Advances in the Synthesis of Benzoazole Compounds

: Benzozole compounds are a kind of nitrogen-containing heterocyclic compounds, which are widely used in medicine and materials, and can also be used as an important intermediate to prepare high molecular compounds. In this paper, the existing synthesis methods of benzozozole compounds are summarized, according to the reaction mechanism, which lays a foundation for the establishment of a greener, more economical and more convenient synthesis method in the future.


Introduction
Benzimidazole, benzothiazole, benzoxazole and other benzoazole derivatives are common nitrogenous heterocyclic compounds, which are characterized by good biocompatibility and biodiversity, complex and variable structure, low toxicity, and are often used as important "pharmacophore" in drugs.Benzazole structures are widely used in medicine as antiviral, antibacterial, anticancer, antihistamine, anti-tuberculosis, anti-hypertension, antiinflammatory and plant growth regulators.Because of their wide application prospect, the research and development of benzazole compounds has been widely concerned.[1]The synthesis method is particularly important.

Review of Synthesis Methods of Benzazole Compounds
In1872, Hoebrecker first synthesized the 2,5-dimethylbenzimidazole.They pioneered the synthesis method of benzimidazole although the yield of this reaction was not high.In 1875, the Ladenburg research group [2]studied the synthesis reaction of 4-methyl-o-phenylenediamine and acetic acid under reflux heating, and the product was benzimidazole.So far, the reaction of o-phenylenediamine and its derivatives with strong acids (such as HCl, polyphosphoric acid PPA, p-toluenesulfonic acid, mixed acid, etc.) at high temperature has become a classic preparation method of benzimidazole compounds, but the reaction conditions are harsh and the reaction time is long.
The synthesis method of 2,5-dimethyl benzimidazole In 1886, Jacobson et al. [3] first synthesized benzothiazole with N-phenylthiobenzamide as raw material under the action of potassium hexacyanoferrate (III) and sodium hydroxide, and established Jacobson's ring method (Fig. 3).Jacobson uses liquid bromine as oxidant to oxidize thioamide to prepare benzothiazole.Because it is difficult to determine the amount of substances involved in the reaction with liquid bromine, by-products are often generated, and liquid bromine is highly corrosive and toxic, it does not meet the economic and environmental requirements of green chemistry.Since there is a method to synthesize benzimidazole and benzothiazole, the synthesis of these compounds has become a hot spot in organic synthesis.Chemists have been trying to find a more economical, efficient and green synthesis method.According to literature review, the synthesis methods of benzozole compounds are mainly as follows: First, aniline substituted by o-amino, o-mercapto and o-hydroxy is prepared by condensation reaction with carboxylic acid, nitrile and ester, which generally needs to be carried out under strong acid and high temperature conditions; Second, aniline substituted by o-amino group, o-mercapto group and ohydroxyl group is prepared by oxidative cyclization reaction with aldehyde or alcohol, which requires stoichiometric oxidant; The third is the method of synthesizing benzimidazole by reaction of N, N-dimethylformamide (DMF) with o-mercapto, o-hydroxy and o-amino substituted aniline reported in recent years.This kind of synthesis method requires expensive reagents such as phosphorus and boron, or needs to be carried out under strong acid, strong oxidation and strong corrosion conditions, which has the disadvantages of high requirements for synthesis conditions, trivial reaction steps and low yield; As well as the recent rise in the use of CO 2 to prepare benzozole compounds, microwave radiation method to prepare benzozole compounds and other new methods.These reactions have their own characteristics.The following is a systematic review of these synthesis methods.
In 2012, Chen et al. [6]studied the method of synthe -sizing benzimidazole with aromatic aldehydes and o-phenylenediamine as raw materials under FeCl 3 /Al 2 O 3 catalysis.Although the conditions of these two methods are relatively mild, they both have the disadvantage of poor selectivity (Figure 6).In 2013, Zhang Zhiwei and others [7]studied a new method of iron catalyzed synthesis of benzimidazole derivatives from disulfides: under room temperature, 2-substituted benzimidazole derivatives were synthesized in one pot with aromatic o-amino disulfides and aromatic aldehydes as raw materials under the catalysis of FeCl 3 • 6H 2 O (Fig. 1-7).

S S
The synthesis of benzimidazole by aromatic aminodisulfide and aldehyde with metal Synthesizing the oxidative cyclization reaction of o-amino and o-mercapto substituted aniline with aldehyde and alcohol, it can be concluded that the reaction mechanism is: o-amino and o-mercapto substituted aniline first forms schiff base with aldehyde, schiff base cyclizes with ortho-NH 2 to form hydrogenation intermediate, and dehydrates to form target product under the action of oxidant.
In 2016, Liu Zhimin et al. [8]proposed a method to synthesize nitrogen containing heterocyclic compounds, which has a high yield: with o-aminothiophenol and DMF as the reaction model, under the catalysis of B (C 6 F 5 ) 3 , CO 2 and Et 2 SiH 2 are used to promote the effect of allyl alcohol on α-For the effective hydration of hydroxy ketones, the yield of the target product benzothiazole can reach 99% at 120 for 24 hours (Fig. 1-8).This method combines B-(C 6 F 5 ) 3 with CO 2 in the atmosphere, which can effectively promote various types of cyclization reactions.It is also suitable for the synthesis of o-phenylenediamine and its derivatives with DMF.A series of nitrogen containing heterocyclic compounds (including benzothiazole, benzoimidazole, p-quinazolone, benzoxazole) can be obtained in 68% -99% yields.This work proposes a new method of preparing nitrogen heterocyclic compounds with metal free catalyst, and also uses carbon dioxide gas that causes greenhouse effect.However, this reaction has the disadvantages of expensive reagents and long reaction time.It is supposed that the possible reaction mechanism is that B (C 6 F 5 ) 3 activates DMF through electrostatic action, which makes it easier for the nucleophilic reaction to form formylated intermediate A, while dimethylamine is released by DMF, which further reacts with CO 2 and silane, pushing the reaction to the right to dehydrate molecule B to form C (Fig. 9).In 2014, Liu Zhimin, Gao Xiang and others in Liu Zhimin's research group [9]prepared benzothiazole with oaminothiophenol and carbon dioxide as raw materials under the joint action of solvent N-methylpyrrolidone (NMP) and catalyst organic base DBN, diethylsilane (Et 2 SiH 2 ) (Fig. 1-10).The yield of the reaction is 82%, but the reaction conditions are harsh and need to be carried out at high temperature.
The possible reaction mechanism:carbon dioxide and hydrosilane are activated by catalyst DBN (1,5-diazabicyclo

Preparation of Benzozoles by Microwave Irradiation
In recent years, microwave radiation has become a widely accepted unconventional energy source in organic synthesis, and has been widely used in cycloaddition reaction, radioisotope synthesis, fullerene chemistry, polymer generation, pharmaceutical chemistry, green chemistry, etc. Microwave assisted organic synthesis, with heating speed and heating efficiency unmatched by traditional heating methods, has the advantages of mild reaction conditions, short reaction time, good reaction selectivity and high product yield.Microwave heating converts electromagnetic energy into heat energy.Energy transmission is caused by dielectric loss, which is contrary to the conduction and convection process observed in traditional heating.The amount of heat heated depends on the dielectric properties of molecules, which means that radiation and heating can be selectively absorbed.Microwave radiation makes the whole volume of materials rapidly heated at the same time, while traditional heating is to slowly transfer heat to the surface of the sample through heat conduction, and then gradually transfer it to the interior of the sample.The thermal effect observed under microwave radiation is the result of reverse heat transfer.The selective absorption of microwave radiation by polar compounds or solvents can rapidly heat the sample inside.After absorbing microwave energy, reactants can improve the reaction process and change the selectivity of the reaction.
In 2015, Kattimani et al. [10]proposed the method of synthesizing benzimidazole in 70% HCl medium using microwave heating and o-phenylenediamine and N, Ndimethylformamide (DMF) as raw materials.Moreover, it proved that this method has good universality.Different Csubstituted amides were used to replace DMF to obtain 2substituted benzimidazoles with yields of 80% -92%.The similarities and differences between conventional heating method and microwave assisted method were compared.This method has short reaction time, simple operation and no catalyst, but it still requires the presence of strong acid (70% HCl) and harsh reaction conditions (Fig. 11).

Conclusion
The above classification and summary of the synthesis of benzoxazole compounds (benzimidazole, benzothiazole, benzoxazole and its derivatives) are based on the reaction mechanism.Although these methods have made outstanding contributions to the synthesis of benzoxazole compounds, the current methods still have some shortcomings, such as very high requirements for reaction conditions, difficult access to raw materials, trivial reaction steps, low yield, etc.Through the summary of this paper, the basis for the next step to establish a more green, more economical and easier to operate synthesis method is laid.

Figure 5 .
Figure 5.The synthesis of benzimidazole by O-phenylenediamine and Ortho-ester

3 OFigure 6 .
Figure 6.The synthesis of benzimidazole by O-phenylenediamine and aldehyde with metal

Figure 10 .
Figure 10.The synthesis of benzothiazole by O-aminobenzene and CO2