Study On The Synthesis Of 3-substituted Quinolinone Derivatives

The development of methodologies for the synthesis of N-containing heterocycle is one of the main branches in organic chemistry and core interests of organic chemists.Among the N-containing heterocycles,quinolinone scaffold is recognized as the privileged structure in drug discovery.Several quinolinone derivatives have been shown to have a wide range of biological activities and could be used as small molecule inhibitors.At the same time,more than 200 alkaloids containing quinolinone skeleton were isolated from Rutaceae by researchers.Therefore,it is of great significance to develop new synthetic methods for synthesizing quinolone derivatives.This thesis focuses on the synthesis of 3-substituted quinolinone derivatives,designed and developed four new synthetic methods.The thesis includes the following aspects.In the chapter 1,the progress of research on the synthesis of quinolone derivatives was systematically summarized.A highly substituent-dependent rearrangement allows for SOCl₂/DMSO induced divergentsynthesisof3-methylthioquinolin-2-onesand3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N-arylpropyamides was developed in Chapter 2.Different para-substituents on aniline moiety triggered divergent reaction pathways leading to the formation of quinolin-2-ones for mild-substituents and spiro[4,5]trienones for both electron-withdrawing and-donating substituents,respectively.On the basis of both computational and the experimental results,a new mechanism has been put forward to account for the exclusive spirolization/defluorination process and substituent effects.In chapter 3,3-chalcogenylated quinolinone derivatives and 3-chalcogenylated spiro[4,5]trienone derivatives could be efficiently obtained through the reaction between N-arylpropynamides and RSe Cl/RSCl via electrophilic intramolecular cyclization under mild conditions.In addition,RSe Cl/RSCl was generated in situ from Ph Cl₂ and disulfides/diselenides.This reaction has the advantages of high selectivity,wide substrate versatility,and no metal involvement.In chapter 4,an efficient and convenient method for construction of trifluoromethylthiolated quinolinone skeletons was described through the electrophilic trifluoromethylthiolation of N-arylpropynamides by using methanesulfenamide as the trifluoromethylthiolating reagent.Through this Bi Cl₃-mediated cyclization process,a series of 3-trifluoromethylthiolated quinolinone derivatives were synthesized.It is expected that these trifluoromethylthio functionalized quinolinones might exert some useful biological properties.An umpolung process X^-to X⁺mediated by phenyliodine（III）diacetate（PIDA）was observed in chapter 5.Through this unique umpolung process,3-halogenated quinolin-2-ones were selectively synthesized from N-arylpropynamides.One striking feature of the approach was the conversion of the halide anions to the unique electrophilic iodonium and Cu（III）species via a umpolung process.The reaction employed the simple and readily available halogenated reagent as the halogen source,and the reaction conditions are mild,and efficient.This protocol provided an efficient synthesis of halogenated quinolinones,which could be used as the precursors for the further synthesis of derivatized quinolinones with high biological activity.In conclusion,in this thesis four efficient methods were designed and established for the synthesis of 3-chalcogenylated/halogenated quinolinone derivatives,through the electrophilic cyclization of readily available N-arylpropynamides and electrophilic active species which was generated in situ.