Sc（OTf）₃ Catalyzed [4+2] Cycloaddition Of Cyclic N,O-acetals With Aryl Olefin To Construct Oxazinone Drug Skeleton

The nitrogen-containing heterocyclic skeleton is one of the most important skeletons of drug molecules.Because it can be transformed into a variety of active new compounds,it is not only widely used in pesticides,materials and biological products,but also favored by medicinal chemistry.In the past few decades,chemists and pharmacologists have focused on efficient construction methods of nitrogen-containing hybrid frameworks and continuously found a series of efficient synthesis pathways.This field has also been highly valued by the pharmaceutical and chemical synthesis communities.Oxazinone compounds,as an important class of nitrogen-containing heterocyclic compounds,exist in many natural products and are therefore regarded as important building blocks for the synthesis of natural products and drug molecules.Therefore,the construction of oxazinone compounds with various structures is of great significance for drug research and development,and the efficient construction of such skeletons is also one of the key points of many researchers in medicinal chemistry and organic synthesis chemistry.In order to solve the efficient synthesis of oxazinone frameworks,this article mainly conducts a new methodological research on the[4+2]addition cyclization reaction between three different types of N,O-acetals and aryl olefins with different substituents under the catalysis of Lewis acid to construct a series of oxazinone drug frameworks.The main results are as follows:1.By referring to the existing research results of our group,three types of cyclic N,O-acetals and ten types of 1,1-disubstituted ethylene substrates were synthesized.2.Optimization Based on the[4+2]cycloaddition reaction of chiral five membered ring N,O-acetal,seven membered ring N,O-acetal and benzo six membered ring N,O-acetal with different substituted aryl alkenes catalyzed by Sc（OTf）₃,a synthesis method containing oxazinone compounds was established.The validation of 22 substrate expansion proved that this method has good substrate applicability,with yields between 33%～95%and selectivity of 51:49～>99:1.In summary,we have established an efficient method for constructing multiple oxazinone drug skeletons using cyclic N,O-acetals and different substituted olefins mediated by cheap metal catalysts.