| Gem-difluorocyclopropane is the core skeleton of various bioactive molecules.Compared to normal cyclopropanes,the gem-difluorocyclopropane molecules have better lipophilicity,bioavailability,and metabolic stability.Besides,gem-difluorocyclopropane derivatives are also important synthons in organic chemistry,which can form 2-fluoro allyl groups through defluorination ring opening reaction.Thioternary/six-membered rings are also important molecules for biological activity and natural products.The introduction of sulfur atom can enhance the biological activity of thioternary/six-membered rings.In some organic chemical reactions,sulfur containing compounds can serve as ligands and catalysts.One of the common synthesis methods to construct gem-difluorocyclopropane is using olefins as starting materials.But,this process can only construct aromatic or alkyl gem-difluorocyclopropane,the construction of other substituted gem-difluorocyclopropane is still limited.This project utilizes the nucleophilicity of sulfur anions to undergo nucleophilic addition/tandem reactions on the C-C double bonds of gem-difluorocyclopropene to construct high diastereoselective thio-substituted gem-difluorocyclopropane/benzopyran derivatives containing gem-difluorocyclopropane.This thesis mainly focused on three parts:The first part described the application and research progress of gem-difluorocyclopropane in drug molecules and pesticides,and the application and research progress of thioternary rings and benzopyran derivatives in drug synthesis and biological activity.The second part describes the high diastereoselective synthesis of gem-difluorocyclopropane by nucleophilic addition of mercaptan or thiophenol to gem-difluorocyclopropene under the action of K2CO3,including the synthetic route,feedstock synthesis,condition screening,substrate suitability,derivatization and possible mechanism are proposed.Under optimal conditions,29 examples of thio-substituted gem-difluorocyclopropane were obtained in moderate to excellent yields（45-95%）.The structures were characterized by NMR and high-resolution mass spectrometry.The third part describes the high diastereoselective synthesis of benzopyran derivatized containing gem-difluorocyclopropane by the tandem reaction of o-mercaptobenzaldehyde and gem-difluorocyclopropylene under the action of K2CO3,including the synthetic route,feedstock synthesis,condition screening,substrate suitability,derivatization and possible mechanism are proposed.This was the first time that benzopyran derivatized containing gem-difluorocyclopropane was formed from a[4+2]cyclization reaction and the problem of regional selectivity in the reaction of gem-difluorocyclopropene with phenylthiophenol was solved.Under optimal conditions,21examples of benzopyran derivatized containing gem-difluorocyclopropane were obtained in medium to excellent yields（60-96%）and high diastereoselectivity.The structures were characterized by NMR and high-resolution mass spectrometry.In summary,this thesis utilized nucleophilic addition/tandem reactions of mercaptan/thiophenol on gem-difluorocyclopropane to construct benzopyran derivatives containing gem-difluorocyclopropane and thio-substituted gem-difluorocyclopropane with high diastereoselectivity.Under the action of inexpensive inorganic bases,the reaction conditions were mild,the functional groups were well tolerated,and the target products could be obtained with medium to high yields and high diastereoselectivity.From the perspective of medicinal chemistry and agricultural chemistry,the introduction of biologically active gem-difluorocyclopropane and sulfur into organic molecules can provide new valuable active molecules for medicinal chemistry and agricultural chemistry and promote the development of related fields. |
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