Site-selective Remote Alkylation And Alkoxylation Of Arylamines

Arylamines are important scaffolds widely exists in pharmaceuticals,agrochemicals,and natural products.Therefore,it is of great significance to develop a variety of synthesis and modification methods for aromatic amine fragments.Due to the advantages of simple steps and atomic economy,direct C-H functionalization has been considered as a powerful tool for organic synthesis.In recent years,considerable attention has been devoted to exploring the efficient and convenient functionalization strategies of small organic molecule drugs with arylamine scaffolds to improve the performance of original drugs or even develop new drugs.C-C and C-O bonds are important skeletons of organic molecules and even more,are critical functional structures of some drugs,materials,or bioactive molecules.Hence,the pace of developing efficient alkylation and alkoxylation strategies to construct new C-C or C-O bonds never stops.Suitable oxidants are essential to excite substrates and initiate site-selective functionalization of arylamines.Oxidants with their unique mechanisms often have different effects on reactions.Therefore,it is important to explore different oxidants and reaction conditions systems to establish efficient and convenient C-H functional protocols of arylamine derivatives,which could enhance the diversity of drugs,materials,and other products based on the skeleton.This article mainly includes three parts:In the first part,the metal-free regioselective remote alkylation of N-phenyl benzamides and N-（quinolin-8-yl）benzamides substrates were achieved using K₂S₂O₈and AIBN（azobisisobutyronitrile）.Moreover,modifications of other functional groups to the substrates can also be accomplished with different radical coupling partners such as other azo compounds or Na Br.This protocol firstly reveals the great potential of K₂S₂O₈ for initiating arylamines substrates by abstracting hydrogen atom to generate N-center radical.In the second part,the TBHP（tert-butyl hydrogen peroxide）was used as methyl radical and oxygen sources to generate methoxy radical,and successfully completed the C5 methoxylation of 8-aminoquinoline derivatives.The Fe Cl₃ catalyst played a key role in inducing TBHP decomposition to generate oxygen.Notably,the good solubility of the fluorine solvent for oxygen was critical to the success of this protocol.After optimization of the reaction conditions,a series of N-（quinolin-8-yl）benzamides substrates were tested and the desired methoxylation products were gained in moderate to good yields.Finally,a proposed SET（single electron transfer）-radical coupling mechanism was outlined after a series of control experiments.In the third part,the solvent acetonitrile was excited to cyanomethyl radical under the Fe ^III/TBHP system,and then converted to cyanomethoxyl radical with the"oxygen"provided by the decomposition of TBHP.As a result,the C5-cyanomethoxylation of the 8-aminoquinoline derivatives was completed successfully through the SET-radical coupling pathway.Further experiments proved that this protocol has mild conditions and good substrate tolerance.Notably,it highlight the important application of TBHP as an"oxygen"source to convert C-centered radical to O-centered radical for the construction of C-O bond.