Synthesis Of Trifluoromethyl-substituted Cyclopropane With 1,3-diyne Functional Group

As the smallest carbon ring structure,cyclopropane exists in many natural products and drug molecules with biological activity.Medicinal chemistry research have shown that the cyclopropane motif can improve the lipophilicity and metabolic stability of molecules,and enhance the drug effect.Combining the benefits of cyclopropane moiety and trifluoromethyl group,trifluoromethyl-substituted cyclopropane has been considered as the star molecule in pharmacochemical research.Therefore,the development of efficient methods for constructionof trifluoromethyl-substituted cyclopropanes has long been an important goal in organic synthesis.In this thesis,a one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF₃-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a base-mediated epimerization sequence is described By optimizing the reaction conditions,DBU turned out to be the optimal base.Under the established optimal reaction conditions,the 2-CF3-3,5-diyne-1-enes were engaging in cyclopropanations with the sulfur ylides,affording trifluoromethyl cyclopropanes featuring diyne-substituted all-carbon quaternary centers.This reaction approach has broad substrate scope regardless of the electronic nature of the substituents on the benzene ring of the ylide.Moreover,alkyl ketone-and ester-containing ylides were also applicable for this reaction,albeit with decreased yield.With respect to the 2-CF₃-3,5-diyne-1-enes,aryl-or alkyl-substituted diyne substrates could be smoothly converted into the corresponding cyclopropanes.And on this basis,to highlight the synthetic utility of the resulting products,the reaction products were subjected to a series of synthetic transformations.The cyclopropane compounds featuring terminal diynes functional groups could be obtained through base-promoted deprotection reactions,which were then subjected to a series of synthetic transformations,including Sonogashira coupling,selective reduction and 1,3-dipolar cycloadditions reactions with azide compounds and oxidized acetonitrile.These transformations afforded a variety of trifluoromethyl-substituted cyclopropanes.In addition,the relative configuration of two of the products was determined by a single-crystal X-ray diffraction method.This method featured mild conditions,broad substrate scope,and the high diastereoselectivity of the products.which provided a new route for the synthesis of cyclopropanes featuring with trifluoromethyl-substituted all-carbon quaternary centers.