Synthesis And Application Of Coumarin Bis-heterocyclic Compounds

Coumarins are an important class of heterocyclic compounds with a wide variety of species.In recent years,heterocyclically modified coumarin derivatives have been widely used in pharmaceutical,analytical,dye,optoelectronic and other fields.The 3-position on the coumarin ring is a reactive active site,and an organic reaction can be used to introduce another heterocycle into the 3-position of coumarin to obtain a double heterocyclic coumarin derivative.In this thesis,three coumarin bis-heterocyclic derivatives were synthesized based on the exploration of the synthesis mechanism of heterocyclic compounds and the combination method of heterocyclic compounds with coumarin analogues.The research contents are as follows:（1）3-（3-coumarinyl）acrolein with conjugated structure and active aldehyde group was obtained by the reaction of 3-acetylcoumarin with Vilsmeier reagent.The reaction yield was highest at 60℃when the amount of 3-acetylcoumarin was 4 mmol,the amount of phosphorus trichloroxylate（POCl₃）was 1.6 m L,and the amount of DMF was 8 m L.The obtained coumarin acrolein was subjected to a multicomponent reaction withβ-dicarbonyl compounds to obtain 2coumarin pyran compounds.5 coumarin pyridine derivatives were obtained by adding ammonium acetate to the multicomponent reaction system.All 7 compounds synthesized above were reported for the first time.（2）Under the condition of 150 W microwave radiation,14 coumarin thiazole hydrazone compounds 9 were synthesized by one pot reaction of 3-（2-bromoacetyl）coumarin,thiosemicarbazone and aromatic formaldehyde for 15-20 minutes with ethanol as solvent without adding any catalyst,of which 10 compounds were reported for the first time.The recognition of compounds to metal ions and the aggregation activity of compounds to Aβ_1-42were investigated.The results showed that compound 9l showed good UV-Vis and naked eye recognition ability for Cu²⁺,CO²⁺and Ni²⁺in 13 different metal ions.The titration results show that compound 9l forms a 1:1 complex with Cu²⁺,and 9l forms a 2:1 complex with CO²⁺and Ni²⁺respectively.When p H is 3,compound 9l can selectively recognize Cu²⁺.Compound 9m showed the strongest inhibition of self-induced Aβ_1-42 aggregation and was stronger than the natural product curcumin,while compound 9n showed the strongest inhibition of Cu²⁺-induced Aβ_1-42 aggregation and was comparable to curcumin.Studies on the cytotoxicity of compounds9h,9i,9m and 9n showed that the survival rate of human cervical cancer cells（He La）was higher than 75%after 24 h of culture,indicating that the compounds are biocompatible and have no significant cytotoxicity to living cells.（3）Under ethanol reflux conditions,p-toluenesulfonic acid was used as a catalyst and acetyl coumarins were linked to aliphatic primary amines by imine bonds to synthesize 6derivatives with nitrogen-containing heterocyclic imine coumarins 11,all 6 compounds are reported for the first time.Three of these compounds,11a,11b and 11c,were investigated for cholinesterase activity inhibition.The results showed that all three compounds had some inhibitory effect on acetylcholinesterase,and compound 11c showed the best inhibition of acetylcholinesterase activity with an IC₅₀ value of 4.28μM.Based on the synthesis of heterocyclic compounds and the combination of heterocyclic compounds and coumarins,three kinds of heterocyclic coumarins were synthesized:coumarin pyridine/pyran bis-heterocyclic compounds,coumarin thiazole hydrazone compounds and nitrogen-containing heterocyclic imine coumarin derivatives.Since these heterocyclic coumarins have two or more heterocyclic skeletons,they have certain research significance in pharmaceutical,analytical and other applications.There are 120 schemes,23 tables and 111 references in this thesis.