The New Reactions of 3-Aminoindazoles

Author:Zhou Yao

Supervisor:song qiu ling


Degree Year:2019





3-Aminoindazoles represent an important class of heterocycles with physiologicalactivity,whichcouldbeutilizedtoforgebiological pyrimido[1,2-b]-indazole derivatives.In recent years,a range of methods have been developed by using 3-aminoindazoles as synthon for the construction of these valuable fused compounds.However,apart from the common reactivity for condensation with carbonyl compounds,other reactivity of 3-aminoindazoles has never been reported up to date.Thus,this dissertation mainly focuses on these undiscovered reactions of 3-aminoindazoles,such as oxidative rearrangement,N-N bond activation,C-N bond activation and so on.This dissertation mainly involves the following seven aspects:One:The research progress of 3-aminoindazole derivatives in recent years is reviewed.This review is discussed from the three aspects including the properties of3-aminoindazoles,the methods have been developed for the synthesis of3-aminoindazoles and the applications of 3-aminoindazoles in organic synthesis.Two:Chemoselective condensation of 3-aminoindazoles.In previous work for condensation of 3-aminoindazoles with carbonyl compounds,the free primary NH2group condensed of the carbonyl compounds preferentially in most occasions.We have developed a boron trifluoride etherate promoted selective condensation of3-aminoindazoles for the construction of various pyrimido[1,2-b]-indazole derivatives by employing the strained 3-ethoxycyclobutanones as annulation partners,in which the heterocyclic nitrogen atoms of 3-aminoindazole attack the carbonyl part of cyclobutanones preferentially.Three:Oxidative rearrangement reaction of 3-aminoindazoles.We reported the first example for ring expansion of 3-aminoindazoles by using water as co-solvent under oxidative conditions,in which diverse functionalized benzotriazinones were achieved at ambient temperature.The current protocol features acid-free,no transition metal catalyst,no inert gas protection,simple operation,mild conditions.In addition,this oxidative rearrangement reaction can be readily scaled up without loss of the efficacy.Benzotriazinones have significant physiological activities such as anti-cancer,anti-bacterial,anti-arthritis,anti-tuberculosis,among others.This method can provide a novel route for the assembly of the benzotriazinones.Four:N-N bond activation of 3-aminoindazoles.Based on the strategies of oxidative N-N bond cleavage,the N-N bond cleavage of 3-aminoindazoles was achieved for the first time by using NBS as bromine source,ceric ammonium nitrate as oxidant and alcohol as nucleophile as well as solvent,in which a variety of2-aminobenzoates were obtained.In addition,mono-and dual-brominated aminobenzoates could be controllably achieved by regulating bromine source and oxidant.Five:Denitrogenative ring-opening reaction of 3-aminoindazoles.Oxidative cleavage of two C-N bonds of 3-aminoindazoles was achieved by using the oxidative system of Cu/TBHP under mild conditions.A broad scope of heterocycles,such as indoles,pyrroles,furan,thiophene and imidazo[1,2-a]pyridines were well compatible in this reaction to afford diverse functionalized nitrile-containing heterocycles via C-H arylation.In addition,the current reaction could be applied to accomplish the C-H arylation of ketene dithioacetals as well.A wide array of aromatic,heterlcyclic and aliphatic thiols could also undergo the coupling reaction of 3-aminoindazoles to afford a series of substituted aryl sulfides under this oxidative system.Mechanism studies indicate that a radical-type reaction is involved in this denitrogenative ring-opening of 3-aminoindazoles.Six:Denitrogenative transannulation of 3-aminoindazoles.1-Aminoisoquinoline and 3-aminobenzothiophene derivatives are diffusely found in many pharmaceutically active moleculars.In this reaction,diverse functionalized 3-aminobenzothiophenes and 1-aminoisoquinolines were obtained via denitrogenative transannulation of3-aminoindazoles with enamines or mercaptoacetates by using the oxidative system of Cu/TBHP under basic conditions.The current reaction features no inert gas protection,simple operation,good functional group tolerance.Seven:Intramolecular radical cyclization reaction of 3-aminoindazoles.We designed to introduce aromatic ring or olefin as free radical acceptor in3-aminoindazoles to accomplish the intramolecular radical cyclization reaction of3-aminoindazoles,which enables the generation of a series of triphenylenes and9-benzylidene fluorenes.The feasible reaction mechanism for this radical cyclization reaction was supported by DFT calculations.Since triphenylenes are widely used in materials,photoelectricity and other fields.This reaction provides an efficient and simple synthesis route for the preparation of cyano-containing triphenylenes and9-benzylidene fluorenes.