Catalytic Ynamide Oxidation And Cycloisomerization Initiated Tandem Reactions

Ynamides are special substituted-alkynes that consist of electron-deficient N-atoms directly attached to C(sp).Due to their unique properties in organic synthesis,ynamides have attracted more and more attentions.Ynamides were regarded as privileged precursors for regiospecific synthesis of highly versatile nitrogen-containing molecules,especialy N-heterocycles.Various efficient synthetic methods utilzing ynamides had been established in the past decades.However,some remained challenging,like hydrations and dimerizations which were easily observed via π-acid catalysts,limited the development of ynamide.In view of the unique activity of ynamide and the high efficiency and atom ecomomy of tandem reactions,the central theme of this project is focused on the development of novol ynamide tandem reactions involving oxidation and cycloisomerization,which are difficult to achieve with common alkynes,for the construction of valuable compounds in particular π-heterocycles and extend the new solutions to unsolved problems in ynamide chemistry.This dissertation is divided into the following sections mainly:In the first part,the development of ynamide chemistry and tandem reactions are briefly introduced.Notably,various elegant protocols of efficient synthesis of versatile N-containing molecules,in particular N-heterocycles were summarized on the basis of literature review.On the basis of above mentioned background,the main research ideas for designing of the thesis are discussed.In the second part for the catalytic ynamide oxidation:(1)An efficient gold-catalyzed C-H functionalization of indoles,anilines by carbenoids generated through intermolecular oxidation of alkynes in water was studied.This strategy was successfully applied to the formal synthesis of the Pfizer’s chiral endothelin antagonist UK-350926.Importantly,it was revealed for the first time that such an oxidative gold catalysis could be assisted by water,which dramatically suppressed the overoxidation of ynamides into the diketones;(2)An efficient zinc(Ⅱ)-catalyzed tandem alkyne oxidation/C-H functionalization was developed,leading to highly site-selective synthesis of a variety of β-carbolines.Importantly,different from the well-established gold-catalyzed intermolecular alkyne oxidation,the relevant over-oxidation can be completely suppressed in such a non-noble metal-catalyzed oxidative cyclization and the reaction most likely proceeds by a Friedel-Crafts-type pathway on the basis of both mechanistic studies and theoretical calculations.In the third part for the catalytic ynamide cycloisomerization:(1)The reversal of regioselectivity in arene-ynamide cyclization by copper catalysis was studied,which represents the first catalytic π-tethered ynamide cyclization involving the reversal of regioselectivity.This strategy allows the expedient and practical synthesis of valuable azepino[4,5-b]indoles and β-carbolines in generally high yields under mild conditions.Moreover,the relevant mechanistic rationale for this cyclization,especially for the observed high regioselectivity,is strongly supported by density functional theory(DFT)calculations;(2)A Br(?)nsted acid-catalyzed tandem intramolecular alkoxylation/Claisen rearrangement/lactone expansion was developed,leading to the highly efficient and stereospecific synthesis of valuable indole-fused bridged[4,2.1]lactones.Significantly,the final lactone expansion represents an unprecedented metal-free intramolecular carbooxygenation of olefins by C-0 cleavage.Moreover,control experiments favor the feasibility of a carbocation pathway for the process.