Metal-Catalyzed Cascade Reaction:Efficient Synthesis Of Multisubstituted Triazoles And Oxindole Derivatives

1,2,3-Triazole is a key scaffold widely used in biochemistry,pharmaceuticals and material sciences.Recently,triazoles are utilized as ligands,directing groups for C-H activation and carbene precursors for organic synthesis.The Huisgen 1,3-dipolar cycloaddition of alkyne with azide was the traditional method toward 1,2,3-triazole.However,this cycloaddition usually needs high temperature and long reaction time.Furthermore,its regioselectivity is poor.In 2002,Sharpless,Fokin,Meldal and co-workers reported copper(I)-catalyzed azide-alkyne cycloaddition(CuAAC),which could deliver 1,4-disubstituted 1,2,3-triazole as a single product.The CuAAC reaction displayed numerous advantages,including high reaction efficiency,mild reaction condition,excellent regio-and chemoselectivities and general substrate scope,and thus has been recongnized as the essential of "click chemistry".The CuAAC reaction has received increasingly attentions for the past few years.Nevertheless,it could only activates terminal alkyne cycloaddition with azide,delivering 1,4-disubstituted 1,2,3-triazole.The activation energy of cycloaddition between internal alkynes and azides is very high,leading to low reaction efficiency and unsatisfactory regioselectivity.The multi substituted 1,2,3-triazoles could be obtained through the C-H bond activation by using the 1,4-disubstituted 1,2,3-triazoles as starting materials.However,the cleavage of C-H bond usually requires rigorous conditions.Thus,this thesis focuses on developing a serious of methods to synthesize trisubstituted triazoles by metal-catalyzed cascade reaction.More details are as follow;Chapter I,we developed a Cu/Pd-catalyzed cycloaddition of alkyne,azide and aryl halide,delivering multisubstituted triazoles in one pot.The classic CuAAC reaction is limited to terminal alkynes.Internal alkynes are hardly activated by using the same reaction conditions to synthesize fully substituted triazoles.The transmetalation between cuprate-triazole and aryl palladium intermediate followed by reductive elimination could obtain the multisubstituted triazoles.This process was conducted under mild conditions with outstanding regioselectivity and widely substrate scopes.Notably,this chemistry could be used in the late-stage functionalization of bioactive natural products and amino acid derivatives.Chapter ?,we demonstrated copper-catalyzed click reaction producing bench-stable 5-stannyl triazoles,which could be carried out futher synthetic applications.The 5-copper(I)triazolide intermediate was trapped by Bu3SnOMe forming the target product 5-stannyl triazole.Although several metalated triazoles have been reported previously,most of them could not be isolated.The specific ligands would stabilize the metalated triazoles,but their applications are limited.The 5-stannyl triazoles were not sensitive to air,moisture,light,and could be stored at 4?for several weeks.The excellent advantages of these 5-stannyl triazoles allowed us to carry out Stille couplings.When the electrophilic trifluoromethylthiolating and trifluoromethylating reagents react with triazole tin compounds,fluorinated triazoles were obtained in good yield.Chapter ?,a Pd-catalyzed intramolecular arylation of unsaturated amides toward 3,3-disubstituted oxindole has been developed.3,3-Disubstituted oxindoles are privileged scaffolds present in pharmacologically active products and natural compounds.3,3-Disubstituted oxindole boronic esters have been efficiently synthesizes by palladium-catalyzed intramolecular arylation/borylation tandem reaction of unsaturated amides.Additionally,with the same reaction conditions except for switching the solvents,reductive Heck products were achieved.Control experiments indicated that deboration of oxindole boronic esters delivered the reductive Heck products.In chapter IV,we have developed an efficient method to construct pyrrolidine via Au-catalyzed direct tetrafunctionalization of nonactivated alkynes.Recently,direct difunctionalization of olefins has gained considerable attentions.Numerous metal-catalyzed or hypervalenthalogen-mediated oxyamidation,dioxygenation,diamination of alkenes have been reported.We extend this methodology to alkynes,and the pyrrolidine aminals were prepared successfully by using gold as catalyst.