Process for the preparation of benzimidazole compounds

Abstract

The application relates to the field of organic chemical synthesis, in particular to a preparation method of a benzimidazole compound. The preparation method uses aryl halide, o-phenylenediamine and carbon dioxide as starting materials, and in a reaction system composed of a palladium metal catalyst, an organic ligand, a reducing agent, an alkaline medium and an organic solvent, a benzimidazole target product can be obtained through a one-step carbonylation process under heating. The synthesis route fully utilizes carbon dioxide as a source of abundant, safe, low-toxic and recyclable carbonyl, and realizes efficient construction of the target molecule. The overall process exhibits the characteristics of easy control of reaction conditions, high selectivity of target product and simple operation process, and at the same time, the dependence on various high-pressure gas materials is abandoned. In addition, the carbon source used in the method is outstanding in economy, the substrate is widely applicable, the raw materials are convenient to obtain, the production cost is controllable, and the method has good industrialization popularization potential.

Description

Technical Field

[0001] This application relates to the field of organic chemical synthesis, specifically to a method for preparing benzimidazole compounds. Background Technology

[0002] Benzimidazoles are an important class of heterocyclic compounds, whose homologues and derivatives are formed by the fusion of a benzene ring and an imidazole ring. This structural unit is widely found in many natural products, such as vitamin B1. 12 It also contains benzimidazole and its related derivatives; it is the core active fragment of cardiotonic agents such as pimobenne and diphenyldiene, and plays a key role in the efficacy of various antitumor and antiulcer drugs. Furthermore, due to their excellent thermal stability, benzimidazole derivatives are widely used in the backbone construction of high-performance, high-temperature resistant polymers.

[0003] From a synthetic perspective, traditional routes typically rely on the condensation cyclization process between benzoic acid and its derivatives and o-diamino aromatics. Inspired by the synthetic strategy of 2-arylimidazoline (J. Org. Chem. 2013, 78, 4158-4164), researchers have developed a novel one-pot route for the preparation of 2-phenylbenzimidazole. This strategy uses isonitriles as the key one-carbon synthon, providing a novel retrosynthetic approach distinct from the classic "carboxylic acid-diamine" condensation mode.

[0004] Carbonylation reactions have long been a focus of synthetic chemistry due to their outstanding atom economy and ability to efficiently construct high-value-added carbonyl-containing compounds. In recent years, using aryl halides as substrates, employing palladium-catalyzed carbonylation processes, and utilizing carbon monoxide as the carbon-1 source to achieve intramolecular cyclization has become a common route for constructing heterocyclic compounds. Eshetu Kebede and his collaborators (Eur. J. Org. Chem. 2015, 5929-5933) further utilized metal carbonyl complexes (such as Mo(CO)5) instead of gaseous CO as the carbon-1 supply source. This method exhibits good adaptability to a variety of substrates while avoiding the operational risks of directly using toxic CO gas.

[0005] However, this approach still faces certain limitations in practical applications. On the one hand, the reaction conditions are quite stringent, typically requiring heating to above 150°C. On the other hand, although it eliminates the dependence on palladium metal, the toxicity of the metal carbonyl complex used cannot be ignored, and molybdenum hexacarbonyl may decompose and release CO gas at high temperatures, posing potential environmental hazards. These shortcomings limit the scope for wider application of this method, especially in industrial-scale production scenarios. Summary of the Invention

[0006] To address the aforementioned technical problems, this application provides a method for preparing benzimidazole compounds. Carbon dioxide, as an ideal C1 building block, possesses significant advantages such as low cost, safety, non-toxicity, and renewable resources. Using it as a carbonyl source for the carbonylation of benzimidazole compounds has significant economic and environmental value. This method uses o-phenylenediamine and its derivatives, aryl halides, and carbon dioxide as reaction substrates. Under the catalytic action of a palladium metal and organophosphine ligand synergistically composed catalytic system, benzimidazole homologues and their derivatives can be obtained through a one-step carbonylation operation. This synthetic route features readily available and cost-effective raw materials, exhibits good selectivity and high conversion efficiency, and has a simple process flow, effectively reducing the overall synthesis cost and possessing the potential for large-scale industrial production.

[0007] To achieve the above objectives, this application adopts the following technical solution:

[0008] First, this application provides a method for preparing benzimidazole compounds, comprising the following steps:

[0009] Using aryl halides of formula (I), o-phenylenediamine compounds of formula (II), and carbon dioxide as reactants, the reaction is carried out under the conditions of palladium metal catalyst, organophosphine ligand, reducing agent, base and organic solvent to obtain benzimidazole compounds of formula (III); wherein the reaction temperature is 60℃~140℃ and the reaction time is 8h~24h.

[0010] , ,

[0011] Wherein, X is selected from halogens; R 1 Selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, naphthyl, or aryl; R 2 It is selected from hydrogen, halogen, C1~C5 alkyl, C1~C5 alkoxy or naphthyl.

[0012] The reducing agent is silane;

[0013] The organophosphorus ligand is selected from one or more monodentate phosphorus ligands and multidentate phosphorus ligands.

[0014] In some embodiments, X in formula (I) is selected from F, Br or I.

[0015] In some embodiments, R 1 It is selected from hydrogen, Cl, Br, methyl, methoxy, tert-butyl, trifluoromethyl, naphthyl or aryl.

[0016] In some embodiments, R 2It is selected from hydrogen, F, methyl, n-propyl, isopropyl or n-butyl.

[0017] In some embodiments, the organophosphine ligand is selected from one or more of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane, bis(diphenylphosphine)methane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)benzene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, bis(2-diphenylphosphine) ether, and 4,6-bis(diphenylphosphine)-10H-phenoxazine.

[0018] In some embodiments, the reducing agent is selected from phenylsilane, diphenylsilane, triethylsilane, triisopropylsilane, trimethoxysilane, or polymethylhydrosiloxane.

[0019] In some embodiments, the molar ratio of o-phenylenediamine compounds to palladium metal catalyst is 100-1000:1.

[0020] In some embodiments, the molar ratio of the o-phenylenediamine compound to the base is 0.1 to 1:1.

[0021] In some embodiments, the molar ratio of the o-phenylenediamine compound to the reducing agent is 0.1 to 1:1.

[0022] In some embodiments, the molar ratio of the ligand to the palladium metal catalyst is 1 to 10:1.

[0023] In some embodiments, the palladium metal catalyst is selected from divalent palladium compounds or coordination compounds of zero-valent palladium.

[0024] In some embodiments, the palladium metal catalyst is selected from one or more of palladium acetate, palladium dichloride, allyl palladium chloride, tetra-triphenylphosphine palladium, trifluoroacetate palladium, bis(acetonitrile) palladium dichloride, bis(triphenylphosphine) palladium dichloride, (1,5-cyclooctadiene) palladium dichloride, bis(acetylacetone) palladium, tri(dibenzylacetone) palladium, and bis(dibenzylacetone) palladium.

[0025] In some embodiments, the organic solvent is selected from dichloromethane, dichloroethane, toluene, xylene, mesitylene, chlorobenzene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, or 1,4-dioxane.

[0026] In some embodiments, the base is selected from triethylamine, ethylenediamine, isopropylamine, triethylenediamine, N-ethyldiisopropylamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5,7-triazidobicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperazine, cesium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, potassium hydroxide, or potassium phosphate.

[0027] Compared with the prior art, this application has the following beneficial effects:

[0028] Carbon dioxide is a widely available, inexpensive, non-toxic, and renewable carbon resource. Using it as a carbonyl source in the synthesis of benzimidazole compounds offers both economic benefits and environmental friendliness. This application uses o-phenylenediamine and its derivatives, iodobenzene, and carbon dioxide as starting materials. Under the catalytic action of a palladium-metal and organophosphine ligand catalysis system, benzimidazole and its derivatives can be efficiently synthesized through a one-step carbonylation process. This method features mild reaction conditions, excellent selectivity, and simple operation. It not only avoids the use of various high-pressure gases but also simplifies the traditional multi-step synthetic route into a single reaction step. Furthermore, this catalytic system exhibits high ligand selectivity, making it widely applicable to different types of aryl halides and o-phenylenediamine derivatives. It has strong substrate adaptability, readily available and low-cost raw materials, and easily controllable reaction progress, demonstrating promising prospects for industrial application. Attached Figure Description

[0029] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only some implementation methods of this application. For those skilled in the art, other drawings can be obtained based on the drawings without creative effort.

[0030] Figure 1 This is the 1H NMR spectrum of compound 1.

[0031] Figure 2 This is the 1H NMR spectrum of compound 2.

[0032] Figure 3 This is the 1H NMR spectrum of compound 3. Detailed Implementation

[0033] To make the technical problems, technical solutions and advantages of this application clearer, a detailed description will be provided below in conjunction with the accompanying drawings and specific embodiments.

[0034] In this application, DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d represents deuterated chloroform.

[0035] "equiv" indicates an equivalent amount in a chemical reaction.

[0036] In this application, room temperature refers to conditions of 20℃ to 25℃; atmospheric pressure refers to conditions of 101kPa to 102kPa.

[0037] In one embodiment, this application provides a method for preparing benzimidazole compounds, comprising the following steps:

[0038] Using aryl halides of formula (I), o-phenylenediamine compounds of formula (II), and carbon dioxide as reactants, the reaction is carried out under the conditions of palladium metal catalyst, organophosphine ligand, reducing agent, base and organic solvent to obtain benzimidazole compounds of formula (III); wherein the reaction temperature is 60℃~140℃ and the reaction time is 8h~24h.

[0039] , ,

[0040] Wherein, X is selected from halogens; R 1 Selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, naphthyl, or aryl; R 2 It is selected from hydrogen, halogen, C1~C5 alkyl, C1~C5 alkoxy or naphthyl.

[0041] As an example, the general reaction formula for preparing benzimidazole compounds using CO2 is:

[0042]

[0043] In some embodiments, X in formula (I) is selected from F, Br or I.

[0044] In some embodiments, R 1 It is selected from hydrogen, Cl, Br, methyl, methoxy, tert-butyl, trifluoromethyl, naphthyl or aryl.

[0045] In some embodiments, R 2 It is selected from hydrogen, F, methyl, n-propyl, isopropyl or n-butyl.

[0046] In some embodiments, the reducing agent is selected from phenylsilane, diphenylsilane, triethylsilane, triisopropylsilane, trimethoxysilane, or polymethylhydrosiloxane.

[0047] In some embodiments, the organophosphine ligand is selected from one or more of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane, bis(diphenylphosphine)methane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)benzene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, bis(2-diphenylphosphine) ether, and 4,6-bis(diphenylphosphine)-10H-phenoxazine.

[0048] In some embodiments, the molar ratio of the o-phenylenediamine compound to the palladium catalyst is 100 to 1000:1. As examples, the molar ratio of the o-phenylenediamine compound to the palladium catalyst can be 100:1, 150:1, 200:1, 210:1, 250:1, 500:1, 800:1, or 1000:1; other ratios within the above ranges are also possible. Preferably, the molar ratio of the o-phenylenediamine compound to the palladium catalyst is 190 to 210:1.

[0049] In some embodiments, the molar ratio of the o-phenylenediamine compound to the base is 0.1 to 1:1. As examples, the molar ratio of the o-phenylenediamine compound to the base can be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, or 1:1. More preferably, the molar ratio of the o-phenylenediamine compound to the base is 0.4 to 0.6:1.

[0050] In some embodiments, the molar ratio of the o-phenylenediamine compound to the reducing agent is 0.1 to 1:1. As an example, the molar ratio of the o-phenylenediamine compound to the reducing agent can be 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, or 1:1; or other ratios within the above range. More preferably, the molar ratio of the o-phenylenediamine compound to the reducing agent is 0.4 to 0.6:1.

[0051] In some embodiments, the molar ratio of the ligand to the palladium metal catalyst is 1 to 10:1. As examples, the molar ratio of the ligand to the palladium metal catalyst can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1; or other ratios within the above range. More preferably, the molar ratio of the ligand to the palladium metal catalyst is 1 to 3:1.

[0052] In some embodiments, the palladium metal catalyst is selected from divalent palladium compounds or coordination compounds of zero-valent palladium.

[0053] In some embodiments, the palladium metal catalyst is selected from one or more of palladium acetate, palladium dichloride, allyl palladium chloride, tetra-triphenylphosphine palladium, trifluoroacetate palladium, bis(acetonitrile) palladium dichloride, bis(triphenylphosphine) palladium dichloride, (1,5-cyclooctadiene) palladium dichloride, bis(acetylacetone) palladium, tri(dibenzylacetone) palladium, and bis(dibenzylacetone) palladium.

[0054] In some embodiments, the organic solvent is selected from dichloromethane, dichloroethane, toluene, xylene, mesitylene, chlorobenzene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, or 1,4-dioxane.

[0055] In some embodiments, the base is selected from triethylamine, ethylenediamine, isopropylamine, triethylenediamine, N-ethyldiisopropylamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,5,7-triazidobicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperazine, cesium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, potassium hydroxide, or potassium phosphate.

[0056] In some embodiments, carbon dioxide is selected from... 12 CO2 or 13 CO2.

[0057] In some embodiments, the pressure of carbon dioxide in the reaction system is 1 bar to 30 bar. That is, in the reaction system for synthesizing benzimidazole compounds from carbon dioxide, the reaction pressure of carbon dioxide is 1 bar to 30 bar.

[0058] In some embodiments, the amount of carbon dioxide added is 1 mL to 20 mL. When the amount of CO2 added is measured in mL, it refers to the volume under normal room temperature and pressure conditions.

[0059] In some embodiments, under nitrogen conditions, the aryl halide of formula (I), the o-phenylenediamine compound of formula (II), the palladium metal catalyst, the organophosphorus ligand, the reducing agent, the base, and the organic solvent are added to the reactor, and then the nitrogen gas in the reactor is purged with carbon dioxide, followed by the introduction of carbon dioxide to the required amount in the reaction system.

[0060] The following embodiments are used to illustrate this application, but are not intended to limit the scope of this application. Any modifications or substitutions made to the methods, steps, or conditions of this application without departing from the spirit and substance of this application are within the scope of this application.

[0061] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art; unless otherwise specified, the reagents used in the embodiments are all commercially available.

[0062] Example 1: Preparation of benzimidazole compound 1.

[0063] Under nitrogen atmosphere, starting material 1 (iodobenzene, 0.3 mmol), starting material 2 (o-phenylenediamine, 0.2 mmol), palladium acetate (Pd(OAc)2, 0.001 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos, 0.002 mmol), phenylsilane (PhSiH3, 0.6 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 mmol), acetonitrile (CH3CN, 19.1 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The tube was placed in a metal module at 60 °C and reacted for 24 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 1 in 88% yield. The reaction formula is as follows:

[0064]

[0065] The NMR data of compound 1 were measured using an NMR spectrometer. The hydrogen NMR spectrum of compound 1 is shown below. Figure 1 As shown, δ represents the chemical shift, with units of ppm. Specifically, the NMR data for compound 1 are as follows:

[0066] 1 H NMR (400MHz, Chloroform-d) δ 8.13-7.99 (m, 2H), 7.65 (d, J=5.9Hz, 2H), 7.49 (d, J=7.0Hz, 3H), 7.31-7.27 (m, 2H).

[0067] 13 C NMR (100MHz, Chloroform-d) δ 151.9, 144.1, 135.7, 131.7, 130.9, 129.8, 127.2, 124.1, 122.5, 119.7, 112.2.

[0068] Example 2: Preparation of benzimidazole compound 2.

[0069] Under nitrogen atmosphere, starting material 3 (p-iodotoluene, 0.3 mmol), starting material 2 (o-phenylenediamine, 0.2 mmol), palladium chloride (PdCl2, 0.001 mmol), triphenylphosphine (PPh3, 0.002 mmol), phenylsilane (PhSiH3, 0.6 mmol), triethylamine (0.6 mmol), N,N-dimethylformamide (DMF, 12.9 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 2 in 86% yield. The reaction formula is as follows:

[0070]

[0071] The NMR data of compound 2 were measured using an NMR spectrometer. The hydrogen NMR spectrum of compound 2 is shown below. Figure 2 As shown, the specific NMR data for compound 2 are as follows:

[0072] 1 H NMR (400MHz, Chloroform-d) δ 7.94 (d, J=8.2Hz, 2H), 7.68-7.61 (m, 2H), 7.34-7.26 (m, 4H), 2.42 (s, 3H).

[0073] 13 C NMR (100MHz, Chloroform-d) δ 151.6, 143.2, 139.7, 135.2, 129.7, 127.6, 126.5, 122.7, 21.1.

[0074] Example 3: Preparation of benzimidazole compound 3.

[0075] Under nitrogen atmosphere, starting material 4 (p-chloroiodobenzene, 0.3 mmol), starting material 2 (o-phenylenediamine, 0.2 mmol), (1,5-cyclooctadiene)palladium dichloride (0.001 mmol), 1,2-bis(diphenylphosphine)ethane (DPPE, 0.002 mmol), diphenylsilane (Ph₂SiH₂, 0.6 mmol), triethylenediamine (DABCO, 0.6 mmol), dimethyl sulfoxide (DMSO, 14.1 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 3 in 93% yield. The reaction formula is as follows:

[0076]

[0077] The NMR data of compound 3 were measured using an NMR spectrometer. The hydrogen NMR spectrum of compound 3 is shown below. Figure 3 As shown, the specific NMR data for compound 3 are as follows:

[0078] 1 H NMR (400MHz, Chloroform-d) δ 7.99 (d, J=8.5Hz, 2H), 7.66 (s, 2H), 7.49 (d, J=8.5Hz, 2H), 7.30 (dd, J=6.1, 3.2Hz, 2H).

[0079] 13 C NMR (100MHz, Chloroform-d) δ 150.1, 143.7, 135.0, 128.9, 128.0, 127.6, 122.8, 121.1, 119.2, 116.2, 116.4.

[0080] Example 4: Preparation of benzimidazole compound 4.

[0081] Under nitrogen atmosphere, starting material 5 (4-methoxyiodobenzene, 0.3 mmol), starting material 2 (o-phenylenediamine, 0.2 mmol), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2, 0.001 mmol), bis(diphenylphosphine)methane (DPPM, 0.002 mmol), phenylsilane (PhSiH3, 0.6 mmol), cesium fluoride (CsF, 0.6 mmol), dichloroethane (DCE, 12.7 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 4 in 89% yield. The reaction formula is as follows:

[0082]

[0083] The NMR data of compound 4 were measured using an NMR spectrometer. Specifically, the NMR data of compound 4 are as follows:

[0084] 1 H NMR (400MHz, Chloroform-d) δ 8.33-8.06 (m, 2H), 7.68 (dd, J=52.5, 7.0Hz, 2H), 7.40-7.11 (m, 4H), 3.96 (s, 3H).

[0085] 13 C NMR (100MHz, Chloroform-d) δ 160.5, 151.1, 143.9, 135.2, 128.2, 122.9, 121.7, 119.1, 116.2, 116.2, 111.3, 55.4.

[0086] Example 5: Preparation of benzimidazole compound 5.

[0087] Under nitrogen atmosphere, starting material 6 (p-bromoiodobenzene, 0.3 mmol), starting material 2 (o-phenylenediamine, 0.2 mmol), tris(dibenzylacetone)dipalladium (Pd2(dba)3, 0.001 mmol), 1,4-bis(diphenylphosphine)butane (DPPB, 0.01 mmol), diphenylsilane (Ph2SiH2, 0.6 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 mmol), N,N-dimethylacetamide (DMAC, 10.8 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel chromatography to obtain compound 5, with the following reaction formula:

[0088]

[0089] The NMR data of compound 5 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 5 are as follows:

[0090] 1 H NMR (400MHz, Chloroform-d) δ 8.11 (d, J=8.4Hz, 2H), 7.75 (d, J=8.3Hz, 2H), 7.60 (s, 2H), 7.21 (s, 2H).

[0091] 13 C NMR (100MHz, Chloroform-d) δ 150.2, 143.8, 135.1, 132.0, 129.4, 128.3, 123.2, 122.7, 122.0, 118.9, 111.4.

[0092] Example 6: Preparation of benzimidazole compound 6.

[0093] Under nitrogen atmosphere, starting material 1 (iodobenzene, 0.3 mmol), starting material 7 (4-methoxy-o-phenylenediamine, 0.2 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.001 mmol), 1,1'-bis(diphenylphosphine)ferrocene (DPPF, 0.002 mmol), triisopropylsilane (0.6 mmol), isopropylamine (0.6 mmol), N-methylpyrrolidone (NMP, 10.4 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 6 in 86% yield. The reaction formula is as follows:

[0094]

[0095] The NMR data of compound 6 were measured using an NMR spectrometer. Specifically, the NMR data of compound 6 are as follows:

[0096] 1 H NMR (400MHz, Chloroform-d) δ 8.28 (d, J=8.1Hz, 2H), 7.70-7.36 (m, 4H), 7.20 (s, 1H), 6.91 (dd, J=8.7, 2.3Hz, 1H), 3.81 (s, 3H).

[0097] 13 C NMR (100MHz, Chloroform-d) 156.5, 151.5, 130.0, 129.9, 129.1, 126.4, 112.6, 55.8.

[0098] Example 7: Preparation of benzimidazole compound 7.

[0099] Under nitrogen atmosphere, starting material 1 (iodobenzene, 0.3 mmol), starting material 8 (4-methyl-1,2-phenylenediamine, 0.2 mmol), allyl palladium chloride (0.001 mmol), 1,3-bis(diphenylphosphine)propane (DPPP, 0.002 mmol), diphenylsilane (Ph₂SiH₂, 0.6 mmol), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN, 0.6 mmol), N,N-dimethylformamide (DMF, 12.9 mmol), and a magnetic pusher were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel chromatography to give compound 7 in 90% yield. The reaction formula is as follows:

[0100]

[0101] The NMR data of compound 7 were measured using an NMR spectrometer. Specifically, the NMR data of compound 7 are as follows:

[0102] 1 H NMR (400MHz, Chloroform-d) δ8.17 (d, J=7.1Hz, 2H), 7.65-7.29 (m, 5H), 7.03 (d, J=7.9Hz, 1H), 2.43 (s, 3H).

[0103] 13 C NMR (100MHz, Chloroform-d) δ 150.6, 143.5, 141.2, 134.4, 129.4, 129.1, 128.2, 123.6, 118.7, 111.3, 21.5.

[0104] Example 8: Preparation of benzimidazole compound 8.

[0105] Under nitrogen atmosphere, starting material 1 (iodobenzene, 0.3 mmol), starting material 9 (4-tert-butylphenyl-1,2-diamine, 0.2 mmol), tris(dibenzylacetone)dipalladium (Pd2(dba)3, 0.001 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, Xantphos, 0.002 mmol), trimethoxysilane (0.6 mmol), cesium carbonate (0.6 mmol), toluene (9.4 mmol), and a magnetic flux were added to a 20 mL glass pressure-resistant tube. The pressure-resistant tube was sealed, the air inside was removed, and 20 mL of carbon dioxide gas was introduced. The pressure-resistant tube was placed in a metal module at 100 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 8 in 84% yield. The reaction formula is as follows:

[0106]

[0107] The NMR data of compound 8 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 8 are as follows:

[0108] 1 H NMR (400MHz, Chloroform-d) δ 12.75 (s, 1H), 8.16 (d, J=7.2Hz, 2H), 7.52 (dt, J=14.1, 7.0Hz, 5H), 7.29 (d, J=9.0Hz, 1H), 1.36 (s, 9H).

[0109] 13 C NMR (100MHz, Chloroform-d) δ162.4, 156.4, 145.9, 137.4, 132.9, 132.6 (q, J=31.2Hz), 131.0, 1 30.6, 130.2, 129.1, 128.4, 125.4 (q, J=3.6Hz), 125.2, 123.7 (q, J=271.2Hz), 122.6, 33.9, 31.0.

[0110] Example 9: Preparation of benzimidazole compound 9.

[0111] Under nitrogen atmosphere, add raw material 1 (bromobenzene, 0.3 mmol), raw material 10 (4-fluoro-1,2-phenylenediamine, 0.2 mmol), tris(dibenzylacetone)palladium (Pd2(dba)3, 0.001 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP, 0.002 mmol), trimethoxysilane (0.6 mmol), cesium carbonate (0.6 mmol), toluene (9.4 mmol), and a magnetic flux to a 20 mL glass pressure-resistant tube. Seal the pressure-resistant tube, remove the air inside, and then fill it with 20 mL of carbon dioxide gas. 13 CO2). The mixture was placed in a metal module at 80°C and reacted for 8 hours. After the reaction was complete, the reaction system was cooled to room temperature and the pressure was slowly released. The mixture was separated by silica gel column chromatography to give compound 9 in 85% yield. The reaction equation is as follows:

[0112]

[0113] The NMR data of compound 9 were measured using a nuclear magnetic resonance spectrometer. Specifically, the NMR data of compound 9 are as follows:

[0114] 1 H NMR (400MHz, Chloroform-d) δ 8.16 (d, J=6.4Hz, 2H), 7.50 (t, J=23.2Hz, 5H), 7.10 (s, 1H).

[0115] 13 C NMR (100MHz, Chloroform-d) δ153.5, 152.6, 144.7, 140.8, 132.2, 130.5, 130.3, 130.2, 130.2, 129. 6, 126.8, 126.7, 120.4, 120.3, 112.5, 112.5, 111.3, 110.7, 110.5, 110.3, 104.8, 104.8, 98.4, 98.1.

[0116] The above description is merely a specific embodiment of this application, but the scope of protection of this application is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in this application, and these modifications or substitutions should all be covered within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A method for preparing a benzimidazole compound, characterized in that, Includes the following steps: Using aryl halides of formula (I), o-phenylenediamine compounds of formula (II), and carbon dioxide as reactants, the reaction is carried out under the conditions of palladium metal catalyst, organophosphine ligand, reducing agent, base and organic solvent to obtain benzimidazole compounds of formula (III); wherein the reaction temperature is 60℃~140℃ and the reaction time is 8h~24h. 、 、 ， Wherein, X is selected from halogens; R 1 Selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, or aryl; R 2 Selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy or naphthyl; The reducing agent is silane; The organophosphorus ligand is selected from one or more monodentate phosphorus ligands and multidentate phosphorus ligands.

2. The preparation method according to claim 1, characterized in that, In formula (I), X is selected from F, Br, or I; R 1 Selected from hydrogen, Cl, Br, methyl, methoxy, tert-butyl, trifluoromethyl, or aryl; R 2 It is selected from hydrogen, F, methyl, n-propyl, isopropyl or n-butyl.

3. The preparation method according to claim 1, characterized in that, The organophosphine ligand is selected from one or more of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane, bis(diphenylphosphine)methane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)benzene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, bis(2-diphenylphosphine) ether, and 4,6-bis(diphenylphosphine)-10H-phenoxazine.

4. The preparation method according to claim 1, characterized in that, The reducing agent is selected from phenylsilane, diphenylsilane, triethylsilane, triisopropylsilane, trimethoxysilane, or polymethylhydrosiloxane.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the o-phenylenediamine compound to the palladium metal catalyst is 100~1000:1; The molar ratio of the o-phenylenediamine compound to the base is 0.1 to 1:

1.

6. The preparation method according to claim 1, characterized in that, The molar ratio of the o-phenylenediamine compound to the reducing agent is 0.1 to 1:1; The molar ratio of the organophosphine ligand to the palladium metal catalyst is 1~10:

1.

7. The preparation method according to claim 1, characterized in that, The palladium metal catalyst is selected from divalent palladium compounds or zero-valent palladium complexes.

8. The preparation method according to claim 1, characterized in that, The palladium metal catalyst is selected from one or more of palladium acetate, palladium dichloride, allyl palladium chloride, tetra-triphenylphosphine palladium, trifluoroacetate palladium, bis(acetonitrile) palladium dichloride, bis(triphenylphosphine) palladium dichloride, (1,5-cyclooctadiene) palladium dichloride, bis(acetylacetone) palladium, tri(dibenzylacetone) palladium, and bis(dibenzylacetone) palladium.

9. The preparation method according to claim 1, characterized in that, The organic solvent is selected from dichloromethane, dichloroethane, toluene, xylene, mesitylene, chlorobenzene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, or 1,4-dioxane.

10. The preparation method according to claim 1, characterized in that, The base is selected from triethylamine, ethylenediamine, isopropylamine, triethylenediamine, N-ethyldiisopropylamine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperazine, cesium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, potassium hydroxide, or potassium phosphate.

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