Study On Synthesis Of Indoles And 1,3,4-Oxadiazoles Under Transition-Metal-Free Conditions

Nitrogen heterocycles,with a broad spectrum of biological activities,are among the structural components most commonly found in pharmaceuticals.Indoles and 1,3,4-oxadiazole compounds are important five-membered nitrogen containing heterocycles commonly found in pharmaceuticals,agrochemicals,natural products,and other functional molecules.At present,various synthetic methods have been reported for the synthesis of indoles and 1,3,4-oxadiazoles,all with significant drawbacks,such as the use of harmful and expensive metal catalysts or oxidants（quite likely leading to environment pollustion）,and harsh reaction conditions.Therefore,it is urgent to develop more green,efficient and sustainable synthetic methods.The thesis introduces a new method for the synthesis of indole and 1,3,4-oxadiazole compounds without transition metals,thus providing a simple,convenient and mild approach to the synthesis of bioactive compounds and the modification of drug structures.In chapter 1,the synthesis of 1H-indoles using N-aryl enamine in the presence of CBr₄ and a suitable base has been developed.This reaction is K₂CO₃-promoted,CBr₄-mediated intramolecular Friedel–Crafts alkylation of N-aryl enamines,affording a facile access to 1H-indoles.With the optimized reaction conditions in hand,28 1H-indole compounds were prepared according to the reported enamine substrates,and characterized by NMR and HRMS.This method also features operational simplicity,high yield,good substrate tolerability and environmental friendliness.Unlike previous intramolecular cross dehydrogenative coupling（CDC）of the same substrates,this process does not require the use of either a transition metal or a stoichiometric amount of oxidant.Simple and mild condition enables this reaction to be scaled up to the gram scale for the gram scale preparation of structurally diverse 1H-indole derivatives,which maks it a envirionmentfriendly complement to the existing strategies for the synthesis of indole derivatives.In chapter 2,Et ONa-promoted,CBr₄-mediated synthesis of brominated 1H-indoles has been developed.On the basis of the work in Chapter 1,the 6-brominated indole was also obtained by adjusting the base with N-aryl enamine as the substrate in good yield.This method is Et ONa-promoted,CBr₄-mediated tandem bromination/intramolecular Friedel–Crafts alkylation of N-aryl enamines to brominated 1H-indoles.According to the enamine substrates reported in the literature,8 brominated 1H-indole compounds were prepared under the optimumed conditions,and characterized by NMR,HRMS and X-ray crystallographic analysis.With readily accessible raw materials,this"one pot method"can be handled easily and the brominated 1H-indoles can be prepared in gram scale.The reaction system is again transition-metal-free.In chapter 3,reactions of hydrazides with activated trifluoromethyl group to form 1,3,4-oxadiazole has been developed.In this method,α-CF₃ of ethyl 3,3,3-trifluoropropionate is activated by Na₂CO₃,subsequently attacked by 1,4-dinucleophile and finally cyclized to afford1,3,4-oxadiazoles.Under optimized conditions,26 of 1,3,4-oxadiazole compounds with different substituents were synthesized in excellent yields,6 of which contained currently marketed drug structures.All products were characterized by NMR,HRMS and X-ray crystallographic analysis.The merits of this method include simple raw materials,a wide range of substrates,and mild conditions.The structure of these compounds belongs to aryl acetic acid derivatives,thus with potentials to be lead compounds for drug discovery.