The Regioselectively Electrochemical Synthesis Of 1,2,3-Triazole And Their Application In Drug Hunting

As an important nitrogen-containing heterocyclic compound,N-sulfonyl-1,2,3-triazole has a wide applications in the design,synthesis and structural optimization of drug molecules.Its structural diversity synthesis and regioselective transformation is a hot research topic in this field.Based on our previous work about a high regioselective synthesis of N~2-substituted-1,2,3-triazole via a radical pathway,we attempted to develop a novel method to trigger the controllable generation of radicals and realize the regioselective synthesis of 1,2,3-triazoles.In this thesis,a new method based on the electrochemical synthesis of N~2-substituted-1,2,3-triazoles was developed by triggering the triazole radical through the electrochemical condition.Through this method,we synthesized a series of N~2-substituted-1,2,3-triazole derivatives with the substitution of different oxygen-containing heterocycle,providing a new route for the synthesis of1,2,3-triazole derivatives.This thesis contains five main chapters:In the first chapter,we present the biological activities of 1,2,3-triazole derivatives and their applications as the bioisosteres in the studies of drug hunting.Based on such research background,we make the description on the development of the synthesis of 1,2,3-triazole and highlight the regioselective synthesis of N~2-substituted-1,2,3-triazole through the free radical pathway and other synthetic strategies.Finally,we introduce different radicals initiated by electrochemical reactions and the challenges of realizing the synthesis of N~2-substituted-1,2,3-triazole through the electrochemical reaction.In Chapter 2,we introduce the electrochemical synthesis of N~2-substituted-1,2,3-triazoles with oxygen-containing heterocycles.Through the initial exploration of the reaction and screening of the conditions,we realize the C-H amination reaction of N-sulfonyl-1,2,3-triazole with tetrahydropyran or tetrahydrofuran under mild conditions and synthesize a series of N~2-oxygen-containing heterocycle-substituted-1,2,3-triazole derivatives in a good yields with regioselectivity.Through the control experiments and DFT calculations to investigate the reaction mechanism,we confirm the radical process in the electrochemical reaction and found that the formation of nitrogen radical-cation instead of traditional radical in 1,2,3-triazole leads to the high regioselectivity of the electrochemical reaction.In Chapter 3,we developed the electrochemical synthesis of N~2-oxygen-containing benzo-heterocycle-substituted-1,2,3-triazole and obtained N~2-isochroman-substituted-1,2,3-triazole products in good yield.Isochroman and other oxygen-containing benzo-heterocycles have multiple competing pathways for side reactions.After dealing with the problem of byproduct and screening the reaction conditions,we synthesize several N~2-substituted-1,2,3-triazole derivatives with the oxygen-containing benzo-heterocycle.In addition,we also conducted the control experiments to prove that the electrochemical synthesis of N~2-benzoxazolyl-substituted-1,2,3-triazole undergoes a radical process.In Chapter 4,we screened the inhibitory activity against human colorectal cancer HCT116based on the N~2-substituted-1,2,3-triazole hemiamine ether derivatives synthesized by our previous works,and found that part of the N~2-substituted-1,2,3-triazole derivatives show great inhibitory activity against HCT116.These results demonstrate that the introduction of different heterocycles into the backbone of 1,2,3-triazole can play a vital role on the study of the biological activity of1,2,3-triazole derivatives and the design of new anticancer drug molecules.Chapter 5 is the conclusionChapter 6 is the experimental partIn this thesis,based on the radical reaction research of our group,the electrochemical synthesis of N~2-oxygen-containing heterocycle-substituted-1,2,3-triazole and N~2-oxygen-containing benzo-heterocycle-substituted-1,2,3-triazoles was developed by initiating the triazole radical as well as other radicals through the electrochemical pathway.The success of the electrochemical reaction provides a novel method for the synthesis of 1,2,3-triazole.