Investigation on the Dearomatization of Proparindole to Construct Polycyclic Indolines and the Multi-Component Ring-Opening Reaction of Cyclic Ethers

Author:Lu Lin

Supervisor:yin biao lin


Degree Year:2019





Indole alkaloids,one of the largest classes of alkaloids,serve as an important and rich source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical transformations and synthetic strategies.Polycyclic indoline scaffolds are widespread found in such alkaloids.Therefore,the synthesis of indolines and derivatives has become an important research topic in organic and medicinal chemistry.Dearomatization of indole is a powerful synthetic strategy providing a direct and economical way to construct architecturally complex polycyclic indolines.Due to enormous efforts devoted to this field,a great number of elegant indole dearomatization reactions have been developed in the past decades.It mainly includes arylation,allylation,halogenation,etc.dearomatization reactions and[2+2],[3+2],[4+2],etc.cycloaddition reactions.However,there are few reports on the alkenylation dearomatization reaction and indole dearomatization[2+2+1]cycloaddition reaction is rare.Therefore,it is very necessary to develop new alkenylation dearomatization reactions and[2+2+1]cycloaddition reactions to construct structurally complex polycyclic indoline.Cyclic ethers,such as THF,1,4-dioxane,and THP,are readily available compounds that can be efficiently transformed into other useful molecules,and thus have attracted much attention from synthetic chemists.The cyclic ether ring-opening reaction in which the previously reportedα-diazo ester is involved is mostly a reaction between two molecules,and most of them require noble metal catalysts.Oku once reported a photolysis three-component reaction of diazo esters,cyclic ethers under metal-free conditions,but the narrow substrate scope and low yields of products limited its application.Therefore,it is necessary to develop highly efficient three-membered cyclic ether ring-opening reaction of anα-diazo ester,a cyclic ether and nucleophilics.In this context,we have studied the synthesis of polycyclic indolines and and multi-component ring-opening reaction of cyclic ether.A series of new results will be presented in the following:Firstly,we have developed a protocol for access to polycyclic sulfonyl indolines via formal[2+2+1]cyclization reactions of N-(1H-indol-3-yl)methyl)propiolamides with NaHSO3 driven by FeCl2 catalysis or UV irradiation in an aqueous medium at room temperature.We used a special 1,6-enyne starting material with a double bond of indole instead of a common double bond to synthesize a series of structurally novel polycyclic sulfonyl indolines under mild green conditions.In addition,the reaction can be extended to the gram scale and a fairly good yield can be obtained.This is the first dearomatization[2+2+1]cycloaddition reaction involving sulfur dioxide as the 1 atom unit.Such[2+2+1]cycloaddition reactions will provide useful research information for the cycloaddition reaction of sulfur dioxide.Subsequently,due to the nucleophilicity of indole C3 position,and the highly-unsaturated and electron-rich nature of alkynyl group,those indoles tethered an alkynyl-containing side chain accordingly were frequently employed as a privileged substrates for the construction of indolines via dearomatizing alkenylation of the indole ring.Using amide branch and acetylene-containing indole derivatives synthesized by the Ugi reaction in one step,we developed a metal-free catalytic dearomatization tandem cyclization reaction to construct complex polycyclic indoline compounds in one step.Firstly,under the catalysis of base,the the third position of indole attacked the alkyne to obtain a spiroindolenine,and then the intramolecular amide bond attacks the imine bond to obtain polycyclic indoline.The construction of carbon-carbon bond under the catalysis of Bronsted base in this reaction is a very novel way to construct carbon-carbon bonds.The reaction requires only a catalytic amount of base to obtain corresponding products in a high yield at room temperature,and the universality of various functional groups of the substrates is very good and atomic utilization up to 100%.Considering the driving force of aromatization,many spiroindolenines obtained by indole dearomatization are easily rearranged to form polycyclic indoles.We designed another proparindole without the formamide branch.Therefore,we have developed a copper and base catalyzed proparindole tandem dearomatization cyclization reduction reaction to synthesize spiro indoline compounds.Not only avoided the risk of aromatization but also improved the economics of the steps.First,a spiroindolenine is formed under the catalysis of base,and then the carbon-nitrogen double bond is reduced by the Cu-H species to obtain the final spiroindolines.The method has good universality of substrate functional groups and provides a new means for dearomatization of indole.Lastly,a protocol for three-component reactions of cyclic ethers,α-diazo esters,and weak N,O,C,and S nucleophiles(pKa=2.2-14.8)to afford a variety of structurally complexα-oxyalkylated esters is reported.These reactions involve intermolecular activation of the cyclic ether(present in excess)by theα-diazo ester to form an oxonium ylide under metal-free conditions,followed by ring opening by the nucleophile.The reaction has the advantages of good regioselectivity,high yields and wide universality of the substrates.And we investigated the use of this protocol for modification of two pharmaceutical compounds.