A method for light-mediated synthesis of benzimidazoles

Abstract

The application provides a method for photo-mediated synthesis of benzimidazole compounds, and belongs to the technical field of chemical synthesis.The method provided by the application comprises the following steps: uniformly mixing compound 1, compound 2, a photosensitizer, a catalyst and a solvent, then performing a reaction under light irradiation, and performing post-treatment after the reaction is completed to obtain a benzimidazole compound; the structural formula of the compound 1 is shown in the description, the structural formula of the compound 2 is shown in the description, and the structural formula of the benzimidazole compound is shown in the description.The reaction activates N-sulfinyl aniline substrates and organic nitrile substrates through a catalyst, and generates free radicals under blue light through a photosensitizer, so that the cyclization of the N-sulfinyl aniline substrates and the organic nitrile substrates is finally realized, and the method has reference significance for modular synthesis of benzimidazole compounds.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for the photo-mediated synthesis of benzimidazole compounds. Background Technology

[0002] Benzimidazoles are a widely used and advantageous structural unit, ubiquitous in various drug molecules, possessing diverse pharmacological activities such as antibacterial, hypoglycemic, antiviral, and antitumor effects. They also have important applications in agriculture and materials science. Therefore, developing simple and modular methods for the synthesis of benzimidazoles has always been a key research focus in synthetic chemistry and medicinal chemistry.

[0003] Currently, the conventional synthesis of benzimidazole compounds mainly relies on the traditional Phillips-Ladenburg and Weidenhagen methods, primarily using o-phenylenediamine or prefunctionalized aniline as starting materials. However, these methods typically require acidic, oxidizing environments or high-temperature conditions. These stringent reaction conditions reduce functional group compatibility, making it difficult to rapidly construct structurally diverse benzimidazole derivatives and hindering subsequent product modification.

[0004] In recent years, visible light redox catalysis has become a research hotspot in the field of organic synthesis due to its advantages such as enabling single-electron activation of substrates under mild conditions. However, as of now, there are no published documents or patents reporting a technical scheme for constructing benzimidazole by visible light cyclization using N-sulfinylaniline substrates and common organic nitriles as raw materials and zinc salts in conjunction with photosensitizers. This field has a significant technological gap. Summary of the Invention

[0005] In view of this, the present invention aims to provide a method for the photo-mediated synthesis of benzimidazole compounds.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for the light-mediated synthesis of benzimidazole compounds, comprising the following steps: Compound 1, compound 2, photosensitizer, catalyst and solvent were mixed evenly and then reacted under light irradiation. After the reaction was completed, post-treatment was performed to obtain benzimidazole compounds. The structural formula of compound 1 is as follows: R 1 Selected from hydrogen, methyl, methoxy, borate, amino, nitro, halogen, ester, carboxyl, disubstituted aryl, pyridyl, and partially saturated aryl; X is C or N; The structural formula of compound 2 is as follows: R 2 Selected from methyl, thioether, trifluoromethyl, halogen, acyl, piperidine ring, benzyl nitrile, aryl nitrile, and heterocyclic nitrile; The structural formula of the benzimidazole compound is as follows: R 1 Choose the same R1 as in compound 1, X is the same as X in compound 1, R 2 With R in compound 2 2 same.

[0007] The present invention discloses the following technical effects: This invention discloses a method for modularly synthesizing benzimidazole compounds using N-sulfinylaniline substrates and organic nitrile substrates under visible light conditions. The reaction involves activation of both the N-sulfinylaniline and organic nitrile substrates via a catalyst, followed by the generation of free radicals under blue light using a photosensitizer. This ultimately achieves the cyclization of the N-sulfinylaniline and organic nitrile substrates, providing a valuable reference for the modular synthesis of benzimidazole compounds.

[0008] This invention uses commercially available N-sulfinylaniline and common organic nitriles to replace highly toxic sodium cyanide. All reagents are commercially available, conventional, low-toxicity chemicals. Laboratory operation and industrial scale-up are safe and controllable. The substrates have a wide range of applications, the raw materials are safe and readily available, gram-scale synthesis can be achieved, and the reaction conditions are mild. Attached Figure Description

[0009] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0010] Figure 1 The hydrogen spectrum of the product obtained in Example 1; Figure 2 The carbon spectrum of the product obtained in Example 1; Figure 3 The hydrogen spectrum of the product obtained in Example 2; Figure 4 The carbon spectrum of the product obtained in Example 2; Figure 5 The hydrogen spectrum of the product obtained in Example 3; Figure 6 The carbon spectrum of the product obtained in Example 3; Figure 7 The hydrogen spectrum of the product obtained in Example 4; Figure 8 The carbon spectrum of the product obtained in Example 4; Figure 9 The hydrogen spectrum of the product obtained in Example 5; Figure 10The carbon spectrum of the product obtained in Example 5; Figure 11 The hydrogen spectrum of the product obtained in Example 6; Figure 12 The carbon spectrum of the product obtained in Example 6; Figure 13 The hydrogen spectrum of the product obtained in Example 7; Figure 14 The carbon spectrum of the product obtained in Example 7; Figure 15 The hydrogen spectrum of the product obtained in Example 8; Figure 16 The carbon spectrum of the product obtained in Example 8 is shown below. Detailed Implementation

[0011] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0012] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0013] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0014] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0015] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0016] Benzimidazoles are a widely used and advantageous structural unit, ubiquitous in various drug molecules, possessing diverse pharmacological activities such as antibacterial, hypoglycemic, antiviral, and antitumor effects. They also have important applications in agriculture and materials science. Therefore, developing simple and modular methods for the synthesis of benzimidazoles has always been a research focus in synthetic chemistry and medicinal chemistry. Existing methods for synthesizing benzimidazole compounds include the traditional Phillips-Ladenburg method and the Weidenhagen method, primarily using o-phenylenediamine or prefunctionalized aniline as starting materials. The reactions are typically carried out under acidic, oxidizing, or high-temperature conditions. These stringent reaction conditions reduce functional group compatibility, making it difficult to rapidly construct structurally diverse benzimidazole derivatives and hindering subsequent product modification. To address the shortcomings of existing traditional synthetic methods, such as "high temperature and strong acidity in conventional processes, poor functional group compatibility, difficulty in rapidly constructing structurally diverse benzimidazole derivatives, difficulty in post-product modification, and the limitations of existing photocatalytic routes with highly toxic raw materials and narrow substrate range," and to fill the technological gap in the photocatalytic cyclization of N-sulfinylaniline / organonitriles, this invention provides a "modular synthesis method for benzimidazole using visible light synergistic catalysis." This method aims to provide a synthetic route with a broad substrate range, excellent functional group tolerance, simple operation, and high efficiency, meeting the diverse needs of industrial production and academic research for benzimidazole compounds. The method of this invention has a wide range of applicable substrates, readily available raw materials, enables gram-scale synthesis, and operates under mild reaction conditions.

[0017] This invention provides a method for the light-mediated synthesis of benzimidazole compounds, comprising the following steps: Compound 1, compound 2, photosensitizer, catalyst and solvent were mixed evenly and then reacted under light irradiation. After the reaction was completed, post-treatment was performed to obtain benzimidazole compounds. The structural formula of compound 1 is as follows: R 1 Selected from hydrogen, methyl, methoxy, borate, amino, nitro, halogen, ester, carboxyl, disubstituted aryl, pyridyl, and partially saturated aryl; X is C or N; The structural formula of compound 2 is as follows: R 2 Selected from methyl, thioether, trifluoromethyl, halogen, acyl, piperidine ring, benzyl nitrile, aryl nitrile, and heterocyclic nitrile; The structural formula of the benzimidazole compound is as follows: R 1 Choose the same R1 as in compound 1, X is the same as X in compound 1, R 2 With R in compound 2 2 same.

[0018] In a preferred embodiment of the present invention The structural formula of compound 1 is selected from one of the following structures: , , , , ; The structural formula of compound 2 is selected from one of the following structures: (TMSCN) (MeCN) , .

[0019] In a preferred embodiment of the present invention, the photosensitizer is tetracarbazole isophthalonitrile (4-CzlPN), Eosin Y, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[2-(2-pyridyl)phenyl]iridium(III) hexafluorophosphate ([Ir(dtbppy)(ppy)2][PF6]), tris(2-phenylpyridine)iridium (fac-Ir(ppy)3) or tris(1,10-phenanthroline)ruthenium(II)bis(hexafluorophosphate) (Ru(phen)3(PF6)2).

[0020] In a preferred embodiment of the present invention, the catalyst is zinc trifluoromethanesulfonate (Zn(OTf)2), copper trifluoromethanesulfonate (Cu(OTf)2), nickel trifluoromethanesulfonate (Ni(OTf)2), lanthanum trifluoromethanesulfonate (La(OTf)3), p-toluenesulfonic acid monohydrate (PTSA·H2O) or trifluoroacetic acid (TFA).

[0021] In a preferred embodiment of the present invention, the solvent is at least one selected from 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, and toluene.

[0022] This invention does not impose any special limitations on the amount of solvent used; the amount used should be sufficient to fully dissolve the raw materials and ensure that the reaction proceeds.

[0023] In a preferred embodiment of the present invention, the molar ratio of compound 1 to compound 2 is 1:10~15; the amount of photosensitizer is 1%~3% of the molar amount of compound 1; and the amount of catalyst is 5%~10% of the molar amount of compound 1.

[0024] In a preferred embodiment of the present invention, the wavelength range of the light irradiation conditions is 465~480nm, the reaction temperature is room temperature, and the reaction process is monitored by thin-layer chromatography.

[0025] In a preferred embodiment of the present invention, the post-processing is as follows: dichloromethane and water are added to the obtained reaction solution for extraction and separation, the organic layers are combined, the organic layers are then dried with a desiccant, the desiccant is removed, and then the solution is concentrated and recrystallized.

[0026] The reaction atmosphere of this invention can be either a nitrogen atmosphere or an air atmosphere, with a nitrogen atmosphere being preferred.

[0027] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0028] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.

[0029] Example 1 Compounds 1aa (0.3 mmol), 2aa (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under nitrogen protection and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the desiccant, concentrated, and recrystallized to obtain a white solid compound 3aa in 84% yield. The reaction equation is as follows: Depend on Figure 1 , Figure 2 It can be confirmed that the product was successfully synthesized.

[0030] Example 2 Compounds 1ab (0.3 mmol), 2aa (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under nitrogen protection and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the desiccant, concentrated, and recrystallized to obtain a white solid compound 3ab in 76% yield. The reaction equation is as follows: Depend on Figure 3 , Figure 4It can be confirmed that the product was successfully synthesized.

[0031] Example 3 Compound 1ac (0.3 mmol), 2aa (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under a light source of 456–480 nm wavelength, under nitrogen protection, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the desiccant, concentrated, and recrystallized to obtain a white solid compound 3ac, with a yield of 69%. The reaction equation is as follows: Depend on Figure 5 , Figure 6 It can be confirmed that the product was successfully synthesized.

[0032] Example 4 Compounds 1ad (0.3 mmol), 2ad (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under a light source of 456–480 nm wavelength and a nitrogen atmosphere. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. 60 mL of dichloromethane and 20 mL of water were added for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the drying agent, concentrated, and recrystallized to give a white solid compound 3ad in 66% yield. The reaction equation is as follows: Depend on Figure 7 , Figure 8 It can be confirmed that the product was successfully synthesized.

[0033] Example 5 Compounds 1ae (0.3 mmol), 2aa (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under nitrogen protection and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the desiccant, concentrated, and recrystallized to obtain a white solid compound 3ae in 41% yield. The reaction equation is as follows: Depend on Figure 9 , Figure 10 It can be confirmed that the product was successfully synthesized.

[0034] Example 6 Compounds 1aa (0.3 mmol), 2ab (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under nitrogen protection and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous sodium sulfate for 30 min, filtered to remove the desiccant, concentrated, and recrystallized to give a white solid compound 3af in 81% yield. The reaction equation is as follows: Depend on Figure 11 , Figure 12 It can be confirmed that the product was successfully synthesized.

[0035] Example 7 Compounds 1aa (0.3 mmol), 2ac (0.45 mmol), 4-CzlPN (0.06 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under a light source of 456–480 nm wavelength, under nitrogen protection, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous Na2SO4 for 30 min, the desiccant was removed, the mixture was concentrated, and recrystallized to give 3 ag of white solid compound, with a yield of 28%. The reaction equation is as follows: Depend on Figure 13 , Figure 14 It can be confirmed that the product was successfully synthesized.

[0036] Example 8 Compounds 1aa (0.3 mmol), 2ad (0.45 mmol), 4-CzlPN (0.006 mmol), Zn(OTf)2 (0.03 mmol), 1,2-dichloroethane (2 mL), and a magnetic stir bar were added sequentially to a ground glass joint reaction tube. The reaction was carried out at room temperature under a light source of 456–480 nm wavelength, under nitrogen protection, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. After the reaction was completed, 60 mL of dichloromethane and 20 mL of water were added to the resulting reaction system for extraction and separation. The organic layers were combined, dried over anhydrous Na2SO4 for 30 min, the desiccant was removed, the mixture was concentrated, and recrystallized to give a white solid compound 3ah, with a yield of 54%. The reaction equation is as follows: Depend on Figure 15 , Figure 16 It can be confirmed that the product was successfully synthesized.

[0037] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for light-mediated synthesis of benzimidazoles, characterized in that, Includes the following steps: Compound 1, compound 2, photosensitizer, catalyst and solvent were mixed evenly and then reacted under light irradiation. After the reaction was completed, post-treatment was performed to obtain benzimidazole compounds. The structural formula of the compound 1 is , R 1 is selected from hydrogen, methyl, methoxy, borate, amino, nitro, halogen, ester, carboxyl, disubstituted aryl, pyridyl, partially saturated aryl; X is C or N; The structural formula of compound 2 is as follows: R 2 Selected from methyl, thioether, trifluoromethyl, halogen, acyl, piperidine ring, benzyl nitrile, aryl nitrile, and heterocyclic nitrile; The structural formula of the benzimidazole compound is as follows: R 1 Choose the same R1 as in compound 1, X is the same as X in compound 1, R 2 With R in compound 2 2 same.

2. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The structural formula of compound 1 is selected from one of the following structures: 、 、 、 、 ； The structural formula of compound 2 is selected from one of the following structures: 、 、 、 。 3. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The photosensitizer is tetracarbazole isophthalonitrile, eosin Y, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[2-(2-pyridyl)phenyl]iridium(III)hexafluorophosphate, tris(2-phenylpyridine)iridium or tris(1,10-phenanthroline)ruthenium(II)bis(hexafluorophosphate).

4. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The catalyst is zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate, nickel trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, p-toluenesulfonic acid monohydrate, or trifluoroacetic acid.

5. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The solvent is at least one selected from 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, and toluene.

6. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:10~15; the amount of photosensitizer is 1%~3% of the molar amount of compound 1; and the amount of catalyst is 5%~10% of the molar amount of compound 1.

7. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The wavelength range of the light irradiation conditions was 465~480nm, the reaction temperature was room temperature, and the reaction process was monitored by thin-layer chromatography.

8. The method for photo-mediated synthesis of benzimidazole compounds according to claim 1, characterized in that, The post-processing is as follows: dichloromethane and water are added to the obtained reaction solution for extraction and separation, the organic layers are combined, the organic layers are then dried with a desiccant, the desiccant is removed, and then the solution is concentrated and recrystallized.

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