Transition-Metal Catalyzed Oxidative Dehydrocyclization Reactions

Cyclic compounds are common in a variety of natural products and drug molecules.However,the construction of various types and sizes of rings during natural product synthesis and drug discovery has always been a challenging and crucial step.Direct oxidative dehydrocyclization has been the focus of organic chemists and conducted extensive research in recent years as an atom economical process.Transition metal-catalyzed oxidative dehydrocyclization shows great potential and application value in organic synthesis due to atomic and step economy,high efficiency of oxidative dehydrogenation,mild reaction conditions and high reaction selectivity.In this thesis,the transition metal-catalyzed oxidative dehydrocyclization is mainly studied from the following three parts.Part I:Palladium-catalyzed intramolecular direct oxidative amination reactions.According to the Baldwin's rules,5-endo-trig type cyclization is forbidden due to mismatch in molecular orbital overlap angles.Therefore,it is more challenging to construct the dihydropyrrole structure by this direct oxidative amination.In this part of the research work,we have carried out the palladium-catalyzed intramolecular amination reaction of alkenes with retention of olefin functionalization under mild reaction conditions.The direct oxidative coupling ofp-toluenesulfonyl protected amine and double bond under palladium catalyst gives a series of 2,3-dihydropyrrole derivatives very efficiently with moderate to high yields.In the condition optimization process,we found that only the chloride containing palladium catalyst can catalyze the reaction process.During the investigation of substrate compatibility,we found that the cyclization of 5-endo-trig occurs easily when the olefin branching sites have electron-withdrawing functional groups by reducing the energy of the intermediates.Through the KIE experiment,we confirmed that the reaction does not involve step-by-step C-H bond cleavage process.Part II:Rhodium-catalyzed macrocyclization via direct intramolecular oxidative cross-coupling of alkenes.The research on the oxidative cross-coupling reactions of intramolecular alkenes is very challenging due to the problems of many side reactions and lower catalytic efficiency.In this part of our work,we used a dilute solution strategy to control the chemo-selectivity of the reaction.Then we introduced a more ionic,stable and hindered additive to keep the activity and stability of the rhodium catalyst.Furthermore,we employed a strong directing amide group and Rh(?)catalyst with excellent coordination and C-H bond activation ability to control the stereoselectivity of the reaction.This reaction has very good chemo-and stereoselectivity,good atomic economy and functional group compatibility.At the same time,we also conducted a preliminary exploration of the late application transformation of macrocyclic diene fragments.Through the KIE experiihent,we confirmed that the reaction involves C-H bond activation process.Part ?:Copper-catalyzed dehydrogenative Diels-Alder reactions.Copper catalyzed dehydrogenative Diels-Alder reaction shows very important research value because it does not need to prepare unstable and toxic a,?-unsaturated carbonyl compounds.In this part of our work,we have first carried out the dehydrogenative Diels-Alder reaction of copper-catalyzed gem-esters and ketones with very good functional group compatibility and atom economy as well as very high dehydrogenation efficiency and yields.We found that electron-deficient bipyridyl ligand can improve the catalytic dehydrogenation efficiency in the reaction conditions screening.Moreover,we also found that the asymmetric diene has very good ortho and para selectivity in the process of substrate development.