Transition Metal-catalyzed ?-C(sp~3)-H Functionalization Of Ethers

Ethers are one of the most important and fundamental moieties presenting in bioactive natural products and synthetic drugs.Transition metal catalyzed C-H functionalization has evolved into a highly efficient,regioselective and atom-economical strategy for the organic synthesis.Therefore,the synthesis of diverse?-substituted ether compounds via transition metal catalyzed C-H functionalization is of far-reaching significance.In this dissertation,we described the synthesis of several?-substituted ethers by transition metal catalyzed?-C(sp3)-H functionalizations.Firstly,a palladium-catalyzed three-component reaction of N-tosylhydrazones,aryl halides and cyclic ethers was investigated.A series of?-alkyl cyclic ethers were synthesized through a three-component reaction and hydrogenation strategy using Pd(OAc)₂ as catalyst,DTBP as oxidant,Xphos as ligand and t-Bu OLi as base.The reaction had a wide range of substrate adaptability.The electronic and steric factors both had little effect on the reaction,and the products were obtained with excellent yields up to 95%.On the basis of the free radical trapping reaction and isotope labelling experiments,the intermediates and the sources of the hydrogen atom on the quaternary carbon in the product were verified.A plausible reaction mechanism including radical initiation,radical addition and radical disproportionation was proposed.This strategy combined a multi-component reaction with C-H functionalization,which provided a viable method for the synthesis of ether-containing compounds.Next,a nickel-catalyzed selective decarboxylation cross-coupling of ethers with arylpropiolic acids was developed.The reaction was carried out with NiCl₂ as catalyst,K₂CO₃ as base and DTBP as free radical initiator.A series of 2-arylvinyl cyclic ethers were synthesized with moderate to excellent yield.The reaction was not only suitable for the phenylalkynic acids containing electron-donating or electron-withdrawing groups,but also compatible with heterocycloarylalkynic acids and fused cycloarylalkynic acids.Several cyclic ethers could be also applied to the reaction.Based on the controlled experiments,the reaction occurred through a free radical process,and the by-product of the reaction was isolated.A reasonable reaction mechanism based on free radical process was proposed.In this work,by using cheap nickel as catalyst,the synthesis of 2-arylvinyl cyclic ethers with potential biological activity was developed via a selective decarboxylative coupling between cyclic ether with arylpropiolic acids.Thirdly,selective photocatalyzed free-radical coupling reaction of ether and arylpropiolic acids was studied.A series of 3-ether-substituted cinnamic acids were synthesized with moderate to excellent yield using Ir₂(dipy)₄Cl₂ as photocatalyst,TBHP as oxidant and 18W blue LED as light source.The reaction was not only suitable for the phenylalkynic acid containing electron-donating or electron-withdrawing groups,but also compatible with heterocycloarylalkynic acids and fused cycloarylalkynic acids.Several other ethers could also be applied to the reaction.Moreover,the yield did not decrease significantly when the reaction was amplified to a gram scale.The cinnamic acids could be directly converted to amides,esters,aldehydes and alcohols by simple reactions.Based on the controlled experiments,a photocatalytic radical-initiated reaction mechanism was proposed.Finally,a selective coupling of ether with?-dicarbonyl compounds was investigated.The ethers were conventionally coupled to the carbon of the active methylene group on the?-dicarbonyl compounds.In this work,an enol ether was synthesized via a selective coupling of ether with the oxygen of a?-dicarbonyl compound using NiBr₂ as catalyst and t-BuOK as base.Unfortunately,the reaction scope was limited due to the high requirement of the reactants.In this thesis,several?-substituted ethers were synthesized via transition metal catalyzed cross coupling between ether with different substrates.Exploring the combined strategies of?-C(sp³)-H functionalization of ethers and multi-component reactions provided more ideas for the synthesis of new ethers derivatives.