CN109265403A - A kind of synthetic method of benzimidazole and its derivative - Google Patents

A kind of synthetic method of benzimidazole and its derivative Download PDF

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CN109265403A
CN109265403A CN201811302354.6A CN201811302354A CN109265403A CN 109265403 A CN109265403 A CN 109265403A CN 201811302354 A CN201811302354 A CN 201811302354A CN 109265403 A CN109265403 A CN 109265403A
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benzimidazole
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CN109265403B (en
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袁建勇
田青强
罗雯
李丹
代泽树
王华均
王雪桐
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Chongqing Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The present invention provides the synthetic method of a kind of benzimidazole and its derivative, and this method is cyclized by the o-phenylenediamine that imidazolium chloride is catalyzed, and realizes the synthesis of multiple functionalized benzimidazole and 2- substituted benzimidazole, method is easy and economical, practical.The present invention does not have any other catalyst or additive, and synthetic method has good functional group tolerance and excellent yield and purity, and the reaction time is short, and does not need harsh reaction condition, is suitble to industrialized production.

Description

synthesis method of benzimidazole and derivatives thereof
Technical Field
The invention relates to benzimidazole and derivatives thereof, in particular to a method for synthesizing benzimidazole and derivatives thereof.
Background
The benzimidazole compound is a benzo heterocyclic compound containing two nitrogen atoms and is a structural unit of various medicaments. Many benzimidazole compounds have remarkable biological activity and have important medical value in the aspects of resisting tumors, cancers, viruses, bacteria, inflammation, parasites and the like. Meanwhile, the benzimidazole compound can also be used in the fields of corrosion inhibitors, transition metal ligands, simulated natural superoxide dismutase (SOD) bioactivity, surface active treating agents, novel epoxy resin curing agents, chemiluminescence and the like. The traditional synthesis method of the benzimidazole compound is mainly divided into two methods, one method is that the benzimidazole compound is prepared by reacting o-phenylenediamine and derivatives thereof with carboxylic acid under the action of strong acid such as hydrochloric acid or polyphosphoric acidThe compound is prepared by reaction, the method usually requires higher reaction temperature and longer reaction time, and the yield is not ideal and has high requirements on equipment. The other one is obtained by cyclization of o-phenylenediamine and derivatives thereof with aldehyde compounds under the action of an oxidant, and the reaction process is simpler, but has more side reactions and more difficult separation. In recent years, a series of new synthetic routes of benzimidazole compounds using lewis acid, transition metal complex and the like as catalysts have been developed in succession on the basis of the conventional synthetic routes. In 1995, Bourgugnon reported that-o-phenylenediamine was treated with DMF in the presence of methylene chloride to synthesize benzimidazole (Desaubry L, Wermuth CG, Bourgugnon JJ. tetrahedron Lett.1995:36: 4249.). In the latter years, improvements to the above reactions have been made successively by using alternative catalysts. For example, Kamble and Bhanage reported an improved process for the formation of benzimidazoles from o-phenylenediamine and DMF, respectively, in their improved process using large amounts of corrosive concentrated hydrochloric acid or the metal Zn (OAc)2As catalyst (Kattimani PP, Kamble RR, Meti GY. RSC Advances.2015:5: 29447.; Nale DB, Bhanage BM. Synlett.2015:26: 2835.). Yadav reports scalable CO by cyclization of o-phenylenediamine with DMF under severe reaction conditions (5MPa and 150 ℃ C.)2Mediated benzimidazole synthesis (Rasal KB, Yadav gd. org. process. res. dev.2016:20: 2067.). However, the utility of these processes is offset by the special reactor and stoichiometric catalyst. Recently, Sun has proposed a new approach using 4 equivalents of phenyl silicon (PhSiH3) as a cocatalyst for the synthesis of benzimidazoles (Zhu J, Zhang Z, Miao C, Liu W, Sun W tetrahedron.2017:73: 3458), but the results show that this synthesis is incompatible when extended to substrates containing electron donating groups.
Disclosure of Invention
The invention aims to provide a method for synthesizing benzimidazole and derivatives thereof, which realizes the synthesis of multi-functionalized benzimidazole and 2-substituted benzimidazole through the cyclization of o-phenylenediamine catalyzed by imidazole hydrochloric acid, and has the advantages of simplicity, convenience, economy and strong practicability.
The purpose of the invention is realized as follows:
a method for synthesizing benzimidazole and derivatives (formula II) thereof is prepared by a compound of formula I and a compound of formula III under the action of a catalyst, and is characterized in that: the catalyst is imidazole hydrochloric acid.
The reaction route is as follows:
wherein,
R1is independently hydrogen, C1-6Alkyl, methoxy, halogen substituted methyl, nitro;
R2is independently hydrogen, C1-6Alkyl, phenyl, pyrrole, methoxyphenyl, p-phenylphenyl.
In the compounds of formula I and formula II herein, R1Can be independently ortho-position, meta-position or para-position, can be simultaneously substituted by the ortho-position, the meta-position and the para-position, and can also be independently substituted.
Further, in the above synthesis method, imidazole hydrochloride, which is a catalyst used in the reaction, is used in an amount of 0.1 to 0.3 equivalent (relative to o-phenylenediamine and its derivatives).
In the synthesis method, the used solvent is selected from one or a combination of more of DMF, benzene, acetonitrile and tetrahydrofuran; DMF is preferred.
In order to improve the yield and purity of the synthesis method, the reaction temperature is 80-140 ℃; preferably 120 to 140 ℃.
Specifically, the synthesis method of benzimidazole and its derivatives (formula II) is prepared from a compound of formula I and a compound of formula III under the action of a catalyst, and is characterized in that: the catalyst used in the reaction is imidazole hydrochloride, and the dosage of the imidazole hydrochloride is 0.1 to 0.3 equivalent (relative to o-phenylenediamine and derivatives thereof); the solvent used in the reaction is DMF; the reaction temperature is 120-140 ℃;
the reaction route is as follows:
wherein,
R1is independently hydrogen, C1-6Alkyl, methoxy, halogen substituted methyl, nitro; r2Is independently hydrogen, C1-6Alkyl, phenyl, pyrrole, methoxyphenyl, p-phenylphenyl.
Advantageous effects
The invention provides a method for synthesizing benzimidazole and derivatives (formula II) thereof, which takes imidazole hydrochloric acid as a catalyst and synthesizes benzimidazole and 2-substituted benzimidazole from o-phenylenediamine and derivatives thereof and DMF derivatives in the absence of any other catalyst or additive. The synthesis method has good functional group tolerance, can synthesize a large amount of benzimidazole derivatives for research in the fields of medicines or other fields, and has excellent yield and purity and high process economy. Taking benzimidazole as an example, the price of the benzimidazole is about 12 ten thousand yuan/ton sold in the market at present, but the cost can be controlled to be about 4 ten thousand yuan/ton by the method, and the benzimidazole has obvious economic value and cost advantage. The synthesis method does not use dichloromethane, corrosive concentrated hydrochloric acid and a metal catalyst, does not need harsh reaction conditions, does not need high-pressure autoclave and high-temperature reaction at 150 ℃, has short reaction time, and is suitable for industrial production.
Examples
Definition of
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "C" as used herein1-6Alkyl "means a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and the like.
The term "DMF" as used herein refers to N, N-dimethylformamide.
In order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention. The raw materials and reagents used in the invention are all commercial products.
Example 1
A10 mL three-necked round flask was charged with the compound of formula I, the acid III form of imidazole salt, and DMF as a solvent, the resulting solution was heated to react, 25mL of water was added after the reaction was completed, and the resulting mixture was extracted twice with 25mL of ethyl acetate. The combined organic layers were successively treated with H2O (50mL), then brine (50mL), then anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography and recrystallized with petroleum ether and ethyl acetate or with petroleum ether/EA to obtain the target product.
In initial experiments, the inventors performed the reaction of o-phenylenediamine with DMF for the catalytic cyclization to synthesize benzimidazole, and the results are listed in table 1. The inventors found that at 140 ℃ o-phenylenediamine did not react with DMF without any additives, the yield was found to be trace when imidazole was added and the ring closure yield was found to be 29% when 0.2 eq hydrochloric acid was added. Subsequently, further at 0.2 equivalents, the temperature was lowered and the yield was found to be trace at 90 ℃. However, the co-presence of 0.2 equivalents of imidazole hcl and DMF significantly improved the reactivity, providing a good yield of 95% of benzimidazole at 140 ℃ (table 1, entries 6-8), indicating that imidazole hcl may be responsible for DMF activation. Encouraging this result, the inventors then tested the effect of the amount of catalyst on the reaction. Surprisingly, the desired product was obtained in good yield even with 0.1 equivalents of catalyst (table 1, entry 9), demonstrating that imidazole hydrochloride is highly efficient for this reaction. Next, when the reaction temperature was varied between 30 ℃ and 140 ℃, the conversion rate was significantly changed, demonstrating that higher temperatures favor the reaction. Specifically, no target product was detected at 30 ℃ (table 1, entry 11) and 68% product was isolated at 90 ℃ (table 1, entry 10). It was also observed that the reaction was carried out at 140 ℃ (table 1, entry 8) giving a satisfactory yield (95%). In addition, the screening of the reaction solvents showed that DMF was the best solvent for most reactions, with lower yields of other solvents such as benzene, acetonitrile and tetrahydrofuran (Table 1, entries 12-15). Finally, the reaction was found to be effective at 120 ℃ with 10 mol% catalyst in 2mL DMF, with a product yield of 94% in 6 hours. The reaction route is as follows:
TABLE 1
aThe reaction was performed with o-phenylenediamine (0.54g, 5mmol, 1 eq.), DMF (2 mL).
bIsolated in yield.
cNo reaction occurred.
dDMF (0.46mL,6mmol,1.2 equiv.), solvent (5 mL).
eTrace yield.
The inventors next began investigating the general applicability of this reaction. The results are summarized in table 2 and show that the process is very general for the synthesis of benzimidazole derivatives from extensively substituted o-phenylenediamines, giving high yields of the product. In particular, o-phenylenediamines with both electron donating and electron withdrawing groups are well tolerated in this reaction and provide the corresponding benzimidazole derivatives in good yields (82-94%). The mono-and di-substituents on the benzene moiety had no significant effect on the reaction results, yielding the desired product in good yield (table 2,2b-2 i). It is noted that under such conditions, functional groups such as bromo (1e) or chloro (1f) are tolerated. Surprisingly, naphthalene-2, 3-diamine also reacted efficiently and gave the desired product in 87% yield (Table 2, 2j). In view of the synthetic usefulness of this reaction, the inventors further investigated its scalability. When the reaction was scaled up to 180mmol (1a, 20 g scale), the desired product 2a was isolated in 90% yield. The reaction route is as follows:
TABLE 2
aSubstituted o-phenylenediamine (1a-1j, 5mmol) and DMF (2mL) were reacted at 120 ℃ for 6h, isolated in yield.bOn a 20 gram scale, yield 90%.
In addition, in order to investigate the effect of different substituted amides on this reaction, the inventors investigated some DMF derivatives (table 3). Although in some cases lower conversions were obtained and longer reaction times were required, the results indicate that the reaction is very general for a range of differently substituted amides under similar reaction conditions. Replacement of H with methyl gave the corresponding product (65-84%, Table 3,3a-3f) as moderate to good. However, for the derivative with ethyl group, the substrate showed lower reactivity (table 3,3g, 63%). On the other hand, aromatic substituted substrates reflect the activity of the model reaction, giving poor yields (62-83%) (Table 3,3h-3 j). The less nucleophilic N, N-dimethyl-4-nitrobenzamide gives the corresponding product in lower yield than N, N-dimethyl-4-methoxybenzamide and N, N-dimethylbenzamide. This may result from electron withdrawing groups that are not conducive to the formation of reactive activated intermediates. In addition, note that the heteroaromatic substrates are also compatible, the reaction proceeds smoothly, giving 3k, 73% yield. The reaction route is as follows:
TABLE 3
aThe experiment was performed with o-phenylenediamine (5mmol, 1 eq.) and DMA (2mL) at 120 ℃ for 6h, isolated in yield. .bThe reaction temperature was 140 ℃. .cThe mixture was reacted with a mixture containing substituted o-phenylenediamine (5mmol, 1equiv) and DMF derivative (7.5mmol, 1.5equiv) in 5mL of xylene at 140 ℃ for 8 hours, and the yield was isolated. .
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1 general procedure for the Synthesis of benzimidazole derivatives (2a-3e)
To a 10mL three-necked round flask were added 1a (0.54g, 5mmol), imidazole hydrochloride (0.09g, 0.5mmol) and 2mL of N, N-dimethylformamide. The resulting solution was warmed to 120 ℃ and the reaction stirred at this temperature, checked by TLC plates, when complete 25mL of water was added and the resulting mixture was extracted twice with 25mL of ethyl acetate. The combined organic layers were washed successively with H2O (50mL), then brine (50mL), then dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography and recrystallized with petroleum ether and ethyl acetate or with petroleum ether/EA to obtain the target product.
General procedure for the Synthesis of benzimidazole derivatives (3f-3j)
A mixture of 1a (0.54g, 5mmol), imidazole hydrochloride (0.09g, 0.5mmol) and N, N-dimethylbenzamide (0.55g, 7.5mmol) in 5mL of xylene was heated to 140 ℃ and the reaction stirred at that temperature, checked by TLC spot plates, when the reaction was complete 50mL of water was added and the resulting mixture was extracted twice with 50mL of ethyl acetate. The combined organic layers were washed successively with H2O (50mL), then brine (50mL), then dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent or recrystallized from petroleum ether/EA to give the desired product.
Nuclear magnetic data of target product
1H-benzimidazole (2a) yellow solid (94%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.48(s,1H),8.25(d,J＝1.3Hz,1H),7.62(dd,J＝6.0,3.4Hz,2H),7.20(dd,J＝6.0,3.1Hz,2H).；13CNMR(150MHz,DMSO-d6)(δ,ppm):142.4,122.1.
5-methyl-1H-benzimidazole (2b), white solid (92%);1H NMR(600MHz,CDCl3)(δ,ppm):9.20(s,1H),8.12(s,1H),7.60(d,J＝8.1Hz,1H),7.48(s,1H),7.15(d,J＝8.1Hz,1H),2.50(s,3H).；13C NMR(150MHz,CDCl3)(δ,ppm):140.5,137.4,136.3,132.7,124.4,115.4,114.8,21.6.
5-methoxy radical1H-benzimidazole (2c) as a white solid (93%);1H NMR(600MHz,CDCl3)(δ,ppm):8.87(s,1H),8.05(d,J＝10.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.10(d,J＝2.1Hz,1H),6.93(dd,J＝8.8,2.2Hz,1H),3.82(s,3H).；13C NMR(150MHz,CDCl3)(δ,ppm):156.6,140.5,137.7,133.0,116.5,112.6,97.6,55.8.
5, 6-dimethyl-1H-benzimidazole (2d), yellow solid (93%);1H NMR(600MHz,CDCl3)(δ,ppm):8.22(s,1H),8.01(s,1H),7.44(s,2H),2.37(s,6H)；13C NMR(150MHz,CDCl3)(δ,ppm):139.9,136.2,131.9,115.5,20.3.
5-bromo-1H-benzimidazole (2e), white solid (88%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.67(s,1H),8.28(d,J＝3.6Hz,1H),7.81(s,1H),7.57(d,J＝8.4Hz,1H),7.34(dd,J＝8.5,1.1Hz,1H).13C NMR(150MHz,DMSO-d6)(δ,ppm):143.7,125.0,114.4.
5-chloro-1H-benzimidazole (2f), yellow solid (85%);1H NMR(600MHz,DMSO-d6)(δ,ppm):8.28(s,1H),7.66(s,1H),7.60(d,J＝8.2Hz,1H),7.21(d,J＝8.3Hz,1H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):143.4,126.1,121.9,116.3,115.2.
5, 6-dichloro-1H-benzimidazole (2g) yellow solid (86%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.74(s,1H),8.35(s,1H),7.94(s,1H),7.82(s,1H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):145.2,143.1,133.3,124.9,124.2,120.7,113.6.
5-fluoro-1H-benzimidazole (2H.) grey solid (84%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.61(s,1H),8.30(s,1H),7.62(t,J＝6.4Hz,1H),7.43(d,J＝9.6Hz,1H),7.08(td,J＝9.3,2.6Hz,1H).13C NMR(150MHz,DMSO-d6)(δ,ppm):159.7,158.1,143.8,110.3,100.0.
5-trifluoromethyl-1H-benzimidazole (2i) yellow solid (82%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.90(s,1H),8.47(s,1H),7.99(s,1H),7.80(d,J＝8.4Hz,1H),7.53(dd,J＝8.5,1.1Hz,1H).13C NMR(150MHz,DMSO-d6)(δ,ppm):144.7,127.7,125.9,124.1,122.5,122.3,118.4.
1H-naphthoimidazole (2j), black solid (87%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.54(s,1H),8.49(s,1H),8.12(s,2H),8.01(dd,J＝6.3,3.3Hz,2H),7.53–6.97(m,2H).13C NMR(150MHz,DMSO-d6)(δ,ppm):146.9,130.1,128.2,123.8.
2-methyl-1H-benzimidazole (3 a.) white solid (84%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.21(s,1H),7.45(dt,J＝6.8,3.2Hz,2H),7.11(ddd,J＝6.0,3.2,1.2Hz,2H),2.49(s,3H).13C NMR(150MHz,DMSO-d6)(δ,ppm):151.70,121.48,15.10.
2-methyl-5-chloro-1H-benzimidazole (3b), grey solid (75%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.38(s,1H),7.50(s,1H),7.45(s,1H),7.12(d,J＝8.3Hz,1H),2.48(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):153.2,125.7,121.6,15.1.
2, 5-dimethyl-1H-benzimidazole (3c) yellow solid (77%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.05(s,1H),7.31(d,J＝8.0Hz,1H),7.23(s,1H),6.91(dd,J＝8.1,1.0Hz,1H),2.45(s,3H),2.38(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):150.8,129.9,122.3,21.1,14.5.
2-methyl-5-nitro-1H-benzimidazole (3d), yellow solid (65%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.94(s,1H),8.37(s,1H),8.06(dd,J＝8.7,1.5Hz,1H),7.64(d,J＝8.0Hz,1H),2.57(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):142.5,117.6,15.3.
2,5, 6-trimethyl-1H-benzimidazole (3e)19White solid (75%);1H NMR(600MHz,DMSO-d6)(δ,ppm):14.97(s,1H),7.51(s,2H),2.78(s,3H),2.36(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):150.2,125.0,129.6,113.6,20.2,12.5.
2-methyl-5, 6-dichloro-1H-benzimidazole (3f), white solid (69%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.55(s,1H),7.72(s,2H),2.49(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):154.9,143.8,134.4,122.,121.6,112.6,15.1.
2-ethyl-1H-benzimidazole (3 g.) brown solid (63%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.16(s,1H),7.45(s,2H),7.10(dd,J＝5.9,3.1Hz,2H),2.82(q,J＝7.6Hz,2H),1.32(t,J＝7.6Hz,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):156.6,144.2,121.5,22.4,12.6.
2- (4-nitrobenzene) -1H-benzimidazole (3H) yellow solid (62%);1H NMR(600MHz,DMSO-d6)(δ,ppm):13.31(s,1H),8.64–8.19(m,4H),7.75(d,J＝7.9Hz,1H),7.60(d,J＝7.8Hz,1H),7.28(dt,J＝14.8,7.0Hz,2H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):149.4,148.2,144.3,136.5,135.7,127.8,124.7,124.0,122.7,119.9,112.2.
2-phenyl-1H-benzimidazole (3 i.) white solid (77%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.98(s,1H),8.23(d,J＝7.9Hz,2H),7.64(s,2H),7.57(t,J＝7.6Hz,2H),7.51(t,J＝7.3Hz,1H),7.23(dd,J＝5.9,3.1Hz,2H).13C NMR(150MHz,DMSO-d6)(δ,ppm):.151.2,130.1,129.7,128.9,126.4,122.1.
2- (4-methoxyphenyl) -1H-benzimidazole (3j) white solid (83%);1H NMR(600MHz,DMSO-d6)(δ,ppm):12.75(s,1H),8.12(d,J＝8.7Hz,2H),7.62(d,J＝7.5Hz,1H),7.50(d,J＝7.5Hz,1H),7.27-7.14(m,2H),7.12(d,J＝8.7Hz,2H),3.84(s,3H).；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.0,151.8,144.3,135.4,128.4,123.1,121.9,118.9,114.8,111.4,55.8.
2- (2-pyridine) -1H-benzimidazole (3k) white solid (73%);1H NMR(600MHz,DMSO-d6)(δ,ppm):δ13.14(s,1H),8.75(d,J＝4.6Hz,1H),8.35(d,J＝7.8Hz,1H),8.01(t,J＝7.4Hz,1H),7.73(d,J＝7.9Hz,1H),7.66–7.42(m,2H),7.21–7.24(m,2H).13C NMR(150MHz,DMSO-d6)(δ,ppm):151.2,149.8,149.0,144.3,138.0,135.4,125.1,123.5,122.3,121.8,119.7,112.5.

Claims (9)

1. A method for synthesizing benzimidazole and derivatives (formula II) thereof is prepared by a compound of formula I and a compound of formula III under the action of a catalyst, and is characterized in that: the catalyst is imidazole hydrochloric acid.
The reaction route is as follows:
wherein,
R1is independently hydrogen, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,Methoxy, halogen substituted methyl, nitro;
R2is independently hydrogen, C1-6Alkyl, phenyl, pyrrole, methoxyphenyl, p-phenylphenyl.
2. The method of claim 1, wherein: the dosage of the catalyst imidazole hydrochloric acid is 0.1-0.3 eq.
3. The method of claim 1 or 2, wherein: the solvent is one or more selected from DMF, benzene, acetonitrile and tetrahydrofuran.
4. The method of claim 3, wherein: the solvent used was DMF.
5. The method of claim 1 or 2, wherein: the reaction temperature is 80-140 ℃.
6. The method of claim 5, wherein: the reaction temperature is 120-140 ℃.
7. A method for synthesizing benzimidazole and derivatives (formula II) thereof is prepared by a compound of formula I and a compound of formula III under the action of a catalyst, and is characterized in that: the catalyst used in the reaction is imidazole hydrochloride, and the dosage of the imidazole hydrochloride is 0.1 to 0.3eq (relative to o-phenylenediamine and derivatives thereof); the solvent used in the reaction is DMF; the reaction temperature is 120-140 ℃;
the reaction route is as follows:
wherein,
R1is independently hydrogen, C1-6Alkyl, methoxy, halogen substituted methyl, nitro; r2Is independently hydrogen, C1-6Alkyl, phenyl, pyrrole, methoxyphenyl, p-phenylphenyl.
8. The method of any one of claims 1-7, wherein: the halogen is selected from fluorine, chlorine, bromine or iodine.
9. The method of any one of claims 1-7, wherein: said C is1-6The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845423A (en) * 2019-12-06 2020-02-28 井冈山大学 Preparation method of 1, 2-substituted benzimidazole compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1834090A (en) * 2005-03-18 2006-09-20 中国科学院上海药物研究所 Benzimidazole compounds, its prepn. and uses
CN104610163A (en) * 2015-02-13 2015-05-13 安徽工业大学 Method for catalytic synthesis of benzimidazole derivatives
CN105237480A (en) * 2015-08-14 2016-01-13 三峡大学 2-trifluoromethyl benzimidazole compound and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1834090A (en) * 2005-03-18 2006-09-20 中国科学院上海药物研究所 Benzimidazole compounds, its prepn. and uses
CN104610163A (en) * 2015-02-13 2015-05-13 安徽工业大学 Method for catalytic synthesis of benzimidazole derivatives
CN105237480A (en) * 2015-08-14 2016-01-13 三峡大学 2-trifluoromethyl benzimidazole compound and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DEBASREE SAHA，等: "Remarkable influence of substituent in ionic liquid in control of reaction: simple, efficient and hazardous organic solvent free procedure for the synthesis of 2-aryl benzimidazoles promoted by ionic liquid, [pmim]BF4", 《GREEN CHEMISTRY》 *
PRAMOD P. KATTIMANI，等: "Expedient synthesis of benzimidazoles using amides", 《RSC ADVANCES》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845423A (en) * 2019-12-06 2020-02-28 井冈山大学 Preparation method of 1, 2-substituted benzimidazole compound

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