Preparation Of [2.2.2] Bicyclic Cycloalkyne Precursors And Their Reactivity Studies

Multi-substituted bicyclic stereocyclic structures exist widely in drug molecules and natural products,so how to efficiently construct polysubstituted bicyclic stereocyclic cycloalkyne structures is of important significance.As a family of highly reactive intermediates,angle-strained cycloalkynes have the advantage of facilely achieving ortho-bifunctionalization.Among them,the research on non-aromatic cycloalkynes lags far behind that of aromatic cycloalkynes.The main reasons are harsh production conditions,low reaction efficiency,and poor functional group compatibility.In recent years,non-aromatic cycloalkynes such as cyclohexyne have gradually attracted people’s attention,but these reports are also limited to two-dimensional planar cyclic alkynes,and few studies on cycloalkynes with three-dimensional configuration have been proposed and explored.In the previous study carried out by our previous group members,the preparation of the polysubstituted cyclohexyne precursors via oxidative dearomatization of Kobayashi aryne precursors was achieved.Inspired by this work,this thesis proposes that the aryne precursor could be converted into multi-substituted cyclohexylenetriene precursor,which can then form a cycloalkyne precursor with poly-substituted [2.2.2]bicyclic stereo configuration through a [4 + 2] reaction.After screening a series of reaction conditions,we found that phenylene precursors containing hydroxyl,under the action of iodobenzene acetate,could be oxidized and dearomatized to form cyclohexylenetriene precursors,both the TMS and OTf groups of which would not be affected in the process,and the resulting cyclohexylenetriene precursors could be further converted to other functional groups.Furthermore,we could activate the cyclohexylenetriene precursors and captured the cyclohexylenetriene intermediates using 2,5-dimethyl furan,obtaining the [4 + 2] cycloaddition product and confirming the generation of the cyclohexylenetriene intermediates in this reaction process.Subsequently,various Diels-Alder reactions were carried out between cyclohexylene-triene precursors and dienophile dienes with different configurations.After optimization of these conditions,cycloacetylene precursors with multiple substituted [2.2.2] bicyclic stereo configurations were effectively prepared.Finally,we studied the reactivity of these [2.2.2] bicyclic cycloalkyne precursors under fluoride-induced activation conditions,bicyclic cycloalkyne precursors 13(Preparation of cyclohexadiene precursor 1 and N-Phenylmaleimide)can afford [2.2.2] bicyclic cycloalkyne intermediates,which were captured by 2,5-dimethylfuran;whereas,other[2.2.2] bicyclic cycloalkyne precursors did not yield the desired product.The reason may be that these cycloalkyne precursors are prone to reverse Diels-Alder reaction,and cyclohexyltriene precursors are formed and then react with the corresponding compounds.In order to solve the problem that [2.2.2] bicyclic cycloalkyne precursor is prone to reverse Diels-Alder reaction,we try to break the nitrogen-oxygen bond on[2.2.2] bicyclic cycloalkyne precursor 17(Preparation of cyclohexadiene precursor 1and tert-Butyl N-hydroxycarbamate)through reduction reaction.Unfortunately,after attempts with different conditions,we did not yield any desired product.In summary,although our study on [2.2.2] bicyclic cycloalkyne precursors encounters some difficulties in the subsequent reactivity test,the concept on cycloalkyne precursors bearing [2.2.2] bicyclic stereoconfiguration is proposed for the first time in this thesis and the successful preparation of the cycloalkyne precursor laid the research foundation for the study of the bicyclic stereo configuration of cycloalkyne.