Nucleophilic Amination And Etherification Research Of Aryl Alkyl Ethers

Owing to the extensive existence of aromatic amines and aryl ethers in medicine,natural products,agrochemistry,and materials,it has enormous significance to develop efficient methods to prepare such compounds and explore their potential application values.In recent years,chemists observe the increasing demands of aromatic amines and aryl ethers,devoting intense efforts to develop the synthesis methodology.At present,the means still exist some disadvantages to prepare aromatic amines and aromatic ethers efficiently,such as high temperature,strong bases,expensive metal catalysts,and ligands,which greatly limit their applications and further development.Therefore,it is one of the most attractive research topics to design etherification and amination methods that involve inexpensive substrates,sample operation,mild reaction condition,and good group tolerance.Csp~2-OR/SR electrophiles are ideal and available materials for transition-metal-catalyzed amination and etherification reactions.However,many factors hinder the development of this type of substrates,like the high activation energy of the Csp~2-O/S bond and easy coordination of alkyl mercaptides with metal catalyst resulting in catalyst deactivation.Inversely,the aromatic nucleophilic substitution reaction has the advantages of simple reaction conditions,metal-free,ligand-free,and high reaction efficiency,which has been widely applied for the synthesis of aromatic amines and aromatic ethers.Therefore,we here focus on the current key issues in preparation of aromatic amines and aromatic ethers,and study the nucleophilic amination and etherification of C-OR and C-SR without transition-metal-catalyst.Simultaneously,bioactivities of some products are also conducted.The detailed research content includes the following five parts:(1)A nucleophilic amination reaction of 1-methylthio-naphthonitrile is successfully achieved by using the aromatic nucleophilic substitution(S_NAr)strategy,which uses-SMe group as the leaving group and KHMDS as base.The method has good functional group tolerance and high substrates applicability for methyl sulfide substrates and aromatic amine substrates,and can be used for the green and efficient synthesis of diarylamines.In addition,due to the advantages of simple operation and mild reaction conditions,the method presents high application potentiality.(2)A nucleophilic etherification reaction of 1-methylthio-naphthalene(benzene)nitrile is successfully realized by using the aromatic nucleophilic substitution(S_NAr)strategy,which uses-SMe group as the leaving group and KO~tBu as base.The method has vast substrates scope for methyl sulfides and alcohols,in which some low activity substrates also proceed smoothly like complex natural alcohols and tertiary alcohols.Besides,a wide range of leaving groups are suitable for the reaction condition to obtain desired products with excellent yields,like-SEt,-S~nHexyl and-S~iBu.(3)A nucleophilic amination reaction of N-heteroaryl alkoxy and halogenated N-heteroaryl is realized successfully by using the aromatic nucleophilic substitution(S_NAr)strategy,which uses alkoxy and halogen as the leaving group and KHMDS as base.The method exhibited good generality of leaving groups including alkoxy(OMe,OEt,O~nBu,SMe),halogens(F,Cl,Br,I)and CN,etc.Meanwhile the reaction has good universality for substrates and can be applied to the efficient synthesis of commercially available drugs such as erlotinib,gefitinib and revaprazan.In addition,the results of anti-tumor activity studies show that some N-heteroarylamine products have excellent cytotoxicity.(4)A fast nucleophilic amination reaction of N-heteroaryl alkoxy is realized successfully by using the aromatic nucleophilic substitution(S_NAr)strategy and promoted by n-Bu Li,which utilizes-OMe as the leaving group.The method has a lot of highlights including high efficiency,rapid reaction rate,and wide scope of substrates,providing an extremely simple and fast pathway to synthesize aromatic amines.(5)A nucleophilic amination reaction of N-heteroaryl alkoxy is realized successfully by using the aromatic nucleophilic substitution(S_NAr)strategy and promoted by KOt Bu,which utilizes-OMe as the leaving group.The rection condition is simple,mild,and metal-free,in which high-efficiency etherification of tertiary alcohols and complex natural alcohols can be achieved.In addition,the reaction has good leaving group universality,providing new ideas for design and construction of new chemical bonds.