Development Of Novel C-H Amination Strategies And Their Application For The Construction Of Nitrogenous Drug Skeletons

BackgroundThroughout the development of clinical drugs,nitrogenous compounds occupy a large proportion in conventional drugs and preclinical candidate drugs,and aromatic amine are the most common among them,often existing as the main core of drug structures.At the same time,it can achieve the construction of complex molecules as an important building block.Therefore,the construction of C-N bonds on benzene has becoming one of the core themes of chemical synthesis.In recent years,the transition metal-catalyzed hydrocarbamination reaction shows good catalytic performance.Directing group strategies in metal-catalyzed hydrocarbamination can occur efficiently,accurately and specifically combining with different types of electrophilic aminating reagents.Compared with the traditional C-N coupling reaction,it is more suitable for the efficient and green chemistry development concept.ObjectiveHydrocarbamination is a direct and high atom economy strategy for the construction of C-H bonds.Therefore,it is very important to develop new amine sources to expand the types of hydrocarbamination.Based on the current mature transition metal-catalyzed C-H activation strategy,this project aims to develop a novel electrophilic aminating reagent with simple preparation,high reactivity and redox neutral properties.To explore green,economical and efficient synthesis methods to construct complex aromatic amine compounds,and provide efficient strategies for the synthesis of medicinal compounds library,so as to expand a new research direction for C-H bond amination reaction.Methods(1)Designing of aminating reagent.N-methoxybenzoamide or N-pyrimidine indoline was used as the guide substrate and under the catalysis of Rh(Ⅲ),C-H amination of aromatic ring occurs by one-pot method.(2)Established the asymmetric catalytic reaction system,optimized related parameters,and investigated the universality of different substrate so as to explore the applicability of developed method.(3)The resulting amine products were transformed into diversity,and the method was applied to the modification of amino acid and known drugs to explore the effectiveness in practical application.(4)Deuterium-labeling experiment,kinetic isotope effect and density functional theory(DFT)were used to investigate the intermediates and paths of the reaction,so as to provide a basis for the subsequent mechanism research.Results(1)We designed a new electrophilic aminating reagent isoxazolone and have successfully achieved the C-H amination cyclization cascade reaction of Nmethoxybenzamide,constructing a series of dihydroquinazolone skeletons with potential application value in one step.Detailed experimental and computational studies have shown that the breaking of the N-O bond in aminating reagents can act as an oxidant to provide a redox neutral catalytic cycle,two new C-N bonds are constructed in a one-pot method,in which nitrenoid and imine species may participate as active intermediates.In addition,in the derivatization of the product,it was found that it can be converted into a compound skeleton with great practical value and biological activity under simple conditions.(2)The aminating reagent in the first part of the work was reasonably designed and modified to obtain N-OTs imide esters,and the C7 primary amination of N-pyrimidine indoline catalyzed by Rh(Ⅲ)was successfully achieved.This method has good site selectivity and high conversion efficiency,and is well compatible with substrates with different groups.In addition,using the obtained primary amine products can have a good functional modification effect on some amino acid molecules and pharmaceutical molecules containing carboxyl groups.ConclusionsIn summary,we have designed two aminating reagents and successfully established the synthesis methodology strategies for directly converting the C-H bond on the aromatic ring into a C-N bond.The core of the transformation is that the N-O bond in the aminating reagent undergoes metal-nitrenoid intermediate after breaking,and after reduction and elimination,isomerization is performed to obtain an imine species.At this time,either intramolecular nucleophilic addition occurs to obtain the cyclization product,or direct protonolysis is performed to obtain the primary amination product.Two different routes were confirmed in N-methoxybenzamide and N-pyrimidine indoline substrates,and provide the products of dihydroquinazolone and 7-aminopyrimidine indoline.In addition,during the derivatization of the product,it was found that the obtained compound can be converted into a compound skeleton with great practical value and biological activity under simple conditions,and has a good modification effect on amino acid molecules or known drug molecules,further proving the synthesis practicality of this reaction.