Tunable C-H Activation Cascade Reactions Between Arylquinazolinones And Cyclopropenones Enable The Construction Of Molecular Diversity

With the progress of human civilization and the development of science and technology,more and more new compounds have been used in industrial production and daily life.Especially under the threat of many major diseases in recent years,scientists have been trying to search for small molecule compounds with high biological activity,to ensure the sustainable development of human society.Although nature has created a variety of natural product molecules,the reserve of natural products is finite,the efficiency of separation and extraction is low,the synthesis is difficult,some natural resource is on the verge of extinction,and hence it is hard to find lead compounds through screening.After the emergence of new technologies,such as high-throughput screening,chemists have a more urgent requirement to rapidly construct new chemical entities with diverse skeletons,complex structures,and rich stereochemistry.The construction of molecular diversity has become one of the technical bottlenecks restricting the research and development of modern chemical drugs.As a result,new synthesis methods and strategies have been continuously developed to meet the shortages of diverse molecules.Featuring step-and atom-economy,carbon-hydrogen（C-H）functionalization represents an appealing strategy to construct molecules,dramatically reshaping the logic of synthetic chemistry and promoting the optimal development of drugs.C-H activation has great potential for diverse synthesis,especially in combination with cascade reactions,multicomponent reactions.Although some progress has been made,there are still many challenges for state-of-the-art methods to create high-level molecular diversity.1)Multiple reaction steps usually are needed,which makes it difficult to synthesize molecules in a one-pot manner,leading to inefficient diversity construction.2)It needs to continuously add as many substrates as possible in different reaction processes,which depends greatly on the number and diversity of substrates.3)By contrast,it is challenging to construct as diverse structures as possible from limited substrates.The previous divergent strategy using the same substrates produced limited diversity,by which only 2 to 3 structures could be synthesized generally.4)Although C-H functionalization cascade has emerged as a powerful strategy to construct complex molecules from limited feedstocks,its research on the construction of molecular diversity is still in its infancy,largely due to the difficulty in precisely controlling the degree and selectivity of reaction cascades that involve cleavage and construction of multiple chemical bonds.To address these challenges,we designed and maximized the construction of the molecular diversity via tunable C-H activation cascade reactions of quinazolinones and cyclopropenones,and developed a series of synthetic methodologies.The main research can be divided into the following four parts:1.Catalyst-Controlled Cascade Reactions to Achieve DiversityOn the one hand,we achieved the strategy of rapid construction of diverse products（products 3-7）from the same substrate by a continuous and controllable transformation of the functional groups formed by cyclopropenones,or by controlling the activated amounts of C-H bonds of quinazolinones.Through condition exploration and optimization,we also developed a series of new skeleton molecular synthesis methodologies.These cascade reactions,or multi-step one-pot reactions,exhibit good chemo-and regio-selectivity,controllable reaction degree,broad functional group tolerance,and excellent conversion efficiency.Also,we obtained the possible mechanism of the reaction based on mechanism experiments and related literature.2.Tunable Versatile Cyclopropenones to Achieve DiversityIn this chapter,by tuning the versatile reaction properties of cyclopropenone to make it undergo different C-H functionalization reactions with quinazolinones under different conditions,new skeleton molecules（products 8 and 9）were constructed by the one-pot method,which is another successful practice of the diversification strategy designed.On the one hand,cyclopropenone can be efficiently converted into acetylene without photocatalyst under ultraviolet and can be rapidly coupled with quinazolinone to generate the corresponding cyclized product 8.On the other hand,cyclopropenones can be transformed into acetone in the presence of potassium carbonate,which can be converted to benzoyl radical in the presence of copper and tert-butyl hydrogen peroxide.Then,the C-H acylation/cyclization of quinazolinone and benzoyl radical under palladium catalysis was carried out to obtain the tertiary alcohol product 9.For these reactions,we have carried out the corresponding conditions optimization,scope investigation,and mechanism study.These multi-step one-pot reactions are simple to operate and have good functional group tolerance and selectivity.In particular,for the synthesis of product 8,the air is directly used as the oxidant,which is a resource with good compatibility,cheap,and easy to obtain,so that the whole reaction process is more economical,environmentally friendly,and practical.3.Tunning Functionalization Sequence of Multiple C-H Bonds to Achieve DiversityThrough controlling the introduction sequences of distinct functional groups in cascade reactions,we successfully synthesized polyheterocycles 10-16 in this chapter.These modular assembly processes,which are as flexible as Legos,allow for clever and rapid diversification.This design and result further highlight the superiority of the diversity strategy.On the one hand,the first introduction of indanol moiety to form the intermediate 3,then the products 10-13 can be selectively generated under different conditions.On the other hand,new products14-17 can be further generated by further reactions of cyclopropenones and the intermediate 8.We have also optimized conditions and investigated substrate scope for these reactions involved in the two major contents.This work has been proved that they are not only an important part of the diversification strategy but also the reactions themselves are valuable methodologies.For the formation of most structures,we have studied the mechanism and proposed possible mechanism.4.Multitasking and Transformable Directing Group（DG）to Realize DiversityIn this chapter,we realized the idea of generating diversity by regulating the role of DG.Since cyclopropenone is the precursor of alkynes,six types of new products（products 18-23）can be synthesized with quinazolinone under different conditions,which greatly promotes the development of rapid structural diversity strategy based on the same substrate.Although these C-H olefination/cyclization cascade reactions involve the cleavage and construction of multiple bonds,the reaction conditions are mostly simple without additional photocatalysts,oxidants,additives,ligands,etc.Especially for the divergent synthesis of products 8,18,20,21,22 and 23,the selective synthesis of different products can be readily achieved almost only by switching the reaction solvent,and the efficiency is high and the yield is considerable.Besides,these cascade reactions,multi-component reactions,and multi-step one-pot reactions have been proved to have good substrate applicability and regional selectivity,providing a green and efficient synthesis method for the synthesis of new conjugated polymers,and have important potential application value.We have also explored their catalytic mechanism and proposed possible mechanism.Finally,we have simply explored the indoleamine 2,3-dioxygenase（IDO）/tryptophan-2,3-dioxygenase（TDO）inhibitory activity of these compounds,in which the product 22c showed obvious TDO inhibitory activity,and its IC₅₀ was 14μM.Although the traditional target screening with the obtained products has not obtained very satisfactory results,because too many targets or interactions have not been tried or successfully applied in drug development,we believe that these methods and products must have their application prospects in the future.Besides,the optical properties of all kinds of compounds have also been preliminarily studied,and the further application of them to biological probes or sensors is underway in our laboratory.We hope that our diversity methods and strategies can be applied to more substrates,and extend a greater variety of compound libraries to provide compound and synthesis technical support for future drugs,biological probes,materials,catalyst screening,and so on.