A Preliminary Investigation On Efficient Construction And Anti-inflammatory Activity Of Diarylmethanes And Alkoxy Gem-difluorides

Gem-dihalocarbons are commonly used as intermediates in organic synthesis,which can be used as coupling reagents for transition metals and as important synthons in organic reactions,and are widely used in the synthesis of pharmaceuticals,pesticides and other fine chemicals.Among them,gem-dichloroalkanes can be used as biphilic reagents in bifunctionalization reactions of single carbon atoms to build structurally diverse products.In addition,because of the advantages of fluorine atoms in improving drug solubility,bioavailability and metabolic stability,the gem-difluoroalkanes have also gained attention and their efficient synthesis is one of the hot spots in the field of fluorine chemistry.In this thesis,based on the previous research of the group,we designed new tandem reactions for the synthesis of series of biologically active diarylmethanes using dichloromethane as C1 synthon.Meanwhile,the synthesis of benzamide derivatives was achieved by the C-H activation reaction catalyzed by rhodium transition metal using the simple and easy-to-access gem-difluorohomoallylic silyl ethers as the coupling reagent.The research of this thesis consists of two parts as follows:Part I:Construction of asymmetric diarylmethane compounds using dichloromethane as a carbon-one synthon.Diindolylmethane（DIM）is the major acid condensation product of indole-3-methanol,which can inhibit platelet aggregation and thrombosis and has certain anti-platelet and anti-thrombotic activities.In addition,DIM and its derivatives also have significant biological activities such as anticancer,antioxidant and antibacterial,which have attracted much attention.Currently,most DIM derivatives are constructed by a two-step Friedel-Crafts reaction between indole and aldehyde with poor selectivity,and the constructed products often have symmetrical nature.And there is a lack of a general synthesis method for asymmetric DIMs.In this study,in the presence of diethylamine,the C1 synthon dichloromethane undergoes the first Friedel-Crafts reaction with 6-nitroindole to construct N-（（6-nitroindol-3-yl）methyl）-N-ethylenediamine intermediates,followed by a second Friedel-Crafts reaction with a variety of substituted indole derivatives to construct asymmetric diindolylmethanes in a one-pot method.Using a similar strategy with dichloromethane,6-nitroindole and electron-rich aromatics as reaction reagents,a two-step one-pot method for the construction of asymmetric diarylmethanes was also developed in this study.The present synthesis method has the following advantages:dichloromethane（DCM）acts as both solvent and C1 synthon to provide methylene groups,which is in line with the principle of atomic economy;it does not require metal catalysts,and the reaction conditions are mild;it has a wide range of functional group tolerance,simple operation,and environmental friendly.In this study,a preliminary study of the anti-inflammatory activity of the synthesized asymmetric diarylmethane was also performed.The study found that all the compounds tested had some anti-inflammatory activity by measuring changes in the expression levels of interleukin-6（IL-6）,one of the cellular inflammatory factors.Part II:The Cp*Rh（III）catalyzed the C-H activation reaction of N-methoxybenzamides by using gem-difluorocarbons as coupling reagents to efficiently construct gem-difluoroalkoxy compounds.Fluorinated drugs have the advantages of better target selectivity,higher activity and lower toxicity,thus organofluorinated compounds are widely used in drug development.Allyl-gem-difluorides are an important class of fluorinated compounds that are widely used in drug discovery and development;they also serve as important precursors for the synthesis of other fluorinated compounds.To date,methods for the construction of such chemicals have been developed,and representative methods include the deoxyfluorination of unsaturated carbonyl compounds by transition metal-catalyzed cross-coupling reactions using coupling reagents containing difluoromethylene（CF₂）.Because of its important role in medicine and functional materials,it is still important to develop the construction of allyl-gem-difluorides.In this study,the gem-difluorinated alkoxides were efficiently constructed by using gem-difluorohomoallylic silyl ethers as coupling reagents and N-methoxybenzamides as substrates in a tandem reaction of C-H activation/olefin insertion/β-H elimination/oxidative addition/protonolysis catalyzed by transition metal rhodium.The advantages of this study are mild conditions,broad functional group tolerance,simple operation,environmental friendliness,and suitability for scale production and post-modification.