C-H Functionalization Reaction Directed To The Construction Of Bioactive Molecules: Research On Novel Osmium Catalytic Systems And Reaction Modes

Research Background and Objectives:Organic heterocyclic molecules represent privileged motifs that feature various types of biological activities as lead compounds in medicinal chemistry.For example,isoquinolinone compounds exhibit anti-tumor,anti-cancer,anti-inflammatory and other biological activities,quinazoline and benzodiazepine compounds exhibit pharmacological effects such as sedation and anti-anxiety.Consequently,the construction of such skeletons in an efficient way has always been an important subject.In the last decades,the development of C-H activation strategy has drawn continuous attentions,which simplifies the starting materials and reaction conditions,reduces the reaction wastes and greatly increases the reaction efficiency,thus proving to be an efficient and practical method for constructing C-C and C-X bond.In addition,the direct C-H functionalization catalyzed by transition metal afford an ideal approach for the derivatization of complex drug molecules,especially for the last-stage modification of lead compounds via transformation of specific C-H bonds in an efficient,high-yield,and controllable manner.Taken together,the C-H activation strategy provides a new route for the modification of lead compounds in late-stage,more importantly,it greatly accelerates the research process of new drug discovery.C-H bonds are ubiquitous in complex drug molecules,and the bond energy of C-H bonds is relatively high,the selective C-H activation encounter huge challenge.More recently,scientists have been committed to seeking effective strategies to solve the problem of site selectivity in this field,e.g.,developing a strategy of introducing directing groups with heteroatom into the substrate to achieve ortho-and remote C-H activation.In addition,with the rapid development of C-H activation strategies,most transition metals in Group VIII,especially palladium,ruthenium,and rhodium complexes have been developed as widely used catalysts,the catalytic properties of different transition metals are also a factor that cannot be ignored in controlling site selectivity.Different metal catalysts own unique catalytic properties,which play an irreplaceable role in the construction of complex drug skeleton molecules as well as the realization of site selective C-H activation.In sharp contrast with the vigorous development of other transition metal catalysts,the osmium metal,which is also in Group VIII,has not been used as catalysts in the field of C-H activation.Based on the C-H activation strategy,drawing lessons from other transition metal catalysts in the field of C-H activation,we try to develop novel catalytic systems and reaction modes using osmium as the catalyst.This will provide more possibilities and options for achieving site selective C-H activation,as well as fill the gap in osmium metal catalysis in the C-H activation strategy.Method:（1）Using N-methoxybenzamide and alkynes as reaction materials,under the catalysis of Os（II）,adding Na OAc as base and Me OH as reaction solvent,reacting at 60°C for 24hours to obtain isoquinolinone derivatives via ortho C-H activation annulation.（2）Using2-phenylpyridine and bromoalkanes as reaction materials,exploring Os（II）catalysts with different ligands,adding Na₂CO₃ as base,and Mes COOH as additive 1,4-dioxane as solvent,a series of meta-C-H alkylation products were synthesized under N₂.Results:（1）We successfully developed a novel reaction modes to synthesis isoquinolinone compounds through the ortho-C-H activation annulation reaction catalyzed by Os（II）.Under mild reaction conditions,the yield is high and has good functional group tolerance.A series of isoquinolinone derivatives with potential biological activities are obtained.（2）A novel model of meta-C-H activation reaction of 2-phenylpyridine catalyzed by Os（II）was developed,the reaction exhibiting high yield and good functional group tolerance,realizing the meta-C-H activation.The compounds obtained by the reaction have obtained characterization datas of ¹H NMR,¹³C NMR and HRMS.（3）These two reactions path of Os（II）-catalyzed system was clarified by studying the reaction mechanism,combining with experiment and DFT theory calculation.Conclusion:（1）Based on the C-H activation strategy,we developed a novel catalytic system for osmium-catalyzed ortho-C-H activation annulation of N-methoxybenzamide,and synthesized a series of isoquinolinone compounds quickly and efficiently.（2）We have developed a novel model of meta-C-H alkylation reaction of 2-phenylpyridine catalyzed by Os（II）.These reactions have the advantages of good functional group tolerance,high atom economy,and mild conditions.（3）Based on the DFT calculations and experimental mechanism studies,we propose a catalytic cycle for N-methoxybenzamide ortho-C-H activation annulation reaction catalyzed by Os（II）within the assistance of HOAc,the formation of intermediate Os（IV）is the key of the catalytic cycle.In addition,we clarified the reaction of the meta-C-H activation prefer the radical mechanism,and the regioselectivity originated from the specific activated para-position by the C-Os bond.