Transition-Metal Catalyzed Synthesis Of Five-Membered N,O-Heterocycles

Five-numbered N,O-heterocyclic compounds,such as isoxazole,isoxazoline,oxazole,oxazoline,are skeletons widely found in natural products and pharmaceutical molecules bearing various anti-bacterial,anti-viral,anti-oxidant,and anti-inflammatory activities.Therefore,the development of new synthetic methods of such heterocycles have been actively sought and numerous reactions have been reported.Among them,transition-metal-catalyzed heterocyclization reactions are the most widely applied.In this thesis,we described our efforts in the syntheses of three kinds of five-numbered N,O-heterocycles by rhodium or gold catalyzed heterocyclization reactions,and can been divided into the following two parts.First,a rhodium catalyzed heterocyclization of alkyne or alkene with amine and tert-butyl nitrite was developed to construct isoxazoles or isoxazolines.With this method,we achieved an efficient synthesis of corresponding pharmaceutical molecules.Preliminary mechanistic investigation of the reaction was explored by controlling experiments.We proposed the amine was selectively oxidized by tert-butyl nitrite to give the nitrile oxide,which then reacts with an alkyne or an alkene to form the target isoxazole or isoxazoline product.It is worth noting that the tert-butyl nitrite not only acts as an oxidant but also provides the oxygen atom of the product.Next,a gold catalyzed heterocyclization of alkynes with cheap and readily available hydroxamic acids leading to 1,4,2-dioxazoles was presented.In this method,the hydroxamic acid provides both the oxygen and nitrogen atom of the product.Using this method,we prepared a series of 1,4,2-dioxazoles with various substituents in high yields.The preliminary mechanism of the reaction was also studied by control experiments.In conclusion,we developed two novel and efficient methods for the syntheses of isoxazole,isoxazoline and 1,4,2-dioxazole via transition-metal catalyzed heterocyclization.The synthetic potential and preliminary mechanism of these methods was also explored.