Multifunctionalization Of Azarene C-H Bonds Cooperatively Promoted By I₂/TBHP

In nature,nitrogen-containing heterocyclic compounds are an important class of alkaloids,a large part of which have biological and medicinal activity.Isoquinolinone and isoquinolinone iodosole,as two kinds of isoquinoline derivatives with important medicinal value,the synthetic methods of which have been reported frequently in literatures.The existing synthetic strategies mainly include two types:one is to design highly preactivated substrates,and the final product is obtained through one-step conversion;the other is to use simple structure substrates,and the final product can be obtained through multi-step structure modification.The vast majority of these methods have the drawbacks of producing large amounts of metal wastes and cumbersome operations.On the other hand,iodine catalysis,as an emerging C-H bond functionalization strategy,has a wide range of applications in building new C-heteroatom bonds(C-O,C-N,C-S)in aromatic compounds.In particular,the combination of iodine and TBHP(tert-butyl hydroperoxide)gives a great deal of shine in the oxidative cross-coupling reactions of aromatics with other compounds.Based on the experience gained by our research group in recent years in the functionalization of aza-arenes C-H bonds without transition metal,we used I2/TBHP as the catalytic/oxidation combination to achieve the multi-functionalization of heteroaryl C-H bonds in one step with simple raw materials.We discussed this thesis from the following two parts:In the first part,we developed a one-pot method for the preparation of N-benzyl-4-iodoisoquinolin-l-ones compounds with non-preactivated isoquinoline and cheaply available methyl arenes used as raw materials.The optimal reaction condition:a solution of isoquinoline(2a,0.4 mmol,l equiv)and I2(0.18 mmol,45 mol%),TBHP(1.6 mmol,4 equiv,70%in H2O)and toluene(3a,0.8 mL)was added with vigorous stirring.The reaction mixture was stirring at 100 ? for 6 h under air,the highest yield was 77%.With molecular iodine and TBHP promoting the multi-functionalization of C-H bonds,such reactions avoided metal catalysts and cumbersome multi-step operations,and achieved gram-scale preparation,which had potential for synthetic application prospects.In the second part,we used the same raw materials to selectively generate N-benzylisoquinoline-1,3,4-triones by reducing the amount of iodine to the catalytic amount and increasing the amount of TBHP.The optimal reaction condition:a solution of isoquinoline(2a,0.4 mmol,l equiv)and I2(0.1 mmol,25 mol%),TBHP(4 mmol,10 equiv,70%in H2O)and toluene(3a,3.2 mmol,8 equiv)was added with vigorous stirring.The reaction mixture was stirring at 110 ? for 24 h under air,the highest yield was 74%.The mechanism studies showed that the reaction underwent benzyl sp3 C-H bond iodination,N-benzylation and azacyclic sp2 C-H oxidation.This method used non-preactivated isoquino line and inexpensive readily available methylarenes as raw materials,free of metal waste,and was a practical synthetic method of N-benzylisoquinoline-1,3,4-triones.