Construction Of Electrophilic N-Alkynylthio And N-Dithio Reagents And Related C-S Bond Formation

As one kind of important organic compounds,sulfur-containing organic molecules have been widely used in material and pharmaceutical industry due to their special chemical and physical properties.In recent years,considerable attention has been paid to the development of effective methods for introducing valuable S-containing structural units.Alkynyl sulfides,with the sulfur atom directly connected to the C-C triple bond,can be transformed to different functional groups by the reaction in both the sulfuryl and alkynyl parts.Furthermore,the elctron-rich property of sulfuryl group can further improve the reactivity of alkynyl parts;disulfide compounds are widely presented in natural products,biomolecules,and drugs,and the disulfur bond can be reductively cleaved by molecules containing thio groups.Attributed to the unstable nature of disulfur bonds,disulfides are extensively used as self-degrading linkage in various drug conjugates,for tumor-targeted drug delivery.In the first part of this thesis,a series of N-alkynylthiophthalimides were designed and prepared for the introduction of alkynylthio group to different C-nucleophiles.The constructed S-electrophiles have a wide scope and good tolerance to multiple functional groups.N-alkynylthiophthalimides could react with various?-ketoesters,phenylboronic acids and Grignard reagents to access a series of alkynylsulfides.Finally,quinine,a natural cinchona base catalyst,was used as a chiral catalyst to incorporate the alkynyl sulfur group into?-ketoester with high yield and good enantioselectivity(70%ee).In the second part of this thesis,diverse N-dithiophthalimide reagents were efficiently prepared with a simple procedure.The synthetic method could be scaled up to gram level.By the reaction of tertiary C-nucleohiles with N-dithiophthalimides,many steric disulfides had been well constructed.It is worth noting that using chiral catalyst(DHQD)₂PHAL,stereoselective synthesis of chrial disulfides could be established in high yield and excellent enantioselectivity.Moreover,the cross-linkage of some functional molecules were also realized with the steric disulfide bond with the present method,which provides a practical protocol for the development of new drugs.In addition,this thesis also continued the work of electrophilic sulfur reagents in our group,and developed a new method for the synthesis of 4-thiopyrazole and 4-selenopyrazole through the intramolecular cyclization induced by S-electrophiles or Se-electrophiles.A sulfenylated analog of Celecoxib was also obtained by this method,which provided a simple method for the structural modification of pyrazole drugs.The corresponding products were characterized by HRMS?¹H NMR and ¹³C NMR.The structures of some products were further confirmed by X-ray single crystal diffraction.The established synthetic method of alkynyl sulfur electrophile and disulfide electrophile are simple and efficient,and provides new ideas for incorporating alkynyl sulfur and disulfide groups in molecules;the 4-thiopyrazole and 4-selenopyrazole compounds are synthesized directly from simple starting materials without any metal catalyst,which not only has step economy,but also meets the requirements of green chemistry.