Method for preparing cyanobenzene compound through C-F bond cleavage of aryl fluoride

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing a cyanobenzene compound through C-F bond cleavage of aryl fluoride. Aiming at the challenges that a traditional cyanide method is high in toxicity and difficult in C-F bond activation and an existing catalytic system is poor in stability, low in selectivity and the like in a water generation environment, a hydrophobic microenvironment is constructed by introducing a copper-boron intercalated hydrotalcite catalyst, so that the problems that a boron reagent is inactivated by hydrolysis and catalytic active sites are interfered by water are effectively solved; the method has the advantages that the high-selectivity synthesis of target products is realized, the use of highly toxic cyanides is successfully avoided, and a novel clean production way with a great prospect is provided for the efficient conversion of aryl fluorides in the fields of medicines, materials, fine chemicals and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage. Background Technology

[0002] Aryl nitrile compounds are important intermediates in organic synthesis, widely used in pharmaceuticals, pesticides, dyes, polymer materials, and fine chemicals. Traditional methods for preparing aryl nitrile compounds, such as introducing cyanide groups through the reaction of aryl halides with highly toxic metal cyanides (e.g., NaCN, KCN), while efficient, generally suffer from significant drawbacks including high toxicity of raw materials, high operational risks, harsh reaction conditions, and severe environmental pollution, severely restricting their widespread application in industrial production. Furthermore, the preparation of aryl nitrile compounds through the oxidative amination or dehydration of aromatic aldehydes or oximes also suffers from poor raw material versatility, numerous reaction steps, and complex byproducts. Therefore, developing an environmentally friendly, safe, efficient, and simple non-cyanide method for preparing aryl nitrile compounds has always been a hot topic and a challenging research area in chemistry.

[0003] In recent years, utilizing carbon and nitrogen sources to replace traditional highly toxic cyanides to achieve the breaking of aryl CF bonds (CF bond activation) and the introduction of cyano groups to synthesize aryl nitrile has attracted widespread attention from researchers because it avoids the toxicity of cyanide and allows for the easy introduction of aryl fluorides during synthesis. The CF bond is one of the most energy-intensive and stable chemical bonds among carbon-halogen bonds, and its activation and breaking are challenging. It typically requires harsh conditions such as strong bases, high temperatures, or transition metal catalysts. Currently, transition metal catalytic systems, especially copper catalysts, are considered a potential alternative to the traditional cyanide route due to their relatively low cost, low toxicity, and ability to effectively activate CF bonds. However, existing copper catalytic systems still face many challenges in achieving CF bond breaking and cyanidation reactions.

[0004] First, in non-cyanide cyanidation reactions, commonly used carbon and nitrogen sources (such as ammonium bicarbonate and formamide) may decompose or exist under reaction conditions, inevitably producing water. The presence of water poses a significant challenge to many transition metal catalysts, particularly boron reagent-based catalytic systems. Water molecules readily deactivate catalyst active sites and hydrolyze boron reagents, severely reducing reaction selectivity and conversion. For example, boron reagents, as important co-catalysts or reducing agents, readily hydrolyze in hydrophilic environments, losing activity and leading to catalytic cycle interruption or a significant decrease in efficiency. This makes achieving efficient and stable CF bond-activated cyanidation reactions in aqueous systems particularly difficult.

[0005] Secondly, many existing copper catalysts are prone to aggregation or leaching during reaction cycles, leading to loss of catalyst activity, shortened lifespan, and difficulty in effective recovery and reuse. This significantly increases production costs and generates secondary pollution. To improve catalyst stability, researchers have attempted to load homogeneous catalysts onto heterogeneous supports to achieve catalyst recovery and reuse. However, traditional loading methods often suffer from problems such as uneven dispersion of active components, limited loading capacity, or susceptibility of active sites to damage when exposed to solvents.

[0006] Furthermore, even with supported catalysts, in complex reaction systems, especially when multiple active components (such as copper, boron, carbon, and nitrogen sources) are present, precisely controlling the synergistic effects between these components and avoiding unnecessary side reactions (such as substrate dehalogenation, intermediate hydrolysis, and cyano self-coupling) to achieve selective synthesis of the target product remains a pressing problem. Homogeneous systems, lacking spatial constraints, allow various active species to exist in a state of disordered Brownian motion, making highly active catalytic species prone to initiating side reactions and resulting in poor chemoselectivity. Therefore, achieving precise spatial isolation and control of reactants and catalyst active sites within the microstructure of heterogeneous catalysts to improve reaction selectivity is a key technological bottleneck currently facing research.

[0007] In summary, current methods for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage still face significant technical challenges in terms of catalyst stability, selectivity, effective utilization of boron reagents, and adaptability to aqueous environments. There is an urgent need to develop a novel heterogeneous catalytic system with excellent resistance to hydrolysis and high selectivity control. Summary of the Invention

[0008] In view of this, the purpose of this invention is to provide a method for preparing benzonitrile compounds by CF bond cleavage of aryl fluorides, in order to solve the problems faced by the method of preparing benzonitrile by CF bond cleavage of aryl fluorides, such as poor catalyst stability in the aqueous generation environment, low selectivity, easy deactivation of boron reagent and difficulty in recovery.

[0009] To achieve the above objectives, the present invention provides a method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, comprising the following steps: S1: Magnesium aluminum carbonate root-type hydrotalcite powder is dispersed in formamide solution and subjected to ultrasonic treatment to peel off the layers and expose the interlayer hydroxyl sites; then it is centrifuged and washed to remove surface impurities, resulting in a clean single-layer hydrotalcite colloidal slurry; S2: Copper trifluoromethanesulfonate was added to the single-layer hydrotalcite colloidal slurry obtained in S1. The mixture was stirred and the copper active sites were localized on the surface of the inorganic layer by the coordination of copper ions with the hydroxyl groups on the layer surface. Boric acid was then added and the pH of the system was adjusted to alkaline so that the boron source was converted into anions and entered the interlayer through electrostatic attraction to complete the pre-assembly. Then, ethyl acetate containing hydroxyl-terminated polydimethylsiloxane was added and tetraethyl orthosilicate was added as a crosslinking agent. Under stirring conditions, a hydrophobic polymer silicone oil film was constructed on the periphery of the layer by dehydration condensation reaction. Finally, the system was dried and granulated to obtain microspherical solid powder. S3: Under an inert atmosphere, pinacol diborate was dissolved in n-hexane and added dropwise onto microsphere solid powder using an equal-volume impregnation method. After the solvent evaporated, a copper-boron intercalated hydrotalcite catalyst with active boron species inside and an anti-hydrolysis organosilicon protective layer on the outside was obtained. S4: An aryl fluoride substrate, a copper-boron intercalated hydrotalcite catalyst, a ligand, an inorganic base, and a nitrogen source are loaded into a reaction vessel. The reaction system is evacuated to remove air and then filled with Freon. Subsequently, the reaction solvent is added, and the mixture is stirred under heating conditions. After the reaction is completed, the product is separated and purified to obtain benzonitrile compounds. The reaction principle is as follows:

[0010] The ratio of magnesium aluminum carbonate hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, tetraethyl orthosilicate, and pinacol diboronate is 8-12g:400-600mg:1.5-2.5g:0.8-1.2mL:4-6g.

[0011] Preferably, the ultrasonic treatment in step S1 has a power of 400-600W and a treatment time of 3-5h.

[0012] Preferably, the washing process in step S1 involves washing three times with anhydrous ethanol.

[0013] Preferably, the pH value is adjusted to 8-10 in step S2, and sodium hydroxide solution is preferably used for adjustment.

[0014] Preferably, the drying and granulation method is spray drying, and the inlet air temperature is 140-160℃.

[0015] Preferably, the organic solvent in step S4 is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and 1,4-dioxane.

[0016] Preferably, the reaction temperature in step S4 is 50-150℃ and the reaction time is 1-24h.

[0017] Preferably, the molar ratio of ammonium bicarbonate to aryl fluoride in step S4 is 1:1 to 5:1.

[0018] Preferably, the molar ratio of Freon to aryl fluoride in step S4 is 1:1 to 10:1.

[0019] Preferably, the amount of catalyst used in step S4 is 10 mol based on copper content.

[0020] Preferably, the ligand in step S4 is 2,2'-bipyridine, and the amount used is 10 mol.

[0021] Preferably, the inorganic base in step S4 is cesium carbonate, and the amount used is 5 equiv.

[0022] Preferably, the separation and purification method in step S4 is vacuum concentration followed by rapid silica gel column chromatography, with the eluent being a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:30.

[0023] The beneficial effects of this invention are: This invention innovatively introduces a hydrophobic cross-linked organosilicon protective layer, significantly altering the wetting kinetics of the catalyst surface. By constructing an effective water-repellent barrier around the hydrophilic inorganic layers, the catalyst cleverly repels water molecules from the bulk solution outside the catalyst, thereby creating a highly anhydrous microenvironment within the interlayer microreactor of the catalyst. This unique structural design successfully solves the problems of easy hydrolysis and deactivation of boron reagents and interference with catalyst active sites by water in aqueous or water-generating reaction systems. It greatly ensures the efficient and selective conduction of CF bond breaking and cyanation reactions, effectively suppressing side reactions such as substrate dehalogenation and intermediate hydrolysis, thus achieving high-yield synthesis of the target product.

[0024] This invention utilizes tetraethyl orthosilicate-mediated chemical crosslinking to anchor the hydrophobic shell, forming a robust covalent network between the organosilicon segments and the hydroxyl groups on the inorganic layer surface. This stable chemical bonding endows the hydrophobic shell with excellent density and integrity under harsh reaction conditions. Compared to simple physical adsorption or non-crosslinked structures, chemical crosslinking significantly restricts the thermal motion of polymer segments, ensuring the structural stability of the hydrophobic protective layer in harsh reaction environments such as long-term exposure and high temperatures. This provides long-lasting and robust protection for the internal active centers, greatly extending the catalyst's lifespan and cycle stability.

[0025] This invention employs a sophisticated boron species pre-assembly strategy, introducing boron species into the interlayer of a layered double hydroxide (LDH) via electrostatic attraction, followed by a hydrophobic outer shell. This internally loaded active boron species design effectively locks the boron species within a protected nanospace. This ingenious spatial isolation not only effectively prevents external water molecules or interfering reagents from eroding and hydrolyzing the boron species, but also potentially utilizes the electrostatic field of the LDH layers to stabilize the active copper-boron intermediate. This allows the boron species to more specifically and efficiently assist the copper active sites in attacking stable CF bonds, thereby significantly improving the effective conversion efficiency of the reaction, ensuring maximum utilization of the boron reagent, and avoiding the waste of boron reagent in traditional methods.

[0026] The copper-boron intercalated layered double hydroxide catalyst constructed in this invention achieves precise control over the challenging CF bond breaking cyanation reaction pathway through meticulous micro / nano structure design. Unlike homogeneous systems where active components exist in a disordered Brownian motion state, the heterogeneous catalyst provided by this invention effectively confines and regulates the copper active sites, boron species, and reactants in space. This effectively avoids common problems in homogeneous systems, such as the side reactions of substrate dehalogenation catalyzed by highly active copper species or the self-coupling of cyano species, thus achieving chemoselectivity far exceeding that of traditional homogeneous systems. This spatial effect based on the principle of heterogeneous catalysis is key to achieving efficient and highly selective CF bond activation cyanation reactions.

[0027] The catalyst of this invention exists in the form of microspherical solid powder, which is easily recovered by simple mechanical separation methods such as centrifugation or filtration. This greatly simplifies the post-processing and reuse of the catalyst, reduces production costs, and aligns with the principles of green chemistry. Simultaneously, this catalytic system avoids the use of highly toxic metal cyanides, employing readily available ammonium bicarbonate and Freon as carbon and nitrogen sources, significantly improving the safety and environmental friendliness of the reaction and opening up new avenues for the clean production of aryl nitrile compounds. This invention possesses significant advantages such as readily available raw materials, simple operation, environmental friendliness, high catalytic efficiency, strong selectivity, and good cycle stability. It is suitable for the efficient conversion of various aryl fluorides and has broad application prospects in high-value-added fields such as pharmaceuticals and materials. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in this invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. Figure 1 The 1H NMR spectrum of 4-methoxybenzonitrile prepared in Example 2 of this invention; Figure 2 The carbon NMR spectrum of 4-methoxybenzonitrile prepared in Example 2 of this invention; Figure 3This is a schematic diagram showing the number of cycles for the catalysts in the embodiments and comparative examples of the present invention. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0030] This invention provides a method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, comprising the following steps: (1) The magnesium aluminum carbonate type hydrotalcite powder was dispersed in a formamide solution and subjected to ultrasonic treatment to peel off the layers and expose the interlayer hydroxyl sites; then it was centrifuged and washed to remove surface impurities, and a clean single-layer hydrotalcite colloidal slurry was obtained. (2) Copper trifluoromethanesulfonate was added to the single-layer hydrotalcite colloidal slurry obtained in S1. The copper active sites were localized on the surface of the inorganic layer by the coordination of copper ions with the hydroxyl groups on the layer surface. Boric acid was then added and the pH of the system was adjusted to alkaline so that the boron source was converted into anions and entered the interlayer through electrostatic attraction to complete the pre-assembly. Then, ethyl acetate with hydroxyl-terminated polydimethylsiloxane alcohol was added and tetraethyl orthosilicate was added as a crosslinking agent. Under stirring conditions, a hydrophobic polymer silicone oil film was constructed on the periphery of the layer by dehydration condensation reaction. Finally, the system was dried and granulated to obtain microsphere solid powder. (3) Under an inert atmosphere, pinacol diboron was dissolved in n-hexane and added dropwise onto microsphere solid powder by equal volume impregnation. After the solvent evaporated, a copper-boron intercalated hydrotalcite catalyst with active boron species inside and an anti-hydrolysis organosilicon protective layer outside was obtained. (4) Aryl fluoride substrate, copper-boron intercalated hydrotalcite catalyst, ligand, inorganic base and nitrogen source are loaded into the reaction vessel; the reaction system is evacuated to remove air and filled with Freon, then the reaction solvent is added, the mixture is stirred under heating conditions, and after the reaction is completed, the product is separated and purified to obtain benzonitrile compounds. The ratio of magnesium aluminum carbonate type hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, ethyl orthosilicate, and pinacol diborate is 8g:400mg:1.5g:0.8mL:4g, specifically, it can be 10g:500mg:2g:1mL:5g; the ratio of magnesium aluminum carbonate type hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, ethyl orthosilicate, and pinacol diborate is 10g:500mg:2g:1mL:5g. The ratio of alcohol esters used is 12g:600mg:2.5g:1.2mL:6g; the ratio of magnesium aluminum carbonate type hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, ethyl orthosilicate, and pinacol diborate is 9g:450mg:1.8g:0.9mL:4.5g; the ratio of magnesium aluminum carbonate type hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, ethyl orthosilicate, and pinacol diborate is 11g:550mg:2.3g:1.1mL:5.5g. The ratio of magnesium aluminum carbonate hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, tetraethyl orthosilicate, and pinacol diboronate is 12g:600mg:1.5g:1.2mL:4g.

[0031] Regarding step (1): In this invention, the power of the ultrasonic treatment is preferably 400-600W, specifically 400W, 450W, 500W, 550W, or 600W; the treatment time is preferably 3-5 hours, specifically 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours.

[0032] Regarding step (2): The pH value is adjusted to 8-10, specifically 8, 8.5, 9, 9.5, or 10; preferably, a sodium hydroxide solution is used for adjustment.

[0033] The drying and granulation method is spray drying, and the inlet air temperature is 140-160℃, specifically 140℃, 145℃, 150℃, 155℃, or 160℃.

[0034] Regarding step (4): The reaction principle is as follows: .

[0035] The organic solvent is selected from one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and 1,4-dioxane; specifically, it may be N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or 1,4-dioxane.

[0036] The molar ratio of ammonium bicarbonate to aryl fluoride is 1:1 to 5:1, specifically, it can be 1:1, 2:1, 3:1, 4:1, or 5:1.

[0037] The molar ratio of Freon to aryl fluoride is 1:1, specifically, it can be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[0038] The catalyst dosage, based on copper content, is 10 mol%. The ligand is 2,2'-bipyridine, and the amount used is 10 mol%. The inorganic base is cesium carbonate, and the dosage is 5 equiv. The separation and purification method is vacuum concentration followed by rapid silica gel column chromatography, with the eluent being a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:30.

[0039] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples: The sources or properties of the raw materials used in the embodiments and comparative examples of this invention are as follows: Magnesium aluminum carbonate root-type hydrotalcite powder: purchased from Sigma-Aldrich, model number 634075; sodium hydroxide solution: mass fraction 10%; hydroxyl-terminated polydimethylsiloxane alcohol: purchased from Dow Corning, model number DC1501.

[0040] Example 1: A method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, the specific steps of which are as follows: (1) Take 8g of magnesium aluminum carbonate type hydrotalcite powder and disperse it in a three-necked flask containing 800mL of formamide solution. Treat it for 3h under ultrasonic power of 400W to peel off the layer and expose the interlayer hydroxyl sites. Then, centrifuge and wash it 3 times with anhydrous ethanol to remove the surface adsorbed impurities to obtain a single layer hydrotalcite colloidal slurry. (2) Add 400 mg of copper trifluoromethanesulfonate to the single-layer hydrotalcite colloidal slurry and stir at room temperature for 1.5 h. Utilize the coordination effect of copper ions with the hydroxyl groups on the surface of the layer to localize the copper active sites on the surface of the inorganic layer. Then add 1.5 g of boric acid and add sodium hydroxide solution to adjust the pH of the system to 8. Stir for 5 h to convert boric acid into borate anions and enter the hydrotalcite interlayer through electrostatic attraction to complete the pre-assembly. Then take another 2.5 g of hydroxyl-terminated polydimethylsiloxane alcohol and dissolve it in 40 mL of ethyl acetate. Then slowly add it to the reaction system. At the same time, add 0.8 mL of tetraethyl orthosilicate as a crosslinking agent. Under vigorous stirring, utilize the hydroxyl groups at the end of the hydroxyl-terminated polydimethylsiloxane alcohol molecules to undergo a dehydration condensation reaction with the hydroxyl groups at the edge of the hydrotalcite layer to enrich and crosslink the hydrophobic polymer silicone oil segments on the periphery of the hydrophilic inorganic layer to form a film. The resulting system is dried and granulated by spray dryer at an air inlet temperature of 140 °C to obtain microsphere solid powder. (3) Weigh 4g of pinacol diborate in an argon-filled glove box and dissolve it in 15mL of n-hexane. Add it dropwise onto the microsphere solid powder using the equal volume impregnation method. After the solvent evaporates, a copper-boron intercalated hydrotalcite catalyst with active boron species inside and an anti-hydrolysis organosilicon protective layer on the outside is obtained. (4) In a dry Schlenk tube, p-methoxyfluorobenzene (0.2 mmol, 1 equiv), copper-boron intercalated hydrotalcite catalyst (50 mg, equivalent to 10 mol% Cu), 2,2'-bipyridine (10 mol%), cesium carbonate (5 equiv), and NH4HCO3 (5 equiv) were loaded. The Schlenk tube was then evacuated to remove air and filled with a difluorochloromethane balloon. N,N-dimethylacetamide (2.0 mL) was added using a syringe. The mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the reaction mixture was concentrated under vacuum and the target product 4-methoxybenzonitrile was obtained by rapid silica gel column chromatography (silica gel, ethyl acetate: petroleum ether ratio of 1:30, v / v).

[0041] Example 2: A method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, the specific steps of which are as follows: (1) Take 10g of magnesium aluminum carbonate type hydrotalcite powder and disperse it in a three-necked flask containing 1000mL of formamide solution. Treat it for 4h under ultrasonic power of 500W to peel off the layer and expose the interlayer hydroxyl sites. Then, centrifuge and wash three times with anhydrous ethanol to remove surface adsorbed impurities to obtain a single layer hydrotalcite colloidal slurry. (2) Add 500 mg of copper trifluoromethanesulfonate to the single-layer hydrotalcite colloidal slurry and stir at room temperature for 2 h. Utilize the coordination effect of copper ions with the hydroxyl groups on the surface of the layer to localize the copper active sites on the surface of the inorganic layer. Then add 2 g of boric acid and add sodium hydroxide solution to adjust the pH of the system to 9. Stir for 6 h to convert boric acid into borate anions and enter the hydrotalcite interlayer through electrostatic attraction to complete the pre-assembly. Then take another 3 g of hydroxyl-terminated polydimethylsiloxane alcohol and dissolve it in 50 mL of ethyl acetate. Then slowly add it to the reaction system. At the same time, add 1 mL of tetraethyl orthosilicate as a crosslinking agent. Under vigorous stirring, utilize the hydroxyl groups at the end of the hydroxyl-terminated polydimethylsiloxane alcohol molecules to undergo a dehydration condensation reaction with the hydroxyl groups at the edge of the hydrotalcite layer. This allows the hydrophobic polymer silicone oil segments to accumulate and crosslink into a film on the periphery of the hydrophilic inorganic layer. The resulting system is dried and granulated by a spray dryer at an inlet air temperature of 150 °C to obtain microsphere solid powder. (3) Weigh 5g of pinacol diborate in an argon-filled glove box and dissolve it in 20mL of n-hexane. Add it dropwise onto the microsphere solid powder using the equal volume impregnation method. After the solvent evaporates, a copper-boron intercalated hydrotalcite catalyst with active boron species inside and an anti-hydrolysis organosilicon protective layer on the outside is obtained. (4) In a dry Schlenk tube, p-methoxyfluorobenzene (0.2 mmol, 1 equiv), copper-boron intercalated hydrotalcite catalyst (50 mg, equivalent to 10 mol% Cu), 2,2'-bipyridine (10 mol%), cesium carbonate (5 equiv), and NH4HCO3 (5 equiv) were loaded. The Schlenk tube was then evacuated to remove air and filled with a difluorochloromethane balloon. N,N-dimethylacetamide (2.0 mL) was added using a syringe. The mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the reaction mixture was concentrated under vacuum and the target product 4-methoxybenzonitrile was obtained by rapid silica gel column chromatography (silica gel, ethyl acetate: petroleum ether ratio of 1:30, v / v).

[0042] Example 3: A method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, the specific steps of which are as follows: (1) Take 12g of magnesium aluminum carbonate type hydrotalcite powder and disperse it in a three-necked flask containing 1200mL of formamide solution. Treat it for 5h under ultrasonic power of 600W to peel off the layer and expose the interlayer hydroxyl sites. Then, centrifuge and wash three times with anhydrous ethanol to remove surface adsorbed impurities to obtain a single layer hydrotalcite colloidal slurry. (2) Add 600 mg of copper trifluoromethanesulfonate to the single-layer hydrotalcite colloidal slurry and stir at room temperature for 2.5 h. Utilize the coordination effect of copper ions with the hydroxyl groups on the surface of the layer to localize the copper active sites on the surface of the inorganic layer. Then add 2.5 g of boric acid and add sodium hydroxide solution to adjust the pH of the system to 10. Stir for 7 h to convert boric acid into borate anions and enter the hydrotalcite interlayer through electrostatic attraction to complete the pre-assembly. Then take another 3.5 g of hydroxyl-terminated polydimethylsiloxane alcohol and dissolve it in 60 mL of ethyl acetate. Then slowly add it to the reaction system. At the same time, add 1.2 mL of tetraethyl orthosilicate as a crosslinking agent. Under vigorous stirring, utilize the hydroxyl groups at the end of the hydroxyl-terminated polydimethylsiloxane alcohol molecules to undergo a dehydration condensation reaction with the hydroxyl groups at the edge of the hydrotalcite layer. This allows the hydrophobic polymer silicone oil segments to accumulate and crosslink into a film on the periphery of the hydrophilic inorganic layer. The resulting system is dried and granulated by a spray dryer at an inlet air temperature of 160 °C to obtain microsphere solid powder. (3) Weigh 6g of pinacol diborate in an argon-filled glove box and dissolve it in 25mL of n-hexane. Add it dropwise onto the microsphere solid powder using the equal volume impregnation method. After the solvent evaporates, a copper-boron intercalated hydrotalcite catalyst with active boron species inside and an anti-hydrolysis organosilicon protective layer on the outside is obtained. (4) In a dry Schlenk tube, p-methoxyfluorobenzene (0.2 mmol, 1 equiv), copper-boron intercalated hydrotalcite catalyst (50 mg, equivalent to 10 mol% Cu), 2,2'-bipyridine (10 mol%), cesium carbonate (5 equiv), and NH4HCO3 (5 equiv) were loaded. The Schlenk tube was then evacuated to remove air and filled with a difluorochloromethane balloon. N,N-dimethylacetamide (2.0 mL) was added using a syringe. The mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the reaction mixture was concentrated under vacuum and the target product 4-methoxybenzonitrile was obtained by rapid silica gel column chromatography (silica gel, ethyl acetate: petroleum ether ratio of 1:30, v / v).

[0043] Comparative Example 1: The difference from Example 2 is that hydroxyl-terminated polydimethylsiloxane alcohol, ethyl acetate and tetraethyl orthosilicate are not added in step (2), and the conditions are the same as in Example 2.

[0044] Comparative Example 2: The difference from Example 2 is that tetraethyl orthosilicate is not added as a crosslinking agent in step (2), and the conditions are the same as in Example 2.

[0045] Comparative Example 3: The difference from Example 2 is that the loading in step (3) is not performed, and pinacol diboron is directly added in step (4), while the conditions are the same as in Example 2.

[0046] Comparative Example 4: The difference from Example 2 is that in step (4), copper-boron intercalated hydrotalcite catalyst is not added, but pinacol diborate and copper acetate (10 mol%) are added directly, and the conditions are the same as in Example 2.

[0047] Performance testing Conversion / Yield: The procedure was performed according to GB / T 23296.1-2009 "Determination of Benzonitrile Compounds by Gas Chromatography" and the general internal standard method for quantification. The specific procedures are as follows: After the reactions described in Examples 1-3 and Comparative Examples 1-4 were completed, the reaction mixture was cooled to room temperature. 20 mg of biphenyl was accurately added to the reaction system as a gas chromatographic internal standard, diluted with 5 mL of ethyl acetate, and ultrasonically vibrated for 5 min to ensure homogeneity. 1 μL of the supernatant was injected into a gas chromatograph equipped with an FID detector and an HP-5 capillary column. The chromatographic conditions were set as follows: injection port temperature 250 °C, detector temperature 280 °C; the temperature program was: initial temperature 60 °C, held for 2 min, increased to 250 °C at a rate of 15 °C / min, and held for 5 min. Based on the ratio of the peak area of ​​the internal standard biphenyl to the peak area of ​​the target product 4-methoxybenzonitrile, the conversion rate and yield of the reaction were calculated by substituting the pre-prepared standard curve correction factor into the ratio. Cyclic stability: The cycling test logic was followed according to GB / T 31590-2015 "Test Method for Activity of Hydrogenation Catalysts After Regeneration". The specific operation is as follows: First-round reaction: The first catalytic reaction was carried out under the conditions described in Example 1 (scaled up 5 times, i.e., substrate 1.0 mmol, to facilitate subsequent recovery operations). Catalyst recovery: After the reaction is complete, the reaction mixture is transferred to a centrifuge tube and centrifuged at 8000 rpm for 10 min. The supernatant is carefully discarded (the supernatant is used for GC analysis of yield). Cleaning and regeneration: The solid precipitate is first washed twice with anhydrous ethanol, and then once with n-hexane to thoroughly remove residual organic products and high-boiling-point solvents. Note: Aqueous solvents must not be used during the washing process, and the operation must be rapid to reduce the time the catalyst is exposed to air. Drying and reloading (key): The cleaned wet solids are dried in a vacuum drying oven at 60°C for 4 hours. Given that the boron reagent is a consumable or easily lost component in the reaction mechanism, before each cycle, the theoretically consumed amount of pinacol diborate is added to the recovered solid powder according to the equal volume impregnation method described in step (3) of Example 1. Cyclic reaction: The dried recovered catalyst is put back into the Schlenk tube, and fresh p-methoxyfluorobenzene, ligand, base and solvent are added according to the proportions of the examples and comparative examples to carry out the next round of reaction; Data recording: After repeating the above steps 5 times, record the yield of the target product each time and calculate the yield retention rate.

[0048] Table 1 Performance Test Results Conversion rate (%) Yield (%) Example 1 86.5 85.4 Example 2 87.2 86.9 Example 3 86.8 85.9 Comparative Example 1 84.5 80.4 Comparative Example 2 85.1 81.8 Comparative Example 3 84.8 81.2 Comparative Example 4 86.5 80.1 Data Analysis: The copper-boron intercalated layered double hydroxide catalyst with a hydrophobic cross-linked shell prepared in this invention exhibits excellent catalytic efficiency and extremely high reaction selectivity in the cyanation reaction of aryl fluorides using ammonium bicarbonate and Freon as carbon and nitrogen sources. This characteristic indicates that although the decomposition of ammonium bicarbonate in the reaction system inevitably produces water molecules, the catalyst system of this invention greatly suppresses the occurrence of side reactions (such as substrate dehalogenation or intermediate hydrolysis) and avoids the safety hazards of using highly toxic metal cyanides in traditional methods. It has the advantages of readily available raw materials, simple operation, and environmental friendliness, and is suitable for the efficient conversion of various aryl fluorides, showing broad application prospects in the fields of medicine and materials.

[0049] As can be seen from the data in Table 1 for Example 2 and Comparative Example 1, in the absence of a hydrophobic protective layer constructed from terminal hydroxyl polydimethylsiloxane alcohol and tetraethyl orthosilicate, although the conversion rate of the reaction decreased only slightly compared to Example 2, the yield of the target product showed a significant drop. This significant difference in data reveals that the hydrophobic interface modification plays a decisive role in the chemoselectivity control of the ammonium bicarbonate-involved cyanation system. It is speculated that this is because the introduction of organosilicon hydrophobic segments significantly altered the wetting kinetics of the catalyst surface, constructing an effective water-repellent barrier that forces water molecules to remain in the bulk solution outside the catalyst, thereby ensuring an anhydrous environment within the interlayer microreactor and ensuring the efficient execution of CF bond breaking and the cyanation reaction.

[0050] As can be seen from the data in Example 2 and Comparative Example 2 in Table 1, tetraethyl orthosilicate-mediated chemical crosslinking anchoring is a key technical feature for constructing a robust protective layer. It is speculated that this is because the use of tetraethyl orthosilicate as a crosslinking agent promotes the dehydration condensation of the organosilicon segments with the hydroxyl groups on the surface of the inorganic layer, forming a strong covalent bond network. This chemical bonding restricts the thermal motion of the polymer segments, maintaining the density and integrity of the hydrophobic shell under harsh reaction conditions, thereby achieving durable and stable protection for the active center.

[0051] As can be seen from the data in Example 2 and Comparative Example 3 in Table 1, changing the way the boron source is introduced plays an irreplaceable role in improving catalytic efficiency. It is speculated that this is because introducing boron species into the interlayer of the hydrotalcite through electrostatic attraction, followed by a hydrophobic outer shell, effectively locks the boron species within a protected nanoscale space. This structure not only isolates external interfering reagents but may also utilize the electrostatic field of the layers to stabilize the active copper-boron intermediate, allowing the boron species to specifically assist copper sites in attacking the CF bond, thereby significantly improving the effective conversion efficiency of the reaction.

[0052] As can be seen from the data in Example 2 and Comparative Example 4 in Table 1, in a homogeneous system, the copper salt, boron reagent, substrate, and in-situ generated active cyano species are in a state of disordered Brownian motion, lacking spatial constraints. This leads to the highly active copper species easily catalyzing the dehalogenation side reaction of the substrate, or the cyano species undergoing self-coupling. However, this invention, through precise micro / nano structure design, achieves accurate control over the challenging CF bond breaking cyanidation reaction pathway, thereby obtaining chemoselectivity far exceeding that of traditional homogeneous systems.

[0053] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A method for preparing benzonitrile compounds from aryl fluorides via CF bond cleavage, characterized in that, Includes the following steps: S1: Magnesium aluminum carbonate root-type hydrotalcite powder is dispersed in formamide solution and ultrasonically treated to obtain a single-layer hydrotalcite colloidal slurry; S2: Add copper trifluoromethanesulfonate to a single-layer hydrotalcite colloidal slurry, followed by boric acid, hydroxyl-terminated polydimethylsiloxane alcohol and tetraethyl orthosilicate, and then dry and granulate to obtain microspherical solid powder. S3: Under an inert atmosphere, pinacol diborate was impregnated onto microsphere solid powder using an equal-volume impregnation method to obtain a copper-boron intercalated hydrotalcite catalyst. S4: An aryl fluoride is added as a substrate to a reaction vessel, along with a copper-boron intercalated hydrotalcite catalyst, a ligand, an inorganic base, and ammonium bicarbonate. The reaction is carried out under a Freon atmosphere with heating and stirring to obtain benzonitrile compounds. The reaction principle is as follows: 。 2. The method according to claim 1, characterized in that, The ratio of magnesium aluminum carbonate hydrotalcite powder, copper trifluoromethanesulfonate, boric acid, tetraethyl orthosilicate, and pinacol diboronate is 8-12g:400-600mg:1.5-2.5g:0.8-1.2mL:4-6g.

3. The method according to claim 1, characterized in that, The ultrasonic treatment in step S1 has a power of 400-600W and a treatment time of 3-5 hours.

4. The method according to claim 1, characterized in that, The drying and granulation method described in step S2 is spray drying, with an inlet air temperature of 140-160℃.

5. The method according to claim 1, characterized in that, The organic solvent used in the heating and stirring reaction in step S4 is selected from one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, and 1,4-dioxane.

6. The method according to claim 1, characterized in that, The reaction temperature in step S4 is 50-150℃, and the reaction time is 1-24h.

7. The method according to claim 1, characterized in that, In step S4, the molar ratio of ammonium bicarbonate to aryl fluoride is 1:1-5:1; the molar ratio of Freon to aryl fluoride is 1:1-10:

1.

8. The method according to claim 1, characterized in that, In step S4, the amount of catalyst used is 10 mol based on copper content; the ligand is 2,2'-bipyridine, and the amount used is 10 mol; the inorganic base is cesium carbonate, and the amount used is 5 equiv.

9. The method according to claim 1, characterized in that, The separation and purification method described in step S4 is vacuum concentration followed by rapid silica gel column chromatography, with the eluent being a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:

30.

10. The method according to claim 1, characterized in that, Used to prepare pharmaceutical intermediates, liquid crystal materials, or organic light-emitting materials.

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