Cross-Dehydrogenative Coupling Of Unactivated Acyclic Ethers And Terminal Alkynes

a-substituted saturated unactivated acyclic ether is a widely existing basic structural unit in medicinal and organic chemistry that can be found in many biologically active molecules and pharmaceuticals.The rapid and efficient construction of such compounds is of great significance.There have been many reports of traditional methods for synthesizing this type of compound.Although these classical synthesis methods can obtain multiple alpha-substituted saturated open-chain ethers in good yield,usually functional groups or highly active reaction sites that needs multiple steps’ convension are necessary.This not only leads to poor step economy and atomic economy,and usually the starting material and final product are also quite different.It is disadvantageous to the construction of a structurally similar compound library.So researchers are still working hard to find a simple,straightforward,and efficient way to build such compounds.On the other hand,alkynyl has demonstrated important functionalities in the fields of biology,chemistry,materials science and medicine.There are often alkyne groups present in drug molecules.And also,alkyne groups can be modified,and introduction of alkyne groups in the molecule facilitates its further functional group transformation.If alpha-alkynyl substituted saturated open-chain ethers can be constructed using the method of hydrocarbon functionalization,one can quickly build a library of structurally similar compounds,to meet the needs of drug activity screening,and helps discover new pharmaceutically active molecules.Direct and efficient hydrocarbon functionalization has good atom economy and meets the requirements of green chemistry.In recent years,great attention has been paid and considerable development has been achieved.Cross dehydrogenation coupling(CDC)reaction is a representative reaction.However,the current studies of CDC reactions mainly focused on the alpha atom of the nitrogen atom.Due to low activity and other reasons,reactions of ethers involved in CDC are limited and mainly focused on cyclic ether and benzyl ether structures.And the CDC reaction of saturated ethers mainly depends on peroxide-mediated oxidation system which usually require severe conditions such as high temperatures and neat.Therefore,by developing a suitable mild oxidation system,direct-hydrocarbon functionalization of this class of substrates with efficiency and diversity is of great importance.In this work,we found that triphenylcarbonium ions can be used to mediate the cross-coupling reactions of saturated acyclic ethers and terminal alkynes.First we chose diethyl ether as the initial substrate and phenylacetylene as another coupling component.By screening various forms of triphenylcarbonium ion source and Lewis acid,Ph3CCl and GaCl3 were selected for in situ formation of triphenylcarbonium cations as the oxidant using cuprous iodide as a catalyst.After selecting the appropriate optimal reaction conditions,we evaluated the range of substrates for this CDC reaction.It was found that whether the electron donating group or the electron donating group is attached to the arylacetylene,CDC with ether can occur at room temperature.Furthermore,heterocyclic arylenes and alkyl-substituted acetylenes are also compatible.And for the extension of the range of ether substrates we found that this reaction is not only applicable to diethyl ether,but also to simple symmetric linear ethers such as propyl ether.Due to the moderate yield for the reaction of alkyl substituted terminal acetylenes,we also extended the substrate with an alkyl-substituted alkynyl boron reagent as a coupling component.Oxidative hydrocarbon alkynylation of a variety of alkyl-substituted alkynyl boron reagents can take place when ethers are diethyl ether,propyl ether and butyl ether in good yields.Alkyl substituted terminal alkyne containing common benzyl ether functional group is also compatible with oxidation systems,providing new reaction sites for subsequent functional group transformations.We have successfully developed a method using triphenylcarbon cations as oxidant and report the CDC reaction of saturated acyclic ethers and terminal alkynes for the first time.Under Ph3CCl/GaCl3-mediated mild oxidation conditions,CDC of saturated acyclic ethers with a range of aryl and alkyl substituted alkynes can occur at room temperature with up to 73%yield.The reaction does not require the use of a large excess of ether as a solvent,thus exhibiting good atom economy.Due to the moderate yield of alkyl substituted terminal acetylenes,we also extended the substrate with an alkyl-substituted alkynyl boron reagent as a coupling component and got a good yield.