Studies On Isocyanide-Based Multicomponent Reactions And The Synthesis Of Biological Activities Of Nitrogenous Heterocyclic Compounds

As a kind of important heterocyclic compounds,nitrogen-containing heterocyclic compounds are often applied in the structural units of natural products and drug molecules.Moreover,nitrogen-containing heterocyclic compounds are easy to carry out structural modification and could introduce various functional groups,which are widely used in organic synthesis,pharmaceutical design and new material development.Ugi reaction,Wittig reaction,van Leusen reaction and Biginelli reaction have the advantages of mild reaction conditions,simple operation,wide substrate applicability and high product yield,which provide a powerful tool for the synthesis of nitrogen-containing heterocyclic compounds.In this paper,the above reactions were employed to react with some post modification reactions,such as Michael reaction,for producing a variety of nitrogen-containing heterocyclic compounds,and the properties of these nitrogen-containing heterocyclic compounds were preliminarily explored.In addition,triazolylbenzopyrans derivatives were designed and synthesized by Knoevenagel condensation/Reduction/Nucleophilic substitution reaction.Because of cis/trans isomerism in condensation,triazolisoquinoline derivatives were obtained by C-H Activation/Nucleophilic substitution of cis isomers.Satisfyingly,their biological activities were explored and some compounds showed good biological activities.1.The research progesses and applications of multicomponent reaction,such as Ugi reaction,Wittig reaction,van Leusen reaction,Biginelli reaction,Michael reaction and triazole fungicides,were reviewed.2.The four-component reaction of the odorless isocyano(triphenylphosphoranylidene)acetates,aldehydes,amines and thiocarboxylic acids produced eighteen new unreported trisubstituted thiazoles?-5 in moderate to good yields in the presence of 1.0 equivalent of triethylamine.The two-component reaction between isocyano(triphenylphosphoranylidene)acetates and thiocarboxylic acids in the presence of triethylamine provided the corresponding nineteen disubstituted thiazoles ?-6 in good yields as well.Five of them are new compounds,and the other fourteen have been reported.Through NMR spectras and mass spectrometry the structure were verified.The method has the advantages of available raw material,mild reaction condition and high yields.Then preliminary screening experiments on the bactericidal,insecticidal and herbicidal activities of target compounds were carried out,the results showed that compounds ?-5n and ?-6g had 90%and 70%fungicidal effects on botryotinia fuckeliana at the concentration of 20 ppm.Compounds ?-6e,?-6g,?-6h,?-6i and?-6m had fungicidal activities on uromyces viciae-fabae of 90%,100%,72%,100%and 77%respectively at 100 ppm.The herbicidal activity on poa annua of compound ?-6q was 70%at 32 ppm.3.Azides,obtained from van Leusen reaction of 2-azidobenzaldehydes,amines and TosMIC(tosylmethyl isocyanide)in the mixed solvent of methanol and DME,reacted with triphenyl phosphine via Staudinger reaction to produce iminophosphorane.A tandem aza-Wittig reaction of iminophosphoranes with isocyanides generated twenty-one new unreported imidazoquinolines ?-7 through carbodiimide intermediates at 180? in moderate to good yields.Then through NMR spectras and mass spectrometry the structure were verified.Compared to other synthesis methods,the method has the advantages of available raw material,simple operation and catalyst-free.Then preliminary screening experiments on the bactericidal,insecticidal and herbicidal activities of target compounds were carried out.The results showed that the compounds ?-7c and ?-7r had 80%insecticidal activity on the myzus persicae at 50 ppm.4.A new efficient and diastereoselective synthesis of multisubstituted isoindolines with two stereogenic centers via sequential Ugi/aza-Michael addition reaction was developed.Ugi-3CR of aldehydes,amines and isocyanides in the presence of catalytic amount of H3PO4 produced intermediates,which were then transformed to thirteen new unreported isoindolines ?-5 with good diastereoselectivity in the presence of K2CO3 by intramolecular aza-Michael addition.Sequential Ugi-azide and aza-Michael addition reaction of aldehydes,amines and trimethylsilyl azide also produced ten substituted isoindolines ?-8 with good diastereoselectivity.Through NMR spectras,mass spectrometry and X-ray crystal analysis the structure were verified.Then preliminary screening experiments on the bactericidal,insecticidal and herbicidal activities of target compounds IV-5 and IV-8 were carried out respectively.The results showed that compounds ?-5h and ?-8b had 80%and 70%bactericidal activities against pythium dissimile at the concentration of 2 ppm respectively.Compound ?-5h had 90%herbicidal activity on arabidopsis thaliana at 10 ppm.5.A mild and highly diastereoselective synthesis of multisubstituted dihydropyrimidoisoindolones/thiones via sequential Biginelli/aza-Michael addition reaction starting from relatively stable o-acrylate benzaldehyde precursors was reported.Intermediates,originated from Biginelli reaction of aldehydes,ethyl acetoacetates and ureas/thioureas in the presence of 1.0 equivalent hydrochloric acid instead of metal catalysis,immediately underwent an intermolecular cyclization reaction in the presence of Cs2CO3 to receive nineteen dihydropyrimidoisoindolones/thiones V-5.Through NMR spectras,mass spectrometry and X-ray crystal analysis the structure were verified.This one-pot process resulted in new and unreported heterocycles--dihydropyrimido[6,1-a]isoindol-1-ones/thiones V-5-with good diastereoselectivity in good to excellent yields.Then preliminary screening experiments on the bactericidal,insecticidal and herbicidal activities of target compounds V-5 were carried out respectively.The results showed that compound ?-5b had 90%fungicidal activity against minimal media zymoseptoria tritici at 20 ppm.6.Using o-iodobenzaldehydes and ?-zolylketones as raw materials,trans/cis ?,?-unsaturated ketones a were produced by Knoevenagel condensation reaction.Nine new unreported triazolylbenzopyrans derivatives were synthesized through corresponding cis ?,?-unsaturated ketones by reduction reaction/nucleophilic substitution reaction.Ten new unreported triazolisoquinoline ketone derivatives and nine new unreported triazolisoquinoline alcohol derivatives were unexpectedly synthesized by C-H Activation/Nucleophilic substitution reaction through corresponding trans ?,?-unsaturated ketones.Through NMR spectras,mass spectrometry and X-ray crystal analysis the structure were verified.At the same time,preliminary screening experiments on the bactericidal,insecticidal and herbicidal activities of target compounds were carried out respectively.The results showed that some of the compounds had good biological activities.Compounds ?-6b and ?-6f had better bactericidal effect on fusarium graminearum than commercial diniconazole.The fungicidal effect of compounds ?-6c and?-8f on magnaporthe grisea was also better than that of commercial diniconazole.Compounds?-6a,?-6i and ?-8a had 100%fungicidal activity against botryotinia fuckeliana at 20 ppm.CompoundsVI-7c had 100%fungicidal activity against minimal media zymoseptoria tritici at 20 ppm.CompoundsVI-6d and VI-6g had 100%insecticidal activity on the myzus persicae at 50 ppm.CompoundsVI-6b and VI-6d had 100%insecticidal activity on the plutella xylostella at 500 ppm.