Process for the preparation of benzimidazole compounds

Abstract

The application discloses a preparation method of a benzimidazole compound and belongs to the field of photocatalytic organic synthesis. The application uses o-aryldiamine and diazosulfonium salt reagent as starting materials, carries out cyclization through double nucleophilic substitution under acidic conditions, uses air as a green oxidizing agent, promotes oxidative aromatization through blue light, and efficiently constructs the benzimidazole compound. The application does not need noble metal catalysts, strong alkali and strong oxidizing agents, only uses air as the green oxidizing agent, can realize efficient conversion under mild conditions, and the reaction raw materials are easy to obtain and have good chemical stability.

Description

Technical Field

[0001] This invention belongs to the field of photocatalytic organic synthesis, specifically relating to a method for preparing benzimidazole compounds. Background Technology

[0002] Due to its structural similarity to nucleosides, the benzimidazole skeleton exhibits significant anticancer activity. Furthermore, benzimidazole can act as a hydrogen bond donor or acceptor, binding to various drug targets involved in cancer progression. Several anticancer drugs containing a benzimidazole core have attracted widespread attention. The four compounds shown below all possess a benzimidazole structural skeleton. Among them, compound A (Bendamustine) is a uniquely structured bifunctional alkylating agent that exerts its antitumor effects through multiple mechanisms, including DNA cross-linking, anti-metabolite activity, mitotic checkpoint inhibition, and apoptosis induction. It has established clear efficacy in lymphoma and leukemia, received FDA approval, and exhibits limited cross-resistance with other alkylating agents, providing an important treatment option for relapsed / refractory patients. (Ayoubi-Chianeh, M.; Kassaee, MZ Struct. Chem. 2020, 31, 2041-2050.). Furthermore, compound B (Nocodazole), containing a similar structure, is a highly efficient and reversible inhibitor of microtubule polymerization. By binding to β-tubulin, it depolymerizes microtubules at high concentrations and inhibits microtubule dynamic instability at low concentrations, thereby inducing mitotic arrest and apoptosis. It exhibits selective toxicity to malignant cells with low myelotoxicity and neurotoxicity, and is widely used in anticancer research and cell biology experiments (Douglas, P.; Ye, R.; Radhamani, S.; Cobban, A.; Jenkins, NP; Bartlett, E.; Roveredo, J.; Kettenbach, AN; Lees-Miller, SP Mol. Cell. Biol. 2020, 40, e00191-19.). Compound C (Dovitinib) is an oral multi-target receptor tyrosine kinase inhibitor (RTKI): it blocks tumor growth and angiogenesis by inhibiting kinases such as FGFR / VEGFR / PDGFR, and induces DNA damage by binding to the minor groove of DNA and poisoning topoisomerase I / II. As a model compound for revealing the off-target DNA damage effect of kinase inhibitors, it has important scientific and clinical reference value (Hagar, FF; Abbas, SH; Atef, E.; Abdelhamid, D.; Abdel‐Aziz, M. Mol.Divers 2025, 29, 1821-1849).Compound D (Pracinostat) is a histone deacetylase inhibitor with potent inhibitory activity against classical zinc-dependent HDAC, affecting the acetylation status of tumor progression-related proteins and exhibiting significant antitumor activity (Chen, J.; Li, N.; Liu, B.; Ling, J.; Yang, W.; Pang, X.; Li, T.. Life Sci., 2020, 248, 117469.). Therefore, benzimidazole compounds demonstrate significant application value in the pharmaceutical field.

[0003]

[0004] The most direct method for synthesizing benzimidazole compounds is to condense o-phenylenediamine with formic acid, but this method often requires high temperature and an excess of carboxylic acid (Martin, EL Org. Synth. 1939, 19, 70.). Another common synthetic method involves the condensation of o-phenylenediamine with an aromatic aldehyde, but this requires strong oxidizing conditions such as hydrogen peroxide and potassium peroxymonosulfonate (Bahrami, K.; Khodaei, MM; Kavianinia, I. Synthesis, 2007, 547-550.; Hati, S.; Kumar Dutta, P.; Dutta, S.; Munshi, P.; Sen, S. Org.Lett. 2016, 18, 3090–3093.). Another method involves the condensation and cyclization of o-haloaromatic amines with aromatic aldehydes and ammonia molecules under strongly alkaline conditions, but this method requires noble metal catalysts, high temperatures, and strongly alkaline conditions (Ke, F.; Zhang, P.; Xu, Y.; Lin, X.; Lin, J.; Lin, C.; Xu, J. Synlett 2018, 29, 2722-2726.).

[0005] Therefore, it is of great significance to develop a simple, efficient, green and economical synthetic method to prepare benzimidazole compounds. Summary of the Invention

[0006] In view of the above, this invention addresses the aforementioned problems in the prior art by providing a method for constructing benzimidazole compounds. This invention utilizes long-wavelength visible light as an energy source to achieve photoinduced conversion, the synthesis operation is simple, the conditions are mild and environmentally friendly, the raw materials used are inexpensive and readily available, chemically stable, and possess excellent substrate versatility.

[0007] The present invention discloses a method for preparing benzimidazole compounds, which uses o-aryl diamine compounds as amphiphilic reagents, and cyclizes them with diazonium sulfonate reagents through amphiphilic substitution under acidic conditions. Air is used as a green oxidant and blue light is used to promote oxidative aromatization, thereby efficiently constructing benzimidazole compounds.

[0008] The reaction route is shown below:

[0009]

[0010] in:

[0011] The two R substituents independently represent phenyl groups; R 1 Selected from one or more of alkyl, halogen, and nitro groups; R 2 Selected from hydrogen and C1-C6 alkyl groups; R 3 It is an alkoxycarbonyl group (such as methoxycarbonyl, ethoxycarbonyl, etc.).

[0012] Furthermore, R 1 It can be a mono-substituted substance at the 4- or 5-position, or a di-substituted substance at the 4,5-position, such as 4,5-dimethyl, 4,5-dichloro, 4-bromine, 4-nitro, etc.

[0013] The reaction is carried out in a solvent system, wherein the solvent is one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, 1,4-dioxane, and N,N-dimethylformamide.

[0014] The acidic conditions of the system were achieved by adding trifluoroacetic acid. The volume ratio of trifluoroacetic acid to solvent was 4:1. Trifluoroacetic acid acted as both an acid and part of the solvent.

[0015] The molar ratio of the diazonium sulfonium salt reagent to the o-aryl diamine compound is 3:1.

[0016] The reaction of this invention does not require inert gas protection or photosensitizers.

[0017] The reaction of this invention requires irradiation with blue light at a wavelength of 455 nm to promote the reaction.

[0018] The specific operation steps are illustrated below:

[0019] Add 0.2 mmol of o-aryl diamine (1.0 equivalence) to a dry 25 mL reaction tube, followed by 0.6 mmol of diazonium trifluoromethanesulfonate reagent (3.0 equivalence), then 1.6 mL of trifluoroacetic acid and 0.4 mL of N,N-dimethylformamide. Irradiate the reaction under a 40 W blue light and stir at room temperature for 12 hours. After the reaction is complete, neutralize with saturated sodium bicarbonate, extract with 25 mL of ethyl acetate, wash twice with saturated sodium chloride solution, dry the organic phase thoroughly with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and then purify by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain benzo[d]imidazolium derivatives.

[0020] Compared with the prior art, the advantages of the present invention are mainly reflected in:

[0021] This invention requires no precious metal catalysts, strong bases, or strong oxidants; it uses only air as a green oxidant and can achieve efficient conversion under mild conditions of blue light irradiation. The reaction raw materials are readily available and have good chemical stability.

[0022] The target product of this invention can be used as a pharmaceutical intermediate, R 3 The functional groups can be converted into carboxylic acids after hydrolysis, and can be further converted into functional groups such as amides and hydrazides, which can be used for the conversion and preparation of drugs such as antitumor, antiviral, and bactericides. Attached Figure Description

[0023] Figure 1 The NMR spectrum of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate is shown.

[0024] Figure 2 The NMR spectrum of ethyl 5,6-dichloro-1H-benzo[d]imidazolium-2-carboxylate is shown.

[0025] Figure 3 The NMR spectrum of ethyl 1-methyl-1H-benzo[d]imidazolium-2-carboxylate is shown.

[0026] Figure 4 The NMR spectrum of ethyl 6-methyl-1H-benzo[d]imidazolium-2-carboxylate.

[0027] Figure 5 The NMR spectrum is that of ethyl 5-bromo-1-methyl-1H-benzo[d]imidazolium-2-carboxylate.

[0028] Figure 6 The NMR spectrum of ethyl 6-nitro-1H-benzo[d]imidazolium-2-carboxylate. Detailed Implementation

[0029] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.

[0030] Example 1:

[0031] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, using dichloromethane as a solvent, is as follows:

[0032] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and dichloromethane (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (15.7 mg, 36% yield).

[0033] Example 2:

[0034] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, using acetonitrile as a solvent, is as follows:

[0035] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and acetonitrile (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (29.3 mg, 67% yield).

[0036] Example 3:

[0037] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate using tetrahydrofuran as a solvent is as follows:

[0038] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and tetrahydrofuran (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (26.2 mg, 60% yield).

[0039] Example 4:

[0040] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate using ethyl acetate as a solvent is as follows:

[0041] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and ethyl acetate (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (24.4 mg, 56% yield).

[0042] Example 5:

[0043] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, using 1,4-dioxane as a solvent, is as follows:

[0044] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and 1,4-dioxane (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, dried thoroughly with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (23.1 mg, 53% yield).

[0045] Example 6:

[0046] The preparation method of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0047] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.0 mL) and N,N-dimethylformamide (1.0 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, dried thoroughly with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (24.4 mg, 56% yield).

[0048] Example 7:

[0049] The preparation method of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0050] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.3 mL) and N,N-dimethylformamide (0.7 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, dried thoroughly with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (25.3 mg, 58% yield).

[0051] Example 8:

[0052] The preparation method of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0053] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.5 mL) and N,N-dimethylformamide (0.5 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (25.8 mg, 59% yield).

[0054] Example 9:

[0055] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, using trifluoroacetic acid as a solvent, is as follows:

[0056] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), and then trifluoroacetic acid (2.0 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (26.2 mg, 60% yield).

[0057] Example 10:

[0058] The preparation of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, using N,N-dimethylformamide as a solvent, is as follows:

[0059] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), and then N,N-dimethylformamide (2.0 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1), and the target product, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate, was almost undetectable.

[0060] Example 11:

[0061] The preparation method of ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0062]

[0063] 4,5-Dimethyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid, ethyl 5,6-dimethyl-1H-benzo[d]imidazolium-2-carboxylate (31.4 mg, 72% yield).

[0064] 1 H NMR (400 MHz, CDCl3) δ = 7.99 (s, 1H), 7.70 (s, 1H), 4.53 (q, J =7.1 Hz, 2H), 2.41 (s, 6H), 1.47 (t, J = 7.2 Hz, 3H).

[0065] Example 12:

[0066] The preparation method of ethyl 5,6-dichloro-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0067]

[0068] 4,5-Dichloro-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, dried thoroughly with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid ethyl 5,6-dichloro-1H-benzo[d]imidazolium-2-carboxylate (38.3 mg, 74% yield).

[0069] 1H NMR (400 MHz, CDCl3) δ = 10.20 (s, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H).

[0070] Example 13:

[0071] The preparation method of ethyl 1-methyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0072]

[0073] N-methyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, dried thoroughly with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid ethyl 1-methyl-1H-benzo[d]imidazolium-2-carboxylate (16.3 mg, 40% yield).

[0074] 1 H NMR (600 MHz, CDCl3) δ = 7.90 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 5.9Hz, 2H), 7.36 (d, J = 5.3 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.16 (s, 3H),1.49 (t, J = 7.2 Hz, 3H).

[0075] Example 14:

[0076] The preparation method of ethyl 6-methyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0077]

[0078] 4-Methyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid ethyl 6-methyl-1H-benzo[d]imidazolium-2-carboxylate (31.0 mg, 76% yield).

[0079] 1 H NMR (400 MHz, CDCl3) δ = 7.62 (s, 1H), 7.45 (s, 1H), 7.17 (d, J =8.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.38 (t, J = 7.2 Hz,3H).

[0080] Example 15:

[0081] The preparation method of ethyl 5-bromo-1-methyl-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0082]

[0083] 4-Bromo-N-methyl-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid ethyl 5-bromo-1-methyl-1H-benzo[d]imidazolium-2-carboxylate (39.6 mg, 70% yield).

[0084] 1H NMR (400 MHz, CDCl3) δ = 8.02 (s, 1H), 7.50 (d, J = 12.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 4.51 (q, J = 7.9 Hz, 2H), 4.13 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H).

[0085] Example 16:

[0086] The preparation method of ethyl 6-nitro-1H-benzo[d]imidazolium-2-carboxylate is as follows:

[0087]

[0088] 4-Nitro-o-phenylenediamine (0.2 mmol, 1.0 equivalence) was added to a dry 25 mL reaction tube, followed by (1-diazo-2-ethoxy-2-oxoethyl)diphenylsulfonium trifluoromethanesulfonate (0.6 mmol, 3.0 equivalence), then trifluoroacetic acid (1.6 mL) and N,N-dimethylformamide (0.4 mL). The reaction was irradiated under a 40 W blue light and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with 25 mL of ethyl acetate, washed twice with saturated sodium chloride solution, and the organic phase was thoroughly dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The solution was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a brown solid ethyl 6-nitro-1H-benzo[d]imidazolium-2-carboxylate (21.2 mg, 45% yield).

[0089] 1 H NMR (600 MHz, CDCl3) δ = 11.22 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H),1.51 (t, J = 7.1 Hz, 3H).

Claims

1. A method for preparing a benzimidazole compound, characterized in that: Using o-aryl diamines as amphiphilic reagents, cyclization was carried out with diazonium sulfonate reagents under acidic conditions via amphiphilic substitution. Air was used as an oxidant and blue light was used to promote oxidative aromatization, thus efficiently constructing benzimidazole compounds. The reaction route is shown below: ； in: The two R substituents independently represent phenyl groups; R 1 Selected from one or more of alkyl, halogen, and nitro groups; R 2 Selected from hydrogen and C1-C6 alkyl groups; R 3 It is an alkoxycarbonyl group.

2. The preparation method according to claim 1, characterized in that: The reaction is carried out in a solvent system, wherein the solvent is one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, 1,4-dioxane, and N,N-dimethylformamide.

3. The preparation method according to claim 1, characterized in that: The acidic conditions of the system are achieved by adding trifluoroacetic acid.

4. The preparation method according to claim 2 or 3, characterized in that: The volume ratio of trifluoroacetic acid to solvent is 4:

1.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the diazonium sulfonium salt reagent to the o-aryl diamine compound is 3:

1.

6. The preparation method according to claim 1, characterized in that: The reaction was carried out under blue light irradiation at a wavelength of 455 nm.

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