Studies On [4+3] Cyclization Of 4-Vinyl Indoles And 1,3-Dipoles

The discovery of drug leader molecules with pharmacological activity has been an extensive research hotspot in the field of new drug development.By summarizing the molecular structures of drugs,it is found that many pharmacologically active compounds contain heterocyclic structures.Especially,indole fused heterocycle is an important heterocyclic structure.By taking advantage of its high biological activity,it is widely applied in the fields of anti-tumor,anti-viral,and anti-inflammatory drugs,meanwhile,it is sought popularly after by lots of medicinal chemists.Because of its unique structure features,it has been treated as a synthetic target for organic chemists as well.As one of the most effective ways to construct ring structures in organic chemistry,cyclization reactions have been extensively studied by researchers.Among them,1,3-dipole has become a kind of widely used synthon in organic synthesis due to its high atom utilization,simple and mild reaction conditions and high stereoselectivity.1,3-dipole and the cycloaddition reaction of a dipolephile becomes a significant way to synthesize a ring structure.It is noted that this method meets the requirements of green chemistry and has high practicability in the fields of organic synthesis and medicinal chemistry.In this paper,α-halogenated hydroxamate is used as the 1,3-dipole precursor to develop the in-situ generation of azaallyl cations and 4-alkenyl indole with the help of inorganic bases[4+3].The cyclization reaction realizes the construction of the indole-based nitrogen-containing seven-membered ring through a simple one-step operation,which provides a novel approach for the synthesis of indoloazidine compounds.By the modification of screening the reaction solvent,base and its amount,the metering ratio of the substrate and other conditions,the ideal reaction conditions are finally obtained as follows:in air atmosphere,at room temperature,using Hexafluoroisopropanol（HFIP）as the reaction solvent,Cesium carbonate（Cs₂CO₃,2 equiv.）as the base and the 1:2 ratio of substrate.As a result,a series of azepinoindole derivatives are prepared with the yield of 26-90%.