Studies On Bifunctionalization Of Alkynes And Benzynes Catalyzed By Transition Metal

As the significant building blocks in modern organic synthesis,alkynes have been extensively utilized in the representative transition-metal catalyzed cyclization,isomerization,bifunctionalization and homologation reactions for the efficient manufacture of complex natural products,organic electronic materials,bioactive molecules,pharmaceutical agents,and others.Among the morden transformations of alkynes,the bifunctionalization reaction is one of the main methods for the regioselective and stereoselective synthesis of tri/tetra-substituted olefins,which exist widely in biologically active molecules and play an important role in the construction of molecular devices and liquid crystal materials.Although numerous powerful methods towards carbo-hetero functionalization of alkynes have been established recently,the achievements in dicarbofunctionalization of alkynes have still been limited.Consequently,it is highly desirable yet still challenging to develop expeditious and versatile protocols to realize dicarbofunctionalization of alkynes through novel strategies.Simultaneously,benzyne is a special and active alkyne containing ring tension.Recently,transition-metal-catalyzed benzyne chemistry has become a powerful platform for1,2-difunctionalization of arenes.In this field,the copper-catalyzed multicomponent reaction attracted our attention,because it provided opportunities for the efficient and practical synthesis of o-substituted anilines which are important structural units in pharmaceutical molecules.In this context,the work during my Ph.D.focused on the development of novel bifunctionalization reactions of alkynes and benzynes.This doctoral dissertation mainly contains the following two parts:?1?A regio-and stereoselective alkynylallylation reaction of electron-deficient internal alkynes through palladium-gold synergistic catalysis has been developed.This reaction affords a series of highly substituted 1,4-diene-6-ynes from simple starting materials in only one step.The alkynyl and allyl moieties generated from allyl propiolates were introduced into internal alkynes to afford the cross-dimerization products under certain conditions.Due to the importance of tetrasubstituted olefins,we have prepared a series of 1,6-enyne compounds by decarboxylation coupling using allyl propiolates and internal alkynes under the synergistic catalysis of palladium and gold catalyst.Such compounds exhibit particular properties due to the"linker"is electron deficient olefins.The reaction has good functional group compatibility,excellent regioselectivity and stereoselectivity,and the only by-product is CO₂.Mechanism studies indicated that the gold catalyst coordinated with alkyne moiety of intermiate instead of substrates.Alkynyl gold intermediate was captured by mass spectrum?MS?.Then we confirmed that vinyl gold intermediate generated from alkynyl gold and internal alkynes can react with allyl methyl carbonate under standard conditions to produce target product.Control experiments show that gold catalyst can significantly inhibit the formation of by-products.?2?A copper-catalyzed three-component reaction of in situ formed arynes,terminal alkynes and O-benzoylhydroxylamines has been developed.The product o-alkynyl anilines compound can be converted to indole derivatives under different conditions.The reaction has good functional group compatibility,include aryl group,alkenyl group,alkyl group and cycloalkyl.By adjusting reaction conditions,the nucleophiles in this transformation can be extended from terminal alkynes to benzoxazoles.This conversion takes advantage of cesium carbonate instead of potassium fluoride to activate the benzyne precursor.The phase transfer catalyst TBABF₄ was added to increase the solubility of cesium carbonate in toluene.At the same time,we found that the ligands paly a key role on the reaction efficiency,and Brettphos was selected finally.Due to the lower activity of benzoxazole,the reaction conditions were more harsh,so the amount of feed ratio,catalyst and base was relatively higher than terminal alkynes.However,this strategy solves the problem of o-benzoxazolyl aniline compounds which are difficult to synthesize by conventional methods.These procedures provide a modular and facile approach to o-alkynyl anilines and o-benzoxazolyl anilines from easily available substrates in only one step.