Efficient carbon-carbon bond construction and synthesis method based on transition metal catalysis

Abstract

The invention discloses an efficient carbon-carbon bond construction and synthesis method based on transition metal catalysis, and relates to the technical field of organic chemistry, and the efficient carbon-carbon bond construction and synthesis method comprises the steps of catalyst preparation and selection, reaction system construction, reaction condition optimization, product separation and catalyst recovery. Traditional expensive metals such as palladium and the like are replaced, a metal organic framework material UiO-66-NH2 and a covalent organic framework material COF-366 are adopted as carriers, metal active sites are accurately dispersed by utilizing the high specific surface area and an adjustable and controllable pore channel structure of the carriers, the metal consumption is reduced, metal atomic-scale accurate loading is realized by combining an atomic layer deposition technology, the catalyst cost is reduced, and meanwhile, the preparation method is simple and easy to implement. The activity and selectivity of the catalyst obtained through high-throughput screening and machine learning optimization are remarkably improved, and efficient proceeding of a carbon-carbon bond construction reaction can be effectively promoted.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and in particular to a highly efficient carbon-carbon bond construction synthesis method based on transition metal catalysis. Background Art

[0002] In the field of organic chemistry, the construction of carbon-carbon bonds is a core step in the synthesis of complex organic molecules, drugs, and materials. Transition metal-catalyzed carbon-carbon bond formation reactions have become an important means of constructing carbon-carbon bonds in organic synthesis due to their advantages such as mild reaction conditions, good functional group compatibility, and high selectivity. From the early Grignard reaction to the modern palladium-catalyzed cross-coupling reaction, transition metal-catalyzed carbon-carbon bond formation reactions have continued to develop, greatly promoting progress in related fields such as synthetic organic chemistry, medicinal chemistry, and materials science.

[0003] However, the existing transition metal-catalyzed carbon-carbon bond construction methods still have many defects. On the one hand, the activity and selectivity of the catalyst need to be further improved. Many reactions require the use of expensive transition metal catalysts, and the catalyst loading is high, which leads to increased reaction costs. At the same time, the substrate range of some reactions is narrow, and it is difficult to achieve efficient carbon-carbon bond construction for some complex structured substrates, which limits its expansion in practical applications. On the other hand, the reaction conditions are relatively harsh and often need to be carried out under strict conditions such as anhydrous and oxygen-free conditions. The experimental operation requirements are high, which increases the complexity and difficulty of the reaction. Moreover, more side reactions may occur during the reaction, which reduces the yield and purity of the target product, and brings about problems such as post-processing difficulties and environmental pollution. To this end, we propose a high-efficiency carbon-carbon bond construction synthesis method based on transition metal catalysis. Summary of the Invention

[0004] The purpose of the present invention is to provide a highly efficient carbon-carbon bond construction synthesis method based on transition metal catalysis.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a method for efficiently constructing carbon-carbon bonds based on transition metal catalysis, comprising catalyst preparation and selection, reaction system construction, reaction condition optimization, product separation, and catalyst recovery. The specific steps of the efficient carbon-carbon bond construction synthesis are as follows:

[0006] Step 1: Select metal organic framework materials and covalent organic frameworks as catalyst supports, and load manganese and nickel transition metals into the supports;

[0007] Step 2: preparing a mixed solvent of halogenated olefin, aryl iodide, potassium phosphate base, pyridine-oxazoline derivative ligand, transition metal catalyst, ionic liquid [BMIM]PF6 and acetonitrile;

[0008] Step 3: stirring the mixed solvent to react according to the photothermal synergistic catalytic reaction;

[0009] Step four, after the reaction is completed, the product is separated from the catalyst using supercritical carbon dioxide extraction technology, and the product and the catalyst are recovered.

[0010] As a further scheme of the present application: in step one, the metal organic framework material is UiO-66-NH2, and the covalent organic framework material is COF-366.

[0011] As a further scheme of the present application: in step one, the prepared catalyst carrier is placed into an atomic layer deposition reaction chamber using atomic layer deposition technology, double manganese is used as a metal source, and cyclic deposition is carried out at 150℃, each cycle including pulse passing of the metal source for 0.1s, nitrogen blowing for 5s, pulse passing of water for 0.1s, and nitrogen blowing for 5s, and the metal loading is controlled at 1wt%-8wt% by controlling the number of cycles.

[0012] As a further scheme of the present application: in step two, the addition amounts of the haloalkene, aryl iodide, potassium phosphate base, and pyridine-oxazoline derivative ligand are 1.2mmol, 1.5mmol, 2.5mmol, and 0.15mmol, respectively, the addition amount of the transition metal catalyst is 2.5% of the total mass of the substrate, and the addition amounts of the ionic liquid [BMIM]PF6 and acetonitrile are 4mL and 2mL, respectively.

[0013] As a further scheme of the present application: in step two, the reaction system is pretreated using a dynamic vacuum-inert gas alternating treatment method, the reaction container is pumped to a vacuum degree of 10 -3 Pa and maintained for 10min, then argon is passed to normal pressure, and this process is repeated 3 times to control the oxygen content in the system to be between 0.01%-0.1%.

[0014] As a further scheme of the present application: in step three, the reaction container is placed in a photo-thermal coupling reaction device, the central wavelength is set to 450nm, and the light intensity is set to 100mW / cm 2 , visible light LED arrays are used in cooperation with an oil bath pot for heating, the reaction temperature is controlled at 70℃, a magnetic stirrer is used for stirring at 500r / min, and the reaction time is 6h.

[0015] As a further scheme of the present application: in step three, for a system with a slow reaction rate, the reaction is transferred to a microfluidic chip with a channel size of 500μm×500μm for processing, and the flow rate of the substrate and catalyst mixed liquid is controlled to be 1mL / min according to a precision syringe pump.

[0016] As a further scheme of the present application: in step four, after the reaction is completed, the reaction mixture is cooled to room temperature, and a supercritical carbon dioxide extraction technology is used for product separation; in the extraction kettle, the supercritical carbon dioxide pressure is controlled to be 15 MPa, and the temperature is controlled to be 35 DEG C; after extraction for 30 min, the product is separated from the catalyst.

[0017] As a further scheme of the present application: in step four, for the supported catalyst with magnetism, a magnetic separation technology is used, and the catalyst is quickly separated by an external magnetic field; after the separated catalyst is ultrasonically cleaned with ethanol and vacuum dried at 80 DEG C, the catalyst is reserved for the next round of reaction.

[0018] Compared with the prior art, the beneficial effects of the present application are as follows:

[0019] 1. By selecting manganese and nickel as active components to replace traditional expensive metals such as palladium, using metal organic framework material UiO-66-NH2 and covalent organic framework material COF-366 as carriers, utilizing the high specific surface area and controllable pore structure to precisely disperse the metal active sites, reducing the metal consumption, combining with the atomic layer deposition technology to realize the metal atomic level accurate loading, the catalyst cost is reduced, at the same time, the catalyst obtained through high-throughput screening and machine learning optimization has significantly improved activity and selectivity, which can effectively promote the efficient progress of carbon-carbon bond construction reaction;

[0020] 2. The reaction system is pretreated by the dynamic vacuum-inert gas alternating treatment method, which is simple to operate and can effectively remove oxygen in the system; the photothermal synergistic catalytic reaction system reduces the reaction temperature, and the reaction conditions are more mild; at the same time, the application of microfluidic mass transfer enhancement technology and in-situ Raman spectrum real-time monitoring feedback system further optimizes the reaction process control, reduces the dependence on special equipment and complex operation, simplifies the reaction process, reduces the experimental operation difficulty, and is convenient for technical popularization and application;

[0021] 3. The reaction system is monitored in real time by in-situ Raman spectrum, and the reaction parameters such as light intensity, temperature and stirring speed are automatically optimized by the feedback control system combined with the pre-established reaction kinetics model, so that the occurrence rate of side reactions is effectively reduced; the photothermal synergistic catalysis and microfluidic mass transfer enhancement technology improve the reaction efficiency and selectivity, improve the yield and purity of the target product, reduce the difficulty and cost of subsequent separation and purification, improve the atom economy, and replace the traditional organic solvent extraction with supercritical carbon dioxide extraction technology, avoiding the use of a large amount of organic solvent and reducing wastewater discharge. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The carbon-carbon bond construction synthesis flowchart in the embodiments of the present application is shown in the figure. DETAILED DESCRIPTION

[0023] The specific embodiments of the present invention will be further described below in conjunction with the accompanying drawings. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention.

[0024] In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0025] Please see the attached Figure 1 The present invention provides a high-efficiency carbon-carbon bond construction synthesis method based on transition metal catalysis, including catalyst preparation and selection, reaction system construction, reaction condition optimization, product separation and catalyst recovery. The specific steps of the high-efficiency carbon-carbon bond construction synthesis are as follows:

[0026] Step 1: Select metal organic framework materials and covalent organic frameworks as catalyst supports, and load manganese and nickel transition metals into the supports;

[0027] Step 2: preparing a mixed solvent of halogenated olefin, aryl iodide, potassium phosphate base, pyridine-oxazoline derivative ligand, transition metal catalyst, ionic liquid [BMIM]PF6 and acetonitrile;

[0028] Step 3: stirring the mixed solvent to react according to the photothermal synergistic catalytic reaction;

[0029] Step 4: After the reaction is completed, the product and the catalyst are separated using supercritical carbon dioxide extraction technology, and the product and the catalyst are recovered.

[0030] In one embodiment of the present invention: in step 1, the metal organic framework material is UiO-66-NH2, and the covalent organic framework material is COF-366.

[0031] In one embodiment of the present invention: in step 1, the prepared catalyst support is placed in an atomic layer deposition reaction chamber using atomic layer deposition technology, and cyclic deposition is performed at 150°C using dimanganese as the metal source. Each cycle includes pulse introduction of the metal source for 0.1s, nitrogen purge for 5s, pulse introduction of water for 0.1s, and nitrogen purge for 5s. The metal loading is controlled within a range of 1wt% to 8wt% by controlling the number of cycles.

[0032] In one embodiment of the present invention: in step 2, the added amounts of halogenated olefin, aryl iodide, potassium phosphate base and pyridine-oxazoline derivative ligand are 1.2 mmol, 1.5 mmol, 2.5 mmol and 0.15 mmol respectively, the added amount of transition metal catalyst is 2.5% of the total mass of the substrate, and the added amounts of ionic liquid [BMIM]PF6 and acetonitrile are 4 mL and 2 m respectively.

[0033] In one embodiment of the present invention, in step 2, the reaction system is pretreated using a dynamic vacuum-inert gas alternating treatment method, and the reaction vessel is evacuated to 10 -3 Pa vacuum degree and maintain it for 10 minutes, then introduce argon to normal pressure, repeat this process 3 times, and control the oxygen content in the system between 0.01% and 0.1%.

[0034] In one embodiment of the present invention: In step 3, the reaction container is placed in a photothermal coupling reaction device, and the central wavelength is set to 450nm and the light intensity is set to 100mW / cm 2 The reaction temperature was controlled at 70°C using a visible light LED array and an oil bath for synergistic heating. A magnetic stirrer was used for stirring at 500 r / min, and the reaction time was 6 h.

[0035] In one embodiment of the present invention: in step three, for a system with a slow reaction rate, the reaction is transferred to a microfluidic chip with a channel size of 500 μm×500 μm, and the flow rate of the substrate and catalyst mixture is controlled to 1 mL / min by a precision injection pump.

[0036] In one embodiment of the present invention: in step 4, after the reaction is completed, the reaction mixture is cooled to room temperature, and the product is separated using supercritical carbon dioxide extraction technology. In the extraction kettle, the supercritical carbon dioxide pressure is controlled to 15 MPa and the temperature is 35°C. After extraction for 30 minutes, the product is separated from the catalyst.

[0037] In one embodiment of the present invention: in step 4, for the magnetic supported catalyst, magnetic separation technology is used to quickly separate the catalyst through an external magnetic field, and the separated catalyst is ultrasonically cleaned with ethanol, vacuum-dried at 80°C, and retained for the next round of reaction.

[0038] Example

[0039] In a fume hood, zirconium nitrate and 2-aminoterephthalic acid were accurately weighed using an electronic balance and added to a 500 mL round-bottom flask at a molar ratio of 1:2. N,N-dimethylformamide was measured using a graduated cylinder and added to the round-bottom flask at a molar ratio of 1:200 to fully dissolve the solid. The mixture in the round-bottom flask was transferred to a reactor at 120°C, the reactor was sealed, and the reaction was continued for 24 hours. After the reaction was completed, the reactor was naturally cooled to room temperature, the reaction mixture was poured into a centrifuge tube, and centrifuged at 8000 r / min for 10 minutes in a centrifuge. The supernatant was discarded to obtain a solid precipitate. The precipitate was washed alternately with ethanol and deionized water three times, and centrifuged after each washing. Finally, the precipitate was placed in a vacuum drying oven and dried at 60°C for 12 hours to obtain the UiO-66-NH2 carrier.

[0040] In a glove box, the trimesic aldehyde and tris(4-aminophenyl)benzene were weighed in sequence, and then the two were added to a 250 mL reaction bottle in a molar ratio of 1:1, followed by adding a mixed solution of 1,4-dioxane, mesitylene and acetic acid in a volume ratio of 2:1:1, and the solid was completely dissolved. After sealing the reaction bottle, it was transferred to a constant temperature drying oven at 120℃ for solvothermal reaction for 72 h. After the reaction was completed, the drying oven was cooled, the reaction bottle was taken out, and the reaction mixture was diluted with a large amount of tetrahydrofuran and then poured into a centrifuge tube. Centrifugation was performed at a speed of 4000 r / min for 15 min, and the precipitate was washed with tetrahydrofuran and methanol alternately for 5 times. After each washing, centrifugal separation was performed. Finally, the precipitate was dried in a vacuum drying oven at 40℃ for 24 h to obtain the COF-366 carrier;

[0041] The prepared UiO-66-NH2 carrier was placed in an atomic layer deposition reaction chamber, and the reaction chamber was sealed. Bis(methylcyclopentadienyl)manganese was used as the metal source, and the reaction temperature was set to 150℃. The cyclic deposition operation was performed, and each cycle was as follows: pulse introduction of the metal source for 0.1 s to make the metal source vapor contact with the surface of the carrier, followed by pulse introduction of nitrogen for 5 s to remove the unreacted metal source vapor, then pulse introduction of water for 0.1 s to initiate the reaction of the metal source with water and achieve the deposition of metal atoms, and finally pulse introduction of nitrogen for 5 s to remove the reaction byproducts. By controlling the number of cycles, the loading amount of manganese was controlled to be 6wt%. After the deposition was completed, the catalyst was taken out under the protection of nitrogen and placed in a desiccator for standby use.

[0042] A micro-reaction array high-throughput screening platform containing 96 independent reaction units was built. In each reaction unit, 0.1 mmol of iodobenzene, 0.12 mmol of ethyl acrylate as a substrate, 0.2 mmol of potassium phosphate as a base, 0.015 mmol of pyridine-oxazoline derivative as a ligand, and different types and loadings of catalysts were added. The amount of catalyst was 2.5% of the total mass of the substrate. A mixed solvent of 0.5 mL of ionic liquid [BMIM]PF6 and 0.25 mL of acetonitrile was also added. The reaction array was placed in a photo-thermal coupling reaction device, and a visible light LED array with a center wavelength of 450 nm and a light intensity of 100 mW / cm 2 The reaction temperature was controlled at 70℃, and the reaction was stirred at a speed of 500 r / min for 6 h. After the reaction was completed, the yield and purity of the product ethyl cinnamate in each reaction unit were detected using a gas chromatograph-mass spectrometer. The experimental data were input into a machine learning algorithm based on a Gaussian process regression model to analyze and predict the activity and selectivity of different catalyst combinations, and the optimal catalyst was screened. The nickel was loaded on a magnetic UiO-66-NH2 catalyst, and the loading amount of nickel was 6wt%;

[0043] Take a special transparent quartz reaction container, use a pipette and an electronic balance to accurately add 1.2mmol iodobenzene and 1.5mmol ethyl acrylate as substrates, 2.5mmol potassium phosphate as a base, and 0.15mmol pyridine-oxazoline derivative as a ligand in sequence, weigh 2.5% of the total mass of the substrate nickel loaded on the magnetic UiO-66-NH2 catalyst (nickel loading 6wt%), then use a graduated cylinder to measure 4mL of a mixed solvent consisting of ionic liquid [BMIM]PF6 and 2mL of acetonitrile and add it to the reaction container, connect the reaction container to a vacuum-inert gas treatment device, first turn on the vacuum pump, and evacuate the reaction container to 10 -3 Pa vacuum and maintain it for 10 min, then introduce argon to normal pressure, repeat this vacuum-argon process 3 times to ensure that the oxygen content in the system is less than 0.1%;

[0044] The pre-treated reaction container was placed in a photothermal coupling reaction device and the visible light LED array (central wavelength 450nm, light intensity 100mW / cm 2 ) and an oil bath, the reaction temperature was set to 70°C, stirred at a speed of 500 r / min by a magnetic stirrer, and the reaction lasted for 6 hours. During the reaction, the reaction system was monitored in real time every 1 hour using an in-situ Raman spectrometer. According to the monitoring results and the pre-established reaction kinetic model, the reaction parameters such as light intensity, temperature, and stirring speed were automatically adjusted by a feedback control system;

[0045] After the reaction is completed, the reaction mixture is cooled to room temperature and then transferred to a supercritical carbon dioxide extraction kettle. The supercritical carbon dioxide pressure in the extraction kettle is set to 15 MPa and the temperature is 35°C. The extraction is carried out for 30 minutes. After the extraction is completed, the extract phase is depressurized by a decompression device to gasify and separate the carbon dioxide to obtain the target product, crude ethyl cinnamate. The extraction pressure is set to 15 MPa, the extraction temperature is 35°C, and the extraction time is 30 minutes.

[0046] For the magnetic nickel-loaded magnetic UiO-66-NH2 catalyst, after the reaction mixture is cooled, the reaction vessel is placed in a strong magnetic field and allowed to stand for 5 minutes to allow the catalyst to aggregate and separate under the action of the magnetic field. The supernatant is carefully transferred to another container, leaving the catalyst at the bottom. An appropriate amount of ethanol is added to the container containing the catalyst and ultrasonic cleaning is performed for 10 minutes to remove impurities adsorbed on the catalyst surface. After cleaning, magnetic separation is performed again, and the ethanol solution is discarded. The separated catalyst is placed in a vacuum drying oven and vacuum dried at 80°C for use in the next round of reaction. The magnetic separation standing time is 5 minutes, the ultrasonic cleaning time is 10 minutes, and the drying temperature is 80°C.

[0047] The specific operations and data verification according to the above embodiments show that the efficient carbon-carbon bond construction synthesis method based on transition metal catalysis proposed in the present invention shows significant advantages and feasibility in catalyst performance, reaction efficiency, product quality, cost control and environmental protection.

[0048] Although the present invention is disclosed above with reference to preferred embodiments, this is not intended to limit the present invention. Any person skilled in the art may make possible changes and modifications without departing from the spirit and scope of the present invention. Therefore, any modifications, equivalent variations, and modifications made to the above embodiments in accordance with the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection defined by the claims of the present invention.

Claims

1. A highly efficient carbon-carbon bond synthesis method based on transition metal catalysis, comprising catalyst preparation and selection, reaction system construction, reaction condition optimization, product separation, and catalyst recovery, characterized in that: The specific steps of constructing and synthesizing the efficient carbon-carbon bond are as follows: Step 1: Select metal organic framework materials and covalent organic frameworks as catalyst supports, and load manganese and nickel transition metals into the supports; Step 2: preparing a mixed solvent of halogenated olefin, aryl iodide, potassium phosphate base, pyridine-oxazoline derivative ligand, transition metal catalyst, ionic liquid [BMIM]PF6 and acetonitrile; Step 3: stirring the mixed solvent to react according to the photothermal synergistic catalytic reaction; Step 4: After the reaction is completed, the product and the catalyst are separated using supercritical carbon dioxide extraction technology, and the product and the catalyst are recovered.

2. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 1, characterized in that: In the step 1, the metal organic framework material is UiO-66-NH2, and the covalent organic framework material is COF-366.

3. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 2, characterized in that: In step 1, the prepared catalyst support is placed in an atomic layer deposition reaction chamber using atomic layer deposition technology, and cyclic deposition is performed at 150° C. using dimanganese as the metal source. Each cycle includes pulse introduction of the metal source for 0.1 s, nitrogen purge for 5 s, pulse introduction of water for 0.1 s, and nitrogen purge for 5 s. The metal loading is controlled within a range of 1 wt% to 8 wt% by controlling the number of cycles.

4. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 3, characterized in that: In step 2, the added amounts of olefin halide, aryl iodide, potassium phosphate base and pyridine-oxazoline derivative ligand are 1.2 mmol, 1.5 mmol, 2.5 mmol and 0.15 mmol, respectively; the added amount of transition metal catalyst is 2.5% of the total mass of the substrate; and the added amounts of ionic liquid [BMIM]PF6 and acetonitrile are 4 mL and 2 mL, respectively.

5. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 4, characterized in that: In the step 2, the reaction system is pretreated using a dynamic vacuum-inert gas alternating treatment method, and the reaction vessel is evacuated to 10 -3 Pa vacuum degree and maintain it for 10 minutes, then introduce argon to normal pressure, repeat this process 3 times, and control the oxygen content in the system between 0.01% and 0.1%.

6. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 5, characterized in that: In step 3, the reaction vessel was placed in a photothermal coupling reaction device, and the central wavelength was set to 450 nm and the light intensity was set to 100 mW / cm 2 The reaction temperature was controlled at 70°C using a visible light LED array and an oil bath for synergistic heating. A magnetic stirrer was used for stirring at 500 r / min, and the reaction time was 6 h.

7. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 6, characterized in that: In step 3, for a system with a slow reaction rate, the reaction was transferred to a microfluidic chip with a channel size of 500 μm×500 μm, and the flow rate of the substrate and catalyst mixture was controlled to 1 mL / min by a precision syringe pump.

8. The method for constructing an efficient carbon-carbon bond based on transition metal catalysis according to claim 7, characterized in that: In the step 4, after the reaction is completed, the reaction mixture is cooled to room temperature and the product is separated using supercritical carbon dioxide extraction technology. In the extraction kettle, the supercritical carbon dioxide pressure is controlled to 15 MPa and the temperature is 35° C. After extraction for 30 minutes, the product is separated from the catalyst.

9. The method for constructing a highly efficient carbon-carbon bond based on transition metal catalysis according to claim 8, characterized in that: In the step 4, for the magnetic supported catalyst, magnetic separation technology is used to quickly separate the catalyst through an external magnetic field. The separated catalyst is ultrasonically cleaned with ethanol, vacuum-dried at 80° C., and retained for the next round of reaction.

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