Studies On Multi-component Construction Of Pyrrole Coumarin Derivatives And Synthesis Of Broad-spectrum Fungicide-Picoxystrobin

This thesis aims at the research on efficient construction of a series of novel pyrrole coumarin derivatives through multi-component reaction strategy.Also,the studies on synthesis of broad-spectrum fungicide—Picoxystrobin has also been developed.It was mainly divided into two parts:Part 1:Multi-component construction of pyrrole coumarin derivativesCoumarin derivatives are known to have various different biological properties,such as antifungal,antiviral,anti-inflammatory,antitumor,and antioxidant activities,while pyrroles are the core structural units in natural compounds and synthetic drugs.Multicomponent reactions can construct multifunctional and diversified small molecule libraries efficiently and rapidly,which can be used to screen lead compounds with pharmacological activity.This part mainly introduced pyrrole ring into coumarin nucleus by using the multi-component reaction strategy to synthesize a series of pyrrole coumarin derivatives,which could enrich the kinds of coumarin derivatives.Some compounds were also tested for their antitumor activities.Details are as follows:In the first chapter,the application of multicomponent reaction in the construction of pyrrole derivatives is reviewed according to the different types of substrates.In the second chapter,a novel and efficient 1,4-diazabicyclo[2.2.2]octane(DABCO)-catalyzed three-component domino reaction was developed to construct 3-pyrrole-4-hydroxycoumarin derivatives from ?-aminocinnamic acid esters,arylglyoxal monohydrates,and 4-hydroxycoumarin.This method has the advantages of mild reaction conditions,short reaction time and a good functional group tolerance.Then,some compounds were tested for their antitumor activities in vitro using MTT method.Unfortunately,most of compounds have no inhibitory effect on A-549 tumor cell lines.In the third chapter,a concise and efficient synthetic approach has been developed for the construction of chromeno[4,3-b]pyrrol-4(1H)-ones via multi-component reaction of 4-aminocoumarin,arylglyoxal monohydrates,and aromatic amines or 1,3-dicarbonyl compounds.The attractive features of this protocol are operational simplicity,short reaction time,easy purification of products,good atomic economy and good to excellent yields.MTT assy showed that these compounds have moderate inhibitory effect on MCF-7,H446 tumor cell lines.Compounds 8g,8n,8q have good inhibitory effect on MCF-7,H446 tumor cell lines,which have the potential for further research.In the fourth chapter,a domino cyclization between 3-aminocoumarins and arylglyoxal monohydrates in the presence of para-toluenesulfonic acid(p-TSA)as a promoter was employed for the synthesis of two libraries of chromeno[3,4-b]-pyrrol-4(3H)-one derivatives.The solvents toluene and ethanol served important roles in the selective formation of the pyrrolocoumarin derivatives characterized by their different substitution patterns.The new protocol features operational simplicity,good yields and the absence of aqueous workup procedure and chromatographic separation.Then,some compounds were tested for their antitumor activities in vitro against A-549 cell using MTT method,and the results showed that compounds 12 had no inhibitory effect on A-549 tumor cell lines,while compounds 13 exhibited certain biological activities for inhibition of A-549.Part 2:Synthesis of broad-spectrum fungicide-PicoxystrobinAs a new type of methoxyacrylate fungicide,Picoxystrobin has great market potential due to the characteristics of high efficiency,low toxicity and good environmental compatibility.Chapter five introduces the main technical route of Picoxystrobin,based on the analysis of the advantages and disadvantages of each route,we gave the improved process for the preparation of Picoxystrobin.3-isochromanone 14 was used as the raw material,which reacted with trimethyl orthoformate by using BF3·OEt2 as catalyst,to get E configuration of methoxyl acrylic ester 15.Methyl(E)-2-(2-(chloromethyl)phenyl)-3-methoxyacrylate 16 was then obtained after ring-opening reaction with SOCl2 and esterification reaction with methanol.Nucleophilic substitution reaction of 16 with 2-hydroxy-6-trifluoromethylpyridine 21 to afford the final product Picoxystrobin.Compared with the existing routes,the formyl trimethyl orthoformate/boron trifluoride ether system completed the formylation and methylation transformation in just one step,which made the process short and high yields,as well as avoiding the use of the low boiling point reagent(methyl formate)and highly toxic methylation reagents(dimethyl sulfate).