Preparation method of first-generation Grubbs catalyst

Abstract

The invention belongs to the technical field of catalyst synthesis, and particularly discloses a preparation method of a first-generation Grubbs catalyst, dichlorophenyl ruthenium (II) dimer is used as a metal source raw material, benzaldehyde and tricyclohexylphosphine are combined to synthesize the first-generation Grubbs catalyst, in the reaction process, a dendritic multi-site di (pentafluorophenyl) boric acid catalyst is introduced, and the first-generation Grubbs catalyst is synthesized by using dichlorophenyl ruthenium (II) dimer as a metal source raw material. A di (pentafluorophenyl) boron group at the tail end forms a superacid center due to a strong electron absorption effect, and benzaldehyde carbonyl can be efficiently activated; the dendritic skeleton provides a multi-site synergistic effect and steric configuration control, enhances the substrate enrichment and transition state stabilization capability, and significantly reduces the activation energy generated by the Ru = CHPh key intermediate, and meanwhile, the key steps of further accelerating aldol condensation, metal-carbon double bond generation and the like are combined with a proper amount of alkaline accelerator, so that the preparation method has the advantages of high yield and high yield. The efficient introduction of a benzaldehyde key C1 construction unit is realized, the reaction condition is mild, and the operation is simple and convenient.

Description

Technical Field

[0001] This invention belongs to the field of catalyst synthesis technology, and specifically discloses a method for preparing a first-generation Grubbs catalyst. Background Technology

[0002] Grubbs catalysts are a class of metal complex catalysts with ruthenium carbene structures. Since their discovery by Robert H. Grubbs et al., they have been widely used in reactions such as olefin metathesis, ring-opening metathesis polymerization (ROMP), and ring-closing metathesis reaction (RCM), and are particularly valuable in organic synthesis, materials science, and medicinal chemistry. Among them, the first-generation Grubbs catalyst RuCl2(=CHPh)(PCy3)2 has been widely studied and applied due to its high catalytic activity, stability in air and water, good functional group tolerance, and ability to synthesize derivatized catalysts. However, existing methods for synthesizing first-generation Grubbs catalysts still have many shortcomings, limiting their further industrial production and widespread application.

[0003] The literature “Synthesis and Applications of RuCl2(=CHR')(PR3)2: The Influence of the Alkylidene Moiety on Metathesis Activity” (J. Am. Chem. Soc. 1996, 118, 1, 100) discloses an early method for synthesizing first-generation Grubbs catalysts. This method typically uses ruthenium tri(triphenylphosphine)dichloride as the starting material, reacts it with phenyldiazomethane to generate an intermediate, and then introduces tricyclohexylphosphine through ligand exchange to obtain the target product. Although this method is feasible, the diazo compound used is highly explosive, the reaction needs to be carried out at an extremely low temperature of -78 degrees Celsius, the operating conditions are extremely harsh, the intermediate has poor stability, the reaction scale is limited, the yield is low, and overall it is not conducive to large-scale production.

[0004] To improve the above methods, existing patents CN101555260A and CN119565680A, as well as several other documents, disclose methods for synthesizing first-generation Grubbs catalysts. Examples include: "One-Pot Synthesis of 2nd Ruthenium Grubbs Catalyst for Preparation of One Stapled Peptide" (Chem. Nat. Compd. 55, 2019, 525); "CrossMetathesis Allowing the Conversion of a Ruthenium Indenylidene Complex into Grubbs' Catalyst" (Adv. Synth. Catal. 2004, 346, 917); and "A General Method for Preparation of Metal Carbenes via Solution- and Polymer-Based..." "Approaches" (General Strategies for the Preparation of Metal Carbenes via Solution and Polymer-Based Methods) (J. Am. Chem. Soc. 2005, 127, 43, 15265); Researchers have attempted to replace diazo compounds with phosphine ylides and thioyl ylides, and designed various new precursor systems, such as ruthenium-indenyne compounds or dichlorobis(2,2'-bipyridine)ruthenium. These precursor systems undergo coordination or olefin exchange reactions with styrene or benzyl dichloride under specific conditions to generate the target catalyst. These methods simplify the operation process and mitigate reaction conditions to some extent, but still have problems at different levels: the reagents used are cumbersome to prepare, the raw materials are expensive, the reaction efficiency is low, resulting in complex post-processing, difficulty in ensuring product purity, and low raw material utilization. In addition, some methods are still sensitive to water and oxygen and do not have the ability to operate stably in open environments.

[0005] Therefore, there is still an urgent need for a new first-generation Grubbs catalyst preparation method that is simpler to operate, safer to operate, has readily available reagents, higher product yields, is more environmentally friendly, and is suitable for large-scale industrial production, in order to meet its growing demand in fine chemicals and organic synthesis. Summary of the Invention

[0006] To address the problems in the background art, this invention discloses a method for preparing a first-generation Grubbs catalyst. Using dichlorophenylruthenium(II) dimer as the metal source, a dendritic multisite bis(pentafluorophenyl)boronic acid catalyst is introduced, and benzaldehyde and tricyclohexylphosphine are combined to synthesize the first-generation Grubbs catalyst. The reaction conditions are mild, the operation is simple, and the product yield and purity are excellent, making it suitable for large-scale industrial production.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: A method for preparing a first-generation Grubbs catalyst, the specific synthetic route is as follows: ; Where Ph represents phenyl and Cy represents cyclohexyl; The preparation method includes the following steps: Under a nitrogen atmosphere, dichlorophenylruthenium(II) dimer, tricyclohexylphosphine, dendritic multisite bis(pentafluorophenyl)boronic acid catalyst, base, and solvent were sequentially added to a three-necked flask in a specific molar ratio. The mixture was stirred thoroughly to dissolve the materials. A certain amount of benzaldehyde was then added dropwise to the three-necked flask at a uniform rate. After the addition was complete, the mixture was stirred and reacted for a period of time at a certain temperature. After the reaction was completed, the resulting product was subjected to solid-liquid separation. The resulting liquid phase was then post-treated to obtain the first-generation Grubbs catalyst.

[0008] Preferably, the dendritic multisite bis(pentafluorophenyl)boronic acid catalyst refers to a supported dendritic Lewis acid catalyst formed by combining bis(pentafluorophenyl)boronic acid with an inorganic support such as SiO2, Al2O3 or TiO2, and the amount of bis(pentafluorophenyl)boronic acid catalyst is 0.1–5% of the molar number of dichlorophenylruthenium(II) dimer.

[0009] Preferably, the amount of bis(pentafluorophenyl)boronic acid catalyst used is 0.5–1.0% of the molar number of dichlorophenylruthenium(II) dimer.

[0010] Preferably, the amount of tricyclohexylphosphine used is 2.0 to 6.0 times the molar number of dichlorophenylruthenium(II) dimer.

[0011] Preferably, the amount of tricyclohexylphosphine used is 3.0 to 5.0 times the molar number of dichlorophenylruthenium(II) dimer.

[0012] Preferably, the amount of alkali used is 1.0 to 4.0 times the molar number of dichlorophenylruthenium(II) dimer, and the alkali is Cs2CO3, K2CO3, N,N-diisopropylethylamine or potassium tert-butoxide.

[0013] Preferably, the amount of benzaldehyde used is 2.0 to 4.0 times the molar number of dichlorophenylruthenium(II) dimer.

[0014] Preferably, the solvent is one or a mixture of more than one of diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, xylene, ketones or esters.

[0015] Preferably, after the benzaldehyde addition is complete, the mixture in the three-necked flask is stirred and reacted for 0.5–48 hours at 0 ℃ to 100 ℃.

[0016] Compared with the prior art, the beneficial effects of the present invention are: This invention discloses a method for preparing a first-generation Grubbs catalyst. Using dichlorophenylruthenium(II) dimer as the metal source, a first-generation Grubbs catalyst is synthesized by combining benzaldehyde and tricyclohexylphosphine. During the reaction, a dendritic multi-site bis(pentafluorophenyl)boronic acid catalyst is introduced. Its terminal bis(pentafluorophenyl)boronic group forms a superacid center due to a strong electron-withdrawing effect, which can efficiently activate the benzaldehyde carbonyl group. The dendritic framework provides multi-site synergistic effects and spatial configuration control, enhancing substrate enrichment and transition state stability, and significantly reducing the activation energy for the formation of the Ru=CHPh key intermediate. Simultaneously, this invention combines an appropriate amount of basic promoter to further accelerate key steps such as aldol condensation and metal-carbon double bond formation, achieving efficient introduction of the key C1 building unit of benzaldehyde. The reaction conditions are mild and the operation is simple. The catalytic efficiency and selectivity of the dendritic multisite di(pentafluorophenyl)boronic acid catalyst in this invention are significantly improved, the product yield and purity are excellent, and it has excellent catalyst cycle stability and adaptability to continuous industrial production. Attached Figure Description

[0017] Figure 1 This is the proton NMR spectrum of the first-generation Grubbs catalyst prepared in Example 1 of this invention; Figure 2 This is the carbon spectrum of the first-generation Grubbs catalyst prepared in Example 1 of this invention. Detailed Implementation

[0018] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0019] This invention utilizes a batch-by-batch, uniformly added benzaldehyde strategy to effectively avoid side reactions caused by localized high concentrations, ensuring catalyst structural stability and reaction selectivity, thereby achieving high-yield preparation. The solvent is preferably an ether solvent, including but not limited to diethyl ether, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, which can simultaneously dissolve the metal source, ligands, and catalyst, and provide a stable solvent environment and good mass transfer conditions for the reaction. Toluene, xylene-like aromatic solvents, ketones, or ester solvents can also be used. In special cases, a mixed solvent system can also be used to improve the solubility of the raw materials or control the crystallization process. Example 1

[0020] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of Cs₂CO₃ were sequentially added to a 1 L three-necked flask. Then, 250 mL of 1,4-dioxane was added to the flask, and the mixture was stirred thoroughly to dissolve. Subsequently, 80 mmol of benzaldehyde was added dropwise at a uniform rate at room temperature over approximately 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 21 hours. After the reaction was complete, 100 mL of dichloromethane was added to the flask to obtain a diluted mixture. The mixture was filtered through diatomaceous earth, and the filter cake was washed repeatedly with 100 mL of dichloromethane in small amounts. The filtrates and washings were combined and concentrated under reduced pressure to half the original volume. 100 mL of n-hexane was added to the concentrated mixture to induce crystallization. The mixture was stirred, and a purple solid precipitated. After filtration and vacuum drying, the first-generation Grubbs catalyst compound was obtained, with a product mass of 65.2 g. g, yield 99%, the product was analyzed by nuclear magnetic resonance (NMR) testing, and the resulting proton and carbon spectra are as follows: Figure 1 and Figure 2 ,in: Depend on Figure 1 As can be seen, the hydrogen spectrum 1 ¹H NMR (400 MHz, CDCl₃), chemical shift (ppm): δ 8.44 (d, J = 7.7Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.33 (dd, J = 8.3, 7.2 Hz, 2H), 2.61 (t, J = 12.9 Hz, 6H), 1.90 – 1.64 (m, 30H), 1.42 (q, J = 12.0 Hz, 12H), 1.30 – 1.07(m, 18H); Depend on Figure 2 As can be seen, carbon spectrum 13 C NMR (101 MHz, CDCl3), chemical shifts (ppm): δ 152.47, 130.79, 129.12, 128.91, 32.13, 32.04, 31.95, 29.57, 27.80, 27.74, 27.69, 26.46; The proton and carbon spectra results showed that the product obtained in Example 1 was consistent with the target compound of the first-generation Grubbs catalyst. Proton and carbon spectra of the products obtained in Examples 2–10 also showed that the products were consistent with the target compound of the first-generation Grubbs catalyst. Example 2

[0021] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of K2CO3 were sequentially added to a 1 L three-necked flask. Finally, 250 mL of tetrahydrofuran was added and stirred thoroughly to dissolve the product. Then, 100 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over a period of approximately 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 60.6 g of a purple solid product, with a yield of 92.0%. Example 3

[0022] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite bis(pentafluorophenyl)boronic acid catalyst, and 80 mmol of potassium tert-butoxide were sequentially added to a 1 L three-necked flask. Finally, 250 mL of tetrahydrofuran was added, and the mixture was stirred thoroughly to dissolve. 80 mmol of benzaldehyde was then added dropwise to the three-necked flask at a uniform rate at 0 °C over approximately 30 minutes. After the addition was complete, the temperature was raised to 25 °C and stirred for 6 hours. After the reaction was completed, the mixture was treated according to the method described in Example 1 to obtain 58.3 g of a purple solid product, with a yield of 88.5%. Example 4

[0023] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of Cs₂CO₃ were sequentially added to a 1 L three-necked flask. Finally, 250 mL of toluene was added, and the mixture was stirred thoroughly to dissolve. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over a period of approximately 30 minutes. After the addition was complete, the mixture was heated to 100°C and stirred for 3 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 56.0 g of a purple solid product, with a yield of 85.0%. Example 5

[0024] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 120 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of Cs₂CO₃ were sequentially added to a 1 L three-necked flask. 250 mL of diethyl ether was added, and the mixture was stirred thoroughly to dissolve the product. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over a period of approximately 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 21 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 51.6 g of a purple solid product, with a yield of 78.3%. Example 6

[0025] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of N,N-diisopropylethylamine were sequentially added to a 1 L three-necked flask, followed by 250 mL of dioxane, and the mixture was stirred thoroughly to dissolve. Then, 80 mmol of benzaldehyde was added dropwise to the flask at a uniform rate at room temperature over approximately 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 18 hours. The reaction was then treated according to the method described in Example 1, yielding 52.7 g of a purple solid product, with a yield of 80.0%. Example 7

[0026] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.2 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of Cs₂CO₃ were sequentially added to a 1 L three-necked flask. Finally, 250 mL of tetrahydrofuran was added and stirred thoroughly to dissolve the product. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over a period of approximately 30 minutes. After the addition was complete, the mixture was heated to 45 °C and stirred for 10 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 59.3 g of a purple solid product, with a yield of 90.1%. Example 8

[0027] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 1.0 mmol of dendritic multisite bis(pentafluorophenyl)boronic acid catalyst, and 80 mmol of base Cs₂CO₃ were sequentially added to a 1 L three-necked flask. Finally, 250 mL of 1,4-dioxane was added, and the mixture was stirred thoroughly to dissolve. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over a period of approximately 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 63.8 g of a purple solid product, with a yield of 97%. Example 9

[0028] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite bis(pentafluorophenyl)boronic acid catalyst, and 80 mmol of Cs₂CO₃ were sequentially added to a 1 L three-necked flask. 500 mL of tetrahydrofuran was added to highly dilute the reactants, and the mixture was stirred thoroughly to dissolve them. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over approximately 30 minutes. After the addition was complete, the three-necked flask was placed in a microwave reactor, heated to 80 °C, and maintained for 30 minutes. After the reaction was complete, the product was processed according to the method described in Example 1, yielding 43.7 g of a purple solid product, with a yield of 66.4%. Example 10

[0029] Under a nitrogen atmosphere, 40 mmol of dichlorophenylruthenium(II) dimer, 160 mmol of tricyclohexylphosphine, 0.4 mmol of dendritic multisite di(pentafluorophenyl)boronic acid catalyst, and 80 mmol of base Cs₂CO₃ were sequentially added to a 1 L three-necked flask. 250 mL of diethyl ether was added, and the mixture was stirred thoroughly to dissolve. Then, 80 mmol of benzaldehyde was added dropwise to the three-necked flask at a uniform rate at room temperature over approximately 30 minutes. After the addition was complete, the mixture was stirred at 0 °C for 48 hours. After the reaction was completed, the product was treated according to the method in Example 1 to obtain 62.5 g of a purple solid product, with a yield of 95.0%.

[0030] In this invention, benzaldehyde is used as a key building block, which has advantages such as wide availability, low cost, and moderate reactivity. A dendritic multisite bis(pentafluorophenyl)boronic acid catalyst is used, and a multisite synergistic activation strategy is employed to efficiently complete the synthesis reaction at room temperature. The process is simpler, the reaction conditions are milder, the operation is simple and safe, the reagents are readily available, the product yield is high, and it is environmentally friendly. It is also suitable for large-scale industrial production, meeting the growing demand for first-generation Grubbs catalysts in fine chemicals and organic synthesis. It avoids the use of highly hazardous diazo compounds and extremely low temperature conditions in traditional methods, greatly improving the safety and simplicity of operation. The method of this invention overcomes the technical bottlenecks of insufficient reactivity, poor catalyst thermal stability, and poor adaptability to scale-up production in existing first-generation Grubbs catalyst synthesis methods.

[0031] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Any other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention, as long as they do not depart from the spirit and scope of the technical solutions of the present invention, should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing a first-generation Grubbs catalyst, characterized in that, The specific synthesis route is as follows: ； Where Ph represents phenyl and Cy represents cyclohexyl; The preparation method includes the following steps: Under a nitrogen atmosphere, dichlorophenylruthenium(II) dimer, tricyclohexylphosphine, dendritic multisite bis(pentafluorophenyl)boronic acid catalyst, base, and solvent were sequentially added to a three-necked flask in a specific molar ratio. The mixture was stirred thoroughly to dissolve the materials. A certain amount of benzaldehyde was then added dropwise to the three-necked flask at a uniform rate. After the addition was complete, the mixture was stirred and reacted for a certain period of time at a specific temperature. After the reaction was completed, the resulting product was subjected to solid-liquid separation. The resulting liquid phase was then post-treated to obtain the first-generation Grubbs catalyst.

2. The method for preparing the first-generation Grubbs catalyst according to claim 1, characterized in that, Dendritic multisite bis(pentafluorophenyl)boronic acid catalyst refers to a supported dendritic Lewis acid catalyst formed by combining bis(pentafluorophenyl)boronic acid with inorganic supports such as SiO2, Al2O3 or TiO2. The amount of bis(pentafluorophenyl)boronic acid catalyst used is 0.1–5% of the molar number of dichlorophenylruthenium(II) dimer.

3. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The amount of bis(pentafluorophenyl)boronic acid catalyst used is 0.5–1.0% of the molar number of dichlorophenylruthenium(II) dimer.

4. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The amount of tricyclohexylphosphine used is 2.0 to 6.0 times the molar number of dichlorophenylruthenium(II) dimer.

5. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The amount of tricyclohexylphosphine used is 3.0 to 5.0 times the molar number of dichlorophenylruthenium(II) dimer.

6. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The amount of alkali used is 1.0 to 4.0 times the molar number of dichlorophenylruthenium(II) dimer, and the alkali is Cs2CO3, K2CO3, N,N-diisopropylethylamine or potassium tert-butoxide.

7. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The amount of benzaldehyde used is 2.0 to 4.0 times the molar number of dichlorophenylruthenium(II) dimer.

8. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, The solvent is one or a mixture of more than one of the following: diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, toluene, xylene, ketones or esters.

9. The method for preparing the first-generation Grubbs catalyst according to claim 2, characterized in that, After the benzaldehyde addition is complete, the mixture in the three-necked flask is stirred and reacted for 0.5–48 hours at 0 ℃ to 100 ℃.

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