Studies On Dehydrogenative Diels-Alder Reactions Via A Thermal Reversible Process And Organocatalytic Cycloaddition-Elimination Cascade For Atroposelective Construction Of Heterobiaryls

The Diels-Alder reaction is a synergistic[4+2]cycloaddition reaction of conjugated diene with substituted alkyne and alkene through cyclic transition state to obtain unsaturated six-membered carbocycles and heterocycles,which is one of the most classical reactions of modern organic synthesis.This reaction not only features excellent regioselectivity and stereoselectivity,but also shows excellent enantioselectivity in asymmetric induction,which is often skillfully applied in the field of total synthesis of complex natural products and bioactive molecules.However,the diene or dienophile component is sometimes commercially unavailable and need to be pre-prepared.The dehydrogenative Diels-Alder(DHDA)reaction avoids extra steps for pre-functionalization of diene or dienophile in classical DA reaction,which greatly improves the synthesis efficiency and attracts the attention of organic chemists.Chapter 1:Research Rrogress of Carbo-DA Reactions and DHDA ReactionsThis chapter introduces the basic theory knowledge of the Diels-Alder reaction,including the definition,mechanism and characteristics.Given a large number of relevant literature reports on the Diels-Alder reaction,and our research group focuses on DHDA reaction to synthesize cyclohexene compounds,the first half of this chapter briefly reviewed the research progress of Carbo-Diels-Alder(Carbo-DA)reactions of all-carbon-based diene with dienophile,which contains Lewis acid-mediated racemic Carbo-DA reactions,metal-catalyzed asymmetric Carbo-DA reactions and organocatalytic asymmetric Carbo-DA reactions.In the latter part of this chapter,we elaborate on the research status of DHDA reaction and DDA reaction.Chapter 2:Metal-Free Dehydrogenative Diels-Alder Reactions of Prenyl Derivatives with Dienophiles via a Thermal Reversible ProcessAfter screening the reaction substrates and optimizing the reaction conditions,we developed a metal-free cross DHDA reaction between prenyl derivatives and dienophiles using 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ)as oxidative dehydrogenation reagent.This reaction overcomes the disadvantage of single dienophile in the previous work of our group,and realizes the synthesis of different types of monocyclic,dicyclic,tricyclic and spirocyclic compounds with high endo-selectivity,providing an efficient approach for the construction of different cyclohexene frameworks.We proposed a mechanism involved a Retro-Diels-Alder reaction process of the DDQ-adduct in the reaction for the first time by studying the reaction mechanism in detail.Chapter 3:Synthesis of Tetrahydroisoindolinones via a Metal-Free Dehydrogenative Diels-Alder ReactionTetrahydroisindolinone,a privileged structural motif,is widely distributed in natural and unnatural products.Many compounds derived from tetrahydroisoindolinone also exhibit considerable biological activities,such as anti-cancer,anti-inflammatory and anti-insect.Therefore,tetrahydroisindolinone is often used as the core skeleton in the development of new pharmaceuticals and agrochemicals.The synthesis of tetrahydroisoindolinone frameworks with novel structure is still facing urgent methodological demands in the fields of organic chemistry and medicinal chemistry,which has aroused widespread attention of synthetic chemists.Based on the study of DHDA reaction in the previous chapter,we have developed a metal-free dehydrogenative Diels-Alder reaction of substituted alkenes with maleimides in the presence of DDQ for the first time.The optimal reaction condition was determined by screening the reaction parameters such as quantity of oxidant,temperatures and solvents.This new method features functional group tolerance and broad substrate scope,providing an efficient access to biologically active tetrahydroisoindolinone skeletons with endo-steroselectivity in good to excellent yields.Chapter 4:Copper(I)/DDQ-Mediated Double-Dehydrogenative Diels-Alder Reaction of Aryl Butenes with 1,4-Diketones and IndolonesA synthetically useful copper(I)/DDQ-mediated double-dehydrogenative Diels-Alder(DDDA)reaction of simple butenes with 1,4-diketones and indolones has been established for the first time.This strategy is based on a tandem double-dehydrogenation/Diels-Alder reaction from non-prefunctionalized starting materials,in which both diene and dienophile were in situ generated via activation of fourfold inert C(sp~3)-H bonds in one catalytic system.The unprecedented DDDA reaction demonstrates broad substrate scope and affords valuable cyclohexene derivatives and spirocyclic oxindoles in good to excellent yields.In addition,mechanistic studies indicate the crucial roles of both DDQ and Cu I in the dehydrogenation process.Chapter 5:Organocatalytic Cycloaddition-Elimination Cascade for Atroposelective Construction of HeterobiarylsThe first chiral phosphoric acid(CPA)catalyzed cycloaddition-elimination cascade reaction of 2-naphtholand phenol-derived enecarbamates with azonaphthalenes has been established,providing a highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities.The success of this strategy derives from the stepwise process involving CPA-catalyzed asymmetric formal[3+2]cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate.In addition,the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.(?)...