Study On The New Synthetic Method Of Oxadiazole And Quinazoline Medicinal Skeleton

The structures of oxadiazole and quinazoline are widely found in natural products,materials,ligands,catalysts and small molecule drugs.Due to the particularity of these two frameworks,they have been extensively studied.Despite the significant synthesis advancements of 1,2,4-oxadiazole and quinazoline,most of these synthesis procedures may suffer from some drawbacks,such as time-consuming,harsh reaction conditions,special starting materials,multi-step procedures,low atom economy,and expensive transition metal complexes,ligands,additives,oxidants,which significantly hindered their further application.However,according to our investigation,we have found that so far there is no method that can obtain the two kinds of frameworks separately by simply changing the conditions under the same system.So,finding and developing a method for synthesizing both types of frameworks remains a big challenge.In recent decades,many research groups at home and abroad have devoted themselves to studying the application of oxygen in organic chemistry.Molecular oxygen is undoubtedly a clean and sufficient energy source,which can greatly avoid the environmental damage caused by metals or organic oxidants.In this project,the reverse synthesis analysis method was used in the design phase of the synthetic route to find the universal precursor benzalbenzylamine of two skeletons,and further simplified the starting materials to benzaldehyde and benzylamine and a different nitrogen source,making the idea that the one method is suitable for the synthesis of two kinds of skeletons can be realized.We chose copper bromide and oxygen catalyzed by the ligand as the oxidant,and based on the synthesis of the oxadiazole skeleton,after many explorations,we found that ethanol was the optimal solvent with a yield of 40%.We used a single factor method to investigate the catalyst,ligand,halogenated reagent,feed equivalent ratio,reaction temperature,and duration.Finally,1.0 equivalent of benzaldehyde and 1.0 equivalent of benzylamine were used as starting materials.1.0 equivalent of hydroxylamine as nitrogen source,ethanol as solvent,10mmol%copper bromide as catalyst,20mmol%1,10-phenanthroline as ligand,1.0 equivalent of dibromohydantoin(DBH)as halogenated reagent,oxygen as The oxidant,refluxing reaction at 80℃ for 8 hours,can synthesize the oxadiazole skeleton with the optimal yield of 90%.Under these conditions,we carried out substrate development.And found that the yield of the electron-donating substitution substrate is always better than that of the electron-withdrawing substrate,and the para-substitution is always better than the meta-position and the ortho-position.Among them,the benzaldehyde derivative is substituted with the para-methyl group.The highest yield was 94%to obtain compound 4ai.At the same time,we screened the conditions for the synthesis of the quinazoline skeleton by a single factor method.Finally,1.0 equivalent of benzaldehyde and 1.0 equivalent of benzylamine were used as starting materials,1.0 equivalent of aniline was introduced as a nitrogen source,and toluene was used as the solvent.Using 10mmol%copper bromide as a catalyst,20mmol%1,10-phenanthroline as a ligand,1.0 equivalent of dibromohydantoin(DBH)as a halogenating reagent,and oxygen as an oxidant,the reaction was refluxed at 100℃ for 14 hours.The oxadiazole skeleton can be synthesized with an optimal yield of 83%.Under the optimal conditions,the substrate expansion is carried out,and the conclusions are similar to the previous ones.Among them,the more special part is the quinazoline aniline derivative part.The aniline with electron donating substitution can obtain the target product,but the electron withdrawing substitution does not occur.reaction.The best yields are the methyl substituted compounds 6ac and 6bb:85%.The gram-scale scale-up experiment was carried out using this method.After the reaction feed was scaled up in equal proportions,the yields of oxadiazole and quinazoline skeletons were 79%and 75%,respectively,which proved that the method has good application potential.In order to explore the reaction mechanism,we first carried out a free radical trapping experiment.By introducing the free radical trapping reagent BHT under standard conditions,the free radical intermediates were trapped,and the accurate molecular weight of the trapped compound was monitored in a high-resolution manner.We also conducted a series of control experiments,including removing the catalytic conditions in the reaction conditions,introducing methyl groups into the benzylamine benzyl position of the reaction raw materials,and giving oxidation conditions from the separation of intermediates.According to the experimental results,we proposed a process that undergoes free radicals.The mechanism of copper-mediated aerobic oxidative cyclization.Finally,we have completed a new 3-component tandem reaction for the synthesis of oxadiazole and quinazoline skeletons.This novel synthesis method is compatible with functional groups.The expansion of substrates for a total of 53 compounds in this framework proves that the method can be widely used in the synthesis of such compounds.