Investigation On Methodology For The Synthesis Of Quinoline,Quinoxaline And Quinazolinone Derivatives

Nitrogen-containing heterocyclic compounds are commonly found in various natural products,bioactive molecules and drugs.They are also widely used in fields such as medicine,pesticides,biochemistry and organic functional materials for their unique properties.Among them,pyrroloquinoxalines,imidazoquinolines and quinazolinones have attracted a great deal of attention.Based on the traditional methods,a series of new synthetic strategies have been reported.We found that many methods suffer from high reaction temperature,the require of expensive catalysts and ligands,the low yield caused by multi-step reactions,pollution or reprocessing problems caused by toxic reagents and limited raw material sources.With the continuous exploration of the latest research hotspots such as copper catalyzed Ullmann reaction and amino acid decarboxylation,we have developed new methods for pyrroloquinoxalines,imidazoquinolines and quinazolinones synthesis,and realized efficient construction of other related structures.In the introduction part,we first presented the progress of the Ullmann type C-N bonds formation in recent years,the types of substrates and mechanism were also reviewed.Then we introduced the carbon coupling reactions involving the TBAI-TBHP oxidation system and the sp3 C-H bonds functionalization of(2-azaaryl)methanes in acidic environment.Finally,the applications of pyrroloquinoxalines,imidazoquinolines and quinazolinones were briefly introduced.In the second chapter,we described a one-pot synthesis of pyrrolo[1,2-a]quinoxaline derivatives via a copper-catalyzed aerobic oxidative domino reaction.The reaction was performed with 1-(2-halophenyl)-1H-pyrroles and amino acids as starting materials,copper acetate as the catalyst,potassium phosphate as the base without additional ligand.The domino process included Ullmann-type N-arylation,aerobic oxidation,intramolecular addition,and decarboxylation.It was interesting that the intramolecular addition step was achieved under conditions with a base rather than an acid.The UV-vis absorption and emission spectra of indolo[1,2-a]quinoxalines in highly dilute solution were collected.This new method had potential applications in the synthesis of biologically and pharmaceutically active compoundsThe next chapter described another method for the metal-free synthesis of pyrrolo[1,2-a]quinoxalines from readily available α-amino acids and 2-(1H-pyrrol-1-yl)anilines.We prepared 2-(1H-pyrrol-1-yl)aniline from 2-nitroaniline and 2,5-dimethoxytetrahydrofuran in two steps,while 2-(1H-indol-1-yl)aniline was obtained from 1-fluoro-2-nitrobenzene and indole through SNAr and nitro reduction reactions.The reaction proceeded from 2-(1H-pyrrol-1-yl)anilines and amino acids with ammonium persulfate as the oxidant in DCE/H2O to give a series of pyrroloquinoxaline derivatives.We also studied the possible reaction mechanism.The sulfate radical anion generated from persulfate played an important role in the reaction,which made the amino acids undergo oxidative decarboxylation,oxidation and hydrolysis steps to generate aldehyde intermediate.Most of the decarboxylation reactions require the participation of transition metals such as silver or palladium.Metal-free decarboxylation reactions of amino acids are rare.Therefore,our new strategy is methodologically significant,and provides an effective complement to the synthesis of related heterocyclic compoundsIn the fourth part,we introduced a direct and metal-free oxidative amination of sp3 C-H bonds for the construction of 2-hetarylquinazolin-4(3H)-ones.Although numerous methods for the synthesis of quinazolin-4(3H)-ones have been developed,reports about construction of 2-hetarylquinazolin-4(3H)-ones have some limitations.Often it is necessary to first pre-functionalize a quinoline substrate to an aldehyde or acid.It is a challenge to construct quinazolin-4(3H)-ones directly from 2-methylazaarene.A suitable Lewis or Bronsted acid can convert the 2-methylazaarene to its enamine counterpart,which makes it a research hotspot for C-H functionalization.We had succeeded in the reaction of substituted 2-aminobenzamides and(2-azaaryl)methanes to construct 2-hetarylquinazolin-4(3H)-ones using the TBAI-TBHP oxidation system.In addition,quinoline-2-carboxaldehyde was an important intermediate of the transformation.We first reported such a novel,simple and low toxicity method for the synthesis of quinoline-2-carboxaldehyde,which may be of great importance for synthesis of other N-containing heterocycles.In the fifth chapter,a metal-free oxidative amination of sp3 C-H bonds was developed for the synthesis of imidazo[1,5-a]quinolines from readily available a-amino acids and(2-azaaryl)methanes.The method was simple and mild with TBAI as the catalyst,TBHP as the oxidant.The metal-free amidation of the(2-azaaryl)methanes and the oxidative decarboxylation of the amino acids were combined to achieve tandem synthesis of the target compounds.Moreover,only a few synthetic routes mainly relied on traditional Vilsmeier-type cyclizations or their variants were reported so far.Therefore,our new method was methodologically meaningful.