Studies On The Synthesis Of 3-sulfonyl Indenones And Sulfocoumarin Derivatives

The sulfonyl,a valuable functional group,is widely used in the field of organic synthesis and medicinal chemistry,due to its diverse synthetic applications and important biological activities.In recent years,in hope with obtaining valuable sulfonyl derivatives,chemists are keen to introduce sulfonyl group into the skeleton of organic compounds.1-Indanone is an important natural skeleton structure,and compounds with this structure are widely present in natural products such as sword leaf anchovy fern,vine,tobacco and guanyin lotus.In addition,1-indanone derivatives also have good biological activity and are widely used in the field of medicine.For example,a range of sulfonyl indine compounds synthesized by the German Pharmaceutical Company are important intermediates of drugs for the prevention or treatment of obesity.So it is of great significance to introduce sulfonyl group into the skeleton of 1-indanone to obtain novel structure of 3-sulfonyl indenones.However,since the last century,there have been only few reports on 3-sulfonyl indenones.Moreover,the synthetic method of 3-sulfonyl indenones is relatively limited.Hence,it is necessary to develop a simple and efficient method for synthesizing 3-sulfonyl indenones.Meanwhile,we also focus on sulfocoumarin,another class of compounds with natural skeleton structure.Sulfocoumarin derivatives,a potent inhibitor of carbonic anhydrase,are bioisosteres of coumarin with similar biological activities to coumarin.It has been used as a leading compound of calcium antagonists in the medical field for the treatment of glaucoma,obesity,epilepsy and other diseases.However,there are currently few methods for synthesizing sulfocoumarin,and exist some disadvantages such as the use of toxic catalysts and long reaction time.Hence,it is meaningful to develop a new and efficient method for the synthesis of sulfocoumarin derivatives under mild conditions.This thesis mainly elaborates on the method of synthesizing two structurally novel compounds: synthesis of 3-sulfonyl indenones via copper-catalyzed redox-neutral coupling reaction;synthesis of sulfocoumarins via three-component coupling reaction of arynes,DMF andβ-keto sulfonyl fluorides.This thesis mainly includes the following aspects:1)3-Sulfonyl indenones via copper-catalyzed redox-neutral coupling reaction: using 1-indanone compound as starting material,a series of 3-sulfonyl-indanone derivatives were synthesized.Indenone oxime ester compounds were obtained via oximation and esterification of1-indenone compounds.The reaction parameters including the equiv ratio of indenone oxime ester and sodium p-toluenesulfinate,solvent,reaction temperature,reaction time and the kinds of copper catalyst were investigated with p-phenyl trifluoromethyl indenone oxime ester and sodium p-toluenesulfinate as model substrates.The optimal reaction conditions were confirmed as following: the equiv ratio of indone oxime to sodium p-toluenesulfinate was 1.0:3.0;the reaction solvent was Me CN;the reaction temperature was 80 °C;the reaction time was 12 hours and the copper catalyst was Cu I.Substrate scope investigation showed that the method had good substrate tolerance,yielding 16 3-sulfonylindanone derivatives in 40-92% yields.The structure of the products weas identified by NMR and HRMS.In addition,in order to highlight the utility of the method,a gram-scale reaction was performed.Under the optimal conditions,the reaction proceeded smoothly and the target product 3-sulfonyl indenone 3aa was obtained in 80% yield.Next,in order to probe the reaction mechanism,a radical capture experiment was conducted.Based on the results,a reasonable reaction mechanism was proposed.2)Three-component coupling reaction was developed to obtain sulfocoumarins.Sulfocoumarins were synthesized from arynes,DMF and β-keto sulfonyl fluorides as raw materials,in which DMF acts as both a solvent and a raw material.First,employing β-sulfonyl fluoroacetophenone and 2-trimethylsilyllphenyl triflate as model substrates,after screening of the type of fluorine source,the β-sulfonyl fluoroacetophenone,the ratio of the equiv of benzyne precursor to potassium fluoride(KF),the concentration of DMF and the temperature,the optimal conditions was established for the synthesis of sulfocoumarin as follows: KF as the fluorine source,the equiv ratio of β-sulfonyl fluoroacetophenone,benzyne precursor and KF was 1.0(equiv):2.5(equiv):3.75(equiv),concentration was 0.04 M,reaction temperature was 40 °C.Experimental results showed that the method has good substrate applicability,and in total 20 sulfocoumarin derivatives were obtained in 50-99% yields.Subsequently,we carried out research on the derivatization of natural products on the basis of the above work.Studies indicated that natural products such as diptera,menthol,and cholesteryl alcohol can be directly converted into the corresponding sulfocoumarin derivatives via this method.The products have passed the identification of NMR and HRMS.Finally,we made reasonable assumptions about this reaction mechanism.