Divergent Synthesis Of Polysubstituted Benzimidazoles And Indazoles Based On Same Substrates

The isomer N-arylbenzimidazoles and N-arylindazoles are nitrogen-containing heterocyclic compounds with significant pharmacological activity.The extensive pharmacological activities of these compounds and their great application value as key intermediate for medicine have led to indepth research on them,their synthetic methods have always been one of the research hotspots of organic and medicinal chemists.At present,N-arylbenzimidazoles are prepared through the condensation of ortho-substituted aniline derivatives with carbonyls such as aldehydes,ketones,carboxylic acids under oxidative condition or metal catalysis.Although these strategies have the advantages of high catalytic activity and great substrate suitability,it still has disadvantages such as excessive amount of oxidant or metal catalysis,complicated after-treatment.On the other hand,the synthetic methods of N-arylindazoles include condensation of aryl hydrazines with ortho-halobenzoyl derivatives or benzynes,but these procedures have deficiencies such as complicated reaction conditions and low yields.In addition,according to literature reported,there are few reports on the synthesis of benzimidazoles from o-amino acetophenone oximes.Among them,there are very few reports on the selective synthesis of N-arylbenzimidazole and N-arylindazole from o-aminoacetophenone oxime.Therefore,it is the focus of our research to explore a new approach to synthesize N-arylbenzimidazole and N-arylindazole simply,efficiently and selectively.And it also has great research significance to provide a new and referable synthesis method for medicine development and synthesis of drug intermediates.Based on the green synthesis concept that our team has always persistence and combining with the survey of related literatures,this paper uses BTC as the reaction medium and Et₃N as the regulator to achieve the selective synthesis of N-arylbenzimidazoles and N-arylindazoles from o-aminoacetophenone oximes and the method is successfully extended to the synthesis of N-benzylindazoles.The main works of this paper are as followed:?1?A new method was developed to prepare N-arylbenzimidazoles.This method using N-arylsubstituted o-amino acetophenone oximes as substrates under the BTC condition and 19 N-arylbenzimidazoles were prepared.The mechanism study showed that the N-substituted o-amino acetophenone oximes undergo Beckmann rearrangement and intramolecular aza-cyclization reaction under BTC condition.This method has the advantages of easy availability of materials,simple operation and great yield.?2?A new method was developed to selectively synthesize N-arylindazoles.This method using Et₃N as the regulator and the N-arylsubstituted o-amino acetophenone oximes as substrates under the BTC condition and the method was successfully extended to the synthesis of N-benzylindazoles.22 N-substituted indazoles were prepared.The mechanism study showed that Et₃N plays two roles in the reaction process,a part of Et₃N neutralized the HCl and inhibiting the Beckmann rearrangement.In addition,the Et₃N served as a nucleophilic promoter thereby enabling a dominant intramolecular nucleophilic substitution reaction to afforded N-arylindazoles under Et₃N condition.This method has the advantages of high chemoselectivity,mild reaction conditions and good yield.The research of this paper further expands the scope of application of BTC and increase the choice of synthesis route of N-arylbenzimidazoles and N-substituted indazoles.Providing a new method for the development of nitrogen-containing medicine and the synthesis of drug intermediates.