Synthesis Of Bromoindole And Its Derivatives Catalyzed By Copper

Indole and its derivatives are one of the heterocyclic compounds widely existing in nature.They are mainly used in medicine,dyestuff,perfume,pesticide,cosmetics,electronic materials and organic functional materials.Indole derivatives are not only important components of amino acids in animal protein,such as tryptophan,5-hydroxytryptamine,melatonin,etc;It is also an important component of natural plant hormones,such as β-Indoleacetic acid,indirubin,bufalin,physostigmine and limonine play key roles in plant growth and development.Indole,as the basic structure skeleton of chemical drugs,plays an important role in many therapeutic fields because of its high biological activity,such as antiviral,anti algae,analgesic,sedative,anti-inflammatory,antibacterial and so on.Indole bromide and its derivatives are a class of very important nitrogen-containing heterocyclic compounds,which widely exist in marine animals and plants.Because of their great applications in dyes,organic synthesis intermediates,medicine and other aspects,exploring a simple and efficient industrial synthesis method of indole bromide has always been a hot topic for researchers.In recent 40 years,transition metal catalyzed reactions,especially those catalyzed by copper,palladium and nickel,have been widely used in the construction of various heterocyclic compounds.Due to the advantages of low cost,non toxicity and low toxicity of copper salts,and their potential in large-scale reactions,their applications in organic synthesis have attracted great attention,Therefore,various new practical and effective methods based on copper catalyzed reactions have been developed,especially the synthesis of indoles in heterocyclic compounds.Transition metal catalyzed synthesis of nitrogen-containing heterocycles is a very hot topic in organic synthesis and has a wide range of applications in organic reactions.In this paper,the copper catalyzed self cyclization of imine intermediates was studied.The copper catalyzed self cyclization reaction was established by using organic synthetic metal catalysis,column chromatography and other experimental methods.α,α-dibromo-β-5-or-6-bromoindoles and their derivatives were prepared by continuous free radical cyclization of imino acid esters.The effects of temperature and time,catalyst type and dosage,solvent type,base and ligand on the yield of the product were studied.The optimal reaction conditions were selected as follows: Cu Br as copper reagent,Cu Br dosage of 1.0 equivalent,acetonitrile as reaction solvent,oil bath heating at 100 °C for 4 h.Under the above conditions,42 kinds of enamine substrates with different substituents were prepared according to the literature reports.Finally,21 kinds of indole bromide and four kinds of indole bromide derivatives were successfully prepared.The experimental results show that the reaction undergoes a continuous process of free radical cyclization in one pot,and has good tolerance to different substituents,such as halogen,alkyl and aromatic groups;It has the advantages of simple operation,convenience,high product yield,economic and practical,environment-friendly,easy to scaleup production in the workshop and so on.