hindered water-soluble thiourea ligand to a Suzuki reaction catalyzed by aqueous recyclable palladium.

[0082] The following is a full description with reference to specific embodiments.

[0083] Example 1

[0084] N 1 ,N 2 - Preparation of bis[(3,5-dicarboxylic acid methyl ester) benzyl]-4-methoxy o-phenylenediamine:

[0085]

[0086] 4-methoxy-o-phenylenediamine (reactant A) (690.8 mg, 5 mmol), 5-bromomethylisophthalic acid dimethyl ester (reactant B) (3.589 g, 12.5 mmol), diisopropylethylamine (1.615 g, 12.5 mmol) and tetrabutylammonium iodide (92 mg, 0.25 mmol) were mixed in a round-bottom flask and heated at 130°C in an oil bath for 1 hour to stop the reaction. After the reaction solution was cooled to room temperature, 15 ml of ethyl acetate and 15 ml of water were added and stirred, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (20 ml x 2), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel flash column chromatography (eluent: petroleum ether: ethyl acetate = 2:1), and evaporated to dryness on a rotary evaporator to obtain a reddish brown oil N 1 ,N 2 -Bis[(3,5-dicarboxylic acid methyl ester) benzyl]-4-methoxy o-phenylenediamine crude product (product A) 2.349 g,

[0087] The yield was 85%. The crude product was used directly in the next reaction without further purification.

[0088]

[0089] In a fume hood, stir at room temperature in a mixture containing N 1 ,N 2 -bis[(3,5-dicarboxylic acid methyl ester) benzyl]-4-methoxy o-phenylenediamine crude product (2.349 g, 4.27 mmol) and anhydrous sodium carbonate (678 mg, 6.4

[0090] mmol) in a round-bottom flask containing 20 ml of tetrahydrofuran, and very slowly drop the thiophosgene

[0091] (736mg, 6.4mmol) in 20ml tetrahydrofuran solution. 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 30ml ethyl acetate and 30ml water were added and stirred. The organic layer was washed with saturated brine (20ml), 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 on a rotary evaporator to obtain 1.341g of a white solid (intermediate product B), with a yield of 53%.

[0092]

[0093] Intermediate product B (1.341 g, 2.26 mmol) and sodium hydroxide (904 mg, 22.6 mmol) were mixed in a round-bottom flask, and water (20 mL) and tetrahydrofuran (20 mL) were added. The mixture was stirred at room temperature for 24 hours, and tetrahydrofuran was removed by rotary evaporation. Under ice-cooling and stirring, hydrochloric acid was carefully added dropwise to adjust the pH to 1. A large amount of white solid precipitated from the solution. The mixture was stirred in an ice bath for 30 minutes. The white solid obtained by suction filtration was washed with water (15 ml x 3) and dried to obtain 1.12 g of white solid, with a yield of 92%.

[0094] The intermediate product and the final product obtained in Example 1 were tested for performance, and the test results were as follows:

[0095]

[0096] White solid; melting point: 200–203°C.

[0097] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=1.2Hz,2H),8.22(d,J=1.6Hz,4H),6.89(dd,J=24.4,9.5Hz,1H),6 .69(dt,J=16.0,8.0Hz,1H),6.55(dd,J=11.9,2.4Hz,1H),5.67(s,4H),3.92(s,12H),3.73(s,3H).

[0098] 13 C NMR (100MHz, CDCl3) δ171.0,165.8,157.0,136.8,136.6,132.8,132.7,131.3,130.3,126.1,110.0,109.9,95.7,56.2,52.7,48.4,48.3.

[0099]

[0100] White solid; melting point: >280℃.

[0101] 1 H NMR (400MHz, DMSO) δ13.21(s,4H),8.36(dd,J=3.5,1.6Hz,2H),8.16(dd,J=20.4,1.5Hz,4H),7.3 6(t,J=9.8Hz,1H),7.14(t,J=6.5Hz,1H),6.88–6.81(m,1H),5.74(d,J=8.3Hz,4H),3.73(s,3H).

[0102] 13 C NMR (100MHz, DMSO) δ169.2,166.0,165.9,156.3,137.3,137.2,132.2,132. 1,132.0,131.4,131.3,129.0,125.2,110.4,110.1,95.7,55.8,46.8,46.7.

[0103]

[0104] The intermediate product and the final product obtained in Example 2 were tested for performance, and the test results were as follows:

[0105]

[0106] White solid; melting point: 212–213°C.

[0107] 1 H NMR(400MHz, CDCl3) δ8.59(d,J=1.5Hz,2H),8.19(dd,J=13.6,1.5Hz,4H),7.87(dd,J=8.4,1.4 Hz, 1H), 7.71 (d, J = 1.1Hz, 1H), 7.07 (d, J = 8.4Hz, 1H), 5.71 (s, 4H), 3.91 (s, 12H), 3.87 (s, 3H).

[0108] 13C NMR (100MHz, CDCl3) δ172.9,166.2,165.7 165.6,136.3,136.2,135.1,132.8,132.5,131.8,131.4,131.3,130.5,130.4,125.7,110.6,108.9,52.7,52.6,48.4,48.3.

[0109]

[0110] White solid; melting point: >280℃.

[0111] 1 H NMR (400MHz, DMSO) δ13.21 (s, 5H), 8.36 (s, 2H), 8.14 (dd, J = 9.4, 1.0Hz, 4H), 7.97 (s ,1H),7.85(dd,J=8.4,1.2Hz,1H),7.57(d,J=8.4Hz,1H),5.84(s,2H),5.80(s,2H).

[0112] 13 C NMR (100MHz, DMSO) δ171.3,166.5,165.9,137.0,136.9,134.3,132.1,131.9,131.5,131.1,129.1,129.0,125.8,125.0,110.8,109.6,47.0,46.8.

[0113] Example 3

[0114] 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 Example 1 and will not be repeated here.

[0115] Example 4

[0116] 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.

[0117] Example 5

[0118]

[0119] Example 6

[0120]

[0121] Example 7

[0122]

[0123] The new large sterically hindered water-soluble thiourea ligand palladium complex prepared in Example 1 catalyzes the acylation Suzuki reaction general steps:

[0124]

[0125] At room temperature, in air, add the new large steric hindered water-soluble thiourea II (1 mol%, 2.7 mg), 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 stirring bar. The mixture is stirred in a round-bottom flask at 25°C or 100°C until the reaction is completed. Add ethyl acetate (10 mL) and water (10 mL) and stir, separate the organic layer, and 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.

[0126] The remaining water layer after post-treatment was stirred under ice bath cooling, hydrochloric acid was carefully added, 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 filtration was washed with water (10ml x 3), and dried to obtain 2.7mg 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 three cycles of catalysis, the recovery and catalytic activity of the new water-soluble thiourea ligand palladium catalyst did not decrease significantly.

[0127] 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 sterically hindered water-soluble thiourea ligand, characterized in that: The structural formula is selected from one of I-III: Among them, R 1 Selected from one of H, Alkyl, OMe, and CO2H.

2. A method for preparing a large sterically hindered water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula I specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; 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 and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I; 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, CO2H, R 2 Select one of Alkyl.

3. A method for preparing a large sterically hindered water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula II specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; 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 and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula II; 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, CO2H, R 2 Select one of Alkyl.

4. A method for preparing a large sterically hindered water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula III specifically comprises the following steps: S1, after reactant A, reactant B, diisopropylethylamine and tetrabutylammonium iodide are mixed, heating and stirring in an oil bath for reaction; 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 and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III; 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, CO2H, R 2 Select one of Alkyl.

5. The method for preparing a sterically hindered water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In step S1, reactant B is selected from one of (1) to (13), and X is Cl or Br, and the molar ratio of reactant A to reactant B is 1:(2-6).

6. The method for preparing a sterically hindered water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In the step S1, the temperature of heating and stirring is 80-180° C., and the time of heating and stirring is 0.5-2 h.

7. The method for preparing a sterically hindered water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of product A to thiophosgene is 1:(1-2).

8. The method for preparing a sterically hindered water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In step S3, the time for adding thiophosgene dropwise is 10-14 hours, and the time for stirring after the addition is 10-14 hours.

9. The method for preparing a sterically hindered water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In the 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.

10. An application of a large sterically hindered water-soluble thiourea ligand, characterized in that: The application comprises applying the large sterically hindered water-soluble thiourea ligand described in claim 1 to a Suzuki reaction catalyzed by aqueous recyclable palladium.

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