Research On Regioselective Fluorination Of 8-aminoquinoline And Aniline Derivatives

Fluorine-containing compounds are widely used in medicine,pesticides and functional materials,because fluorine atom has the greatest electronegativity and the atomic radius is equal to hydrogen atom.When fluorine or fluorine-containing functional groups are introduced into aromatic compounds,their physical,chemical and biological properties will change unexpectedly.However,there are very few fluorinated organic compounds in nature,most of which rely on artificial synthesis.Early electrophilic or nucleophilic fluorinating reagents such as F2,CH3 COOF,CF3OF and FCl O3 have high reactivity,but they are toxic,explosive and difficult to preserve.Moreover,these reactions have poor selectivity,sensitivity to organic substances and harsh reaction conditions.In recent years,scientists have developed a kind of safer,stable and environmentally friendly N-F electrophilic fluorinating reagents,such as N-fluoropyridinium salt,N-fluoro-bisbenzene sulfonimide(NFSI)and 1-Chloromethyl-4-Fluoro-1,4-Diazoniabicyclo[2.2.2]Octane Bis(Tetrafluoroborate)(Selectfluor).These novel fluorinating reagents have greatly promoted the development of moderate C-H fluorination.With metal-free or transition metal catalyzed C-H bond activation strategy has gradually become one of the most powerful tools to the field of organic synthesis,many adjacent C-H functional groups of aromatic hydrocarbons have been successfully realized,and the field of remote selective C-H activation has also been brilliant.Traditional methods of introducing fluorine into aromatic compounds,such as the classical Balz-Schiemann reaction,generally require pre-functionalization of substrates,with complex operation and low conversion rate.Therefore,the development of direct C-H fluorinated synthesis methodologies for aromatic hydrocarbons has attracted great attention.Quinoline and quinoline derivative fragment structure compounds usually play an irreplaceable role in medicine,materials and other fields.In the past few years,our laboratory has been devoted to the regioselective functionalization of 8-aminoquinoline as a bidentate ligand,and has achieved highly selective C-5 chlorination,bromination and iodization catalyzed by transition metals.This paper consists of two parts: Firstly,we continue to study the construction of selective C-F bonds based on 8-aminoquinoline,which has the greatest potential and challenge.Choosing Selectfluor as fluorine source and oxidant,HOAc as the only additive,we have achieved novel and efficient C5 monofluorination of 8-aminoquinoline amide and 8-aminoquinoline sulfonamide derivatives in mild metal-free system.According to the optimal reaction conditions,we have explored 23 suitable 8-aminoquinoline substrates and obtained their C-5 fluorinated products.The reaction simplifies the method of fluorination synthesis,avoids the waste of metal catalysts,and has a wide range of substrates.It can be enlarged in laboratory to obtain a higher separation yield,and hydrolyze to 5-fluoro-8-aminoquinoline,which is widely used.According to the free radical trapping experiment and the control experiment,we determined that the reaction involved the free radical reaction process,and proposed the possible mechanism: the substrates were oxidized by Selectfluor to form the free radical structure of spin-delocalization resonance,then the directional transfer of fluorine radicals occurred to complete the selective fluorination of 8-aminoquinoline at C-5 position.In the second part,we found a novel type of mild selective ortho-C-H monofluorination of aniline derivatives by using Selectfluor-Cu(OAc)2-HOAc transition-metal catalytic system,N-phenylpyridine amide as the substrate,CH3NO2 as solvent,HOAc as the additive,and sealing reaction at 100 ?.The reaction underwent electrophilic process with various substrates and obtained considerable yields,with 15 o-fluorinated aniline derivatives obtained.It can also enlarge the separation yield and further hydrolyze to obtain widely used o-fluoroaniline.Finally,we proposed the corresponding mechanism that the selectivity of o-fluorination was controlled by the bidentate coordination of two nitrogen atoms of pyridylamide and copper atom.