Preparation And Transformation Of Nitroso And Quinoline Drug Molecular Skeletons

Although most of the nitroso compounds are carcinogenic,a part of them exhibit various biological activities.For example,those NO donors can release NO in human's body,and be proven to exhibit different physiological activities.Furthermore,the nitroso compounds are an important kind of synthetic intermediate,and can be transformed to various functionalized compounds,such as nitrated compounds,amines,Sydnones and so on,which are widely applied to the synthesis of pharmaceuticals and organic materials.Therefore,study of the nitroso compounds is of great importance in organic chemistry and medicinal chemistry.Since quinoline and its derivatives as an important kind of alkaloid have antimalarial,anticancer,antibacterial and other activities,the exploration of more effective quinoline-containing pharmaceuticals is focused by various chemists,in which the funcationalization of quinolines is one of the most popular approachesIn this thesis,the studies were concentrated on three sections,such as t-butyl nitrite(TBN)promoted synthesis of the N-nitrosoacylhydrazides,the direct nitration of anilinesusing N-nitroso anilines as the self-providing nitro group source and the functionalization of quinolines.The details are listed below:1.In the presence of TBN and dioxygen,the C-N bond activation of N,N'-dialkylacylhydrazineswas realized,providing a series of N-nitrosoacylhydrazines in high yields.Different from the strategies of transition-metal catalysis and radical C-N bond activation,this reaction is mediated by a nitrogen-centered radical of the corresponding acylhydrazine followed by further P-fragmentation to cleave the inert C-N bond.This new method to the synthesis of nitroso compounds was realized by the C-N bond activation.2.In the presence of dioxygenand acid,an efficient synthesis of nitrated N-alkyl anilines was realized using N-nitroso anilines as the starting material.According to the mechanistic study,the N-nitroso anilines served as a self-providing nitro group source to promote the direct nitration of N-alkylanilines,avoiding the undesired protection of amine group,and realizing the mild nitration of anilines3.Initiated by t-butyl nitrite/acid catalyst system underdioxygen atmosphere,a Minisci-type reaction between tetrahydrofuran and 4-methylquinoline were realized,introducing a functional group on the 2-position of the quinolone ring.Interestingly,under the standard conditions,a series of tandem reactions including coupling and ring-opening occurred smoothly,providing the 2-acylquinoline in moderate yield.Then,a new kind of super electron donor(NaH/MeOCH2CH2OH)was developed to initiated the cascade reaction of sp3C-H bond activation,Minisci-typeaddition and further functionalization on 3-position of quinoline.This study indicates that the current catalyst system is different from those widely used super electron donor,such as tBuONa or tBuOK and organic small molecule additives,and might be extended to trigger more general radical reactions.