Studies On The Synthesis Of Nine-membered Nitrogen Heterocycles Through [3+2] Cycloaddition/[3,3]-Rearrangement

As one of the most concerned medium-sized?8-12 ring?heterocyclic compounds,nine-membered nitrogen heterocyclic compounds exist widely in natural products and bioactive drug molecules.Due to its rigid structure,it has played important roles in the design of drug molecules and the control of pharmacological activity.At the same time,it is also an important organic synthesis intermediate,which can be converted into novel nitrogen heterocyclic compounds by simple chemical reactions,such as the formations of indole and pyrrole rings,as well as other important nitrogen heterocyclic frameworks.Therefore,the construction of nine-membered nitrogen heterocyclic compounds is a very significant research topic.As an important 1,3-dipole in organic synthesis,nitrone can participate in many cycloaddition reactions.Recently,N-vinyl-?,?-unsaturated nitrones have attracted much attention in organic synthesis due to their rich chemical conversion of the double bonds on N-atom.This thesis focuses on the development of novel methods to construct nine-membered nitrogen heterocyclic compounds through intermolecular[3+2]cycloaddition/[3,3]-rearrangement cascade strategy from N-vinyl-?,?-unsaturated nitrones with different electrophiles such as arynes and methylenecyclopropanes,and the further application of the obtained the nine-membered nitrogen heterocyclic compounds.Based on these results,we designed a new N-arylation/[3+2]cycloaddition/[3,3]-rearrangement cascade reaction to synthesize 2,3-quaternary fused indolines alkaloids by using alkynyl oximes as the substrates.This thesis is divided into the following four parts:In the first part,we established the method for the synthesis of nine-membered nitrogen heterocycles from the[3+2]cycloaddition/[3,3]-rearrangement of N-vinyl-?,?-unsaturated nitrones and arynes.It was found that nine-membered nitrogen heterocyclic compounds were efficiently synthesized in acetonitrile in the presence of cesium fluoride as base at room temperature.The reaction had a wide range of substrate scope,good compatibility of functional groups,simple operation,and easy gram scale preparation.The study of electronic effect and steric hindrance effect revealed that different substituents on arynes had great influence on the regioselectivity of[3,3]-rearrangement.We further demonstrated the regular of N-O bond cleavage for the obtained nine-membered N-heteroycles and it was found that polysubstituted pyrrole-tethered benzopyrans and linear ketone-substituted phenols were obtained in good yields by zinc powder reduction and iron/copper co-catalyzed selective N-O bond cleavage,respectively.In the second part,we investigated the synthesis of nine-membered nitrogen heterocyclic compounds containing three stereocenters with high diastereoselectivity from[3+2]cycloaddition/[3,3]-rearrangement from N-vinyl-?,?-unsaturated nitrones and methylenecyclopropanes.Mechanistic studies indicated that Yb?OTf?₃ catalyst can not only accelerate the reaction and shorten the reaction time,but also improve the diastereoselectivity of the reaction affording kinetically controlled cis-diastereomer as the main product.Under the thermal conditions,the thermodynamically controlled trans-diastereomer was obtained as the main product.The nine-membered nitrogen heterocycles containing estrone and cholesterol were easily prepared by this method.The enantioselective synthesis of nine-membered nitrogen heterocycles was studied through chiral auxiliary group and asymmetric induction,respectively.In the third part,we explored the efficient construction of nine-membered nitrogen heterocycles fused endoperoxides containing five stereocenters through a new cascade process of Yb?OTf?₃-visible light relay catalysis for[3+2]cycloaddition/[3,3]-rearrangement and[4+2]cycloaddition with air from N-vinyl-?,?-unsaturated nitrones and methylenecyclopropanes.The reaction had a wide range of substrate scope,good compatibility of functional groups,and easy gram scale preparation,and features atomic economy and the formation of seven new chemical bonds in one step.The developed cascade method was also used to modify estrone and cholesterol to afford estrone and cholesterol derived nine-membered nitrogen heterocycles fused endoperoxides in good yields.Moreover,asymmetric relay catalysis has also been realized to afford nine-membered nitrogen heterocycles fused endoperoxides with good enantioselectivity.The study of biological activity showed that some nine-membered nitrogen heterocycles fused endoperoxides had good anti-inflammatory activity.In the fourth part,we studied the method for the synthesis of 2,3-quaternary fused indoline alkaloids in one pot though N-arylation,[3+2]cycloaddition and[3,3]-rearrangement cascade strategy from alkynyloximes.This reaction provided various fused indolines skeletons,simultaneously generated four new chemical bonds,formed two quaternary carbon centers,and produced five and six-membered ring skeleton.Further study showed that when the oxygen atom connecting to the alkynyl group was replaced by a nitrogen atom,the[3,3]-rearrangement product 2,3-fused indoline and[1,3]-rearrangement product 3,4-fused tetrahydroquinoline were both obtained in moderate yields.The obtained 2,3-quaternary fused indoline were converted into various indoline and quinoline skeletons through simple chemical reactions.