Palladium-Catalyzed Cyclization Reaction Of 2-Haloaniline With Carbon Oxide

2-Haloaniline is a bifunctional substrate with high reactivity,it could be converted into a variety of nitrogen-containing heterocyclic compounds through cyclization reaction in the presence of palladium,copper or other metal catalyst and base.Based on our previous study on the palladium-catalyzed cyclization reaction of 2-haloaniline with carbon dioxide and isonitrile（or carbon monoxide）,this thesis revised the previously proposed reaction mechanism on the basis of mass and computational study,and developed a palladium-catalyzed cyclization reaction of 2-haloaniline with carbonyl sulfur and isonitrile to synthesize benzothiazinediones.1.The substrate scope of the palladium-catalyzed cyclization of 2-bromoaniline with carbon dioxide and isonitrile substrates was firstly investigated.It’s found only the highly steric isonitriles could react successfully to obtain quinazoline-（1H,3H）-2,4-diones,other isonitriles with less hindered alkyl substituted and aryl isonitriles could not successfully separate the target products.In the mass study,the key species of isonitrile insertion in the reaction pathway of which isonitrile reacted firstly was successfully detected,but the key six-membered ring species in the reaction pathway of which carbon dioxide reacted firstly was not observed.In the computational study,it’s found that the activation energies of every steps of which isonitrile（or carbon monoxide）reacted firstly are much lower than that of which carbon dioxide reacted firstly.It’s concluded that the reaction mechanism is more likely to be that the oxidation addition of palladium catalyst with 2-haloaniline,then the insertion of isonitrile and the followed reaction with carbon dioxide,the final quinazolinedione product is obtained by reductive elimination and isomerization.2.A palladium-catalyzed cyclization reaction of N-alkyl substituted 2-iodoaniline with carbon monoxide and carbonyl sulfur to synthesize benzothiazinediones was developed.The optimized reaction conditions are:10 mol%Pd（CH₃CN）₂Cl₂ as palladium source,20 mol%Xantphos as ligand,2 equivalent cesium acetate as base,toluene as solvent at 60 ^oC for 2hours.The reactivity of electron-deficient 2-iodoaniline substrates is higher than electron-rich substrates.The structure of the product was confirmed by X-ray single crystal diffraction.The possible reaction mechanism included:the oxidation addition of palladium（0）with2-iodoaniline and then insertion of carbon monoxide into the C-Pd bond gave the acyl palladium intermediate,the attack of nitrogen atom on carbonyl sulfur formed thiocarbamate anion in the presence of base,and nucleophilic attack of sulfur atom on the palladium produced thiocarbamate acyl palladium intermediate,which conducted the reductive elimination to obtain benzothiazinedione product and regenerate the palladium（0）catalyst.Unsubstituted 2-iodoaniline could not give benzothiazinedione through this cyclization reaction,but it could react with carbonyl sulfur to give urea product in good yield using potassium tert-butoxide as base and DMSO as solvent.