Studies On The Synthesis Of 2,4-Disubstituted Quinazoline Derivatives

Quinazolines have attracted immense interesting due to their potential pharmacological and biological activities.Therefore,the synthesis of quinazoline and its derivatives has been a hot research topic in the field of organic synthesis.Although many literatures on preparing quinazoline derivatives are available,there still exist some disadvantages,such as using toxic POCl3 as reagent,high catalyst loading,narrow scope of substrates,etc.Therefore,more efficient,convenient and green synthesis routes of quinazoline derivatives need to be explored.Based on our research work on quinazolines,we here(in this thesis)develop several new methodologies for the synthesis of 2,4-disubstituted-quinazolines derivatives:Firstly,with an expectation to provide another efficient route for the synthesis of 4-(hetero)arylquinazolines,we have developed a mild and efficient protocol for the synthesis of 2,4-disubstituted-quinazolines via nickle-catalyzed cross-coupling reactions of 4-tosyloxyquinazolines and Grignard reagents.Secondly,based on the widely application of organoindium reagents in organic synthesis,we have developed method for the synthesis of 2,4-disubstituted-quinazolines via palladium-catalyzed cross-coupling reactions of 4-tosyloxyquinazolines with organoindium compounds and one-pot reaction of quinazolinones,TsCl and organoindium compounds.The present method has advantages of mild conditions and good compatibility with alkyl and heterocyclic functional groups.Thirdly,organobismuths could be readily prepared,which are nontoxic and stable to air.We have developed a highly efficient route for the synthesis of 2,4-disubstituted-quinazolines via palladium-catalyzed cross-coupling reactions of 4-tosyloxyquinazolines with organobismuths compounds.The present method has advantages of simple materials and good compatibility with alkyl and heterocyclic functional groups.Fourthly,quinazoline and indole frameworks have attracted immense interesting due to their potential biological activities.The synthesized new indol-quinazoline skeleton has the potential to exhibit more efficient biological activities.Therefore,an efficient route is described to give a wide array of 4-(1H-indol-1-yl)-quinazolines in good to excellent yields under mild reaction conditions through cross-coupling reactions of 4-tosyloxyquinazoline with indole derivatives.Additionally,organophosphorus have attracted immense interesting due to their potential biological activities.We have developed an efficient route for the synthesis of 4-phosphated quinazolines via palladium-catalyzed cross-coupling reactions of 4-tosyloxyquinazolines with phosphites,and a series of 4-phosphated quinazolines have been synthesized for the first time.Finaly,using cheap,readily available and the most economic MnO2 as the oxidant,a series of 2,4-disubstituted-quinazoline 3-oxides are synthesized in good to excellent yields by oxidation of the corresponding 1,2-dihydroquinazoline 3-oxides under mild conditions.We also investigate the 1,3-dipolar cycloaddition reaction between 2-aryl quinazoline 3-oxide with dimethyl acetylenedicarboxylate,furnishing the product 1,3-benzodiazepines in good yields.Different from 2-H-substituted-Quinazoline 3-Oxides or 2-aliphatic-substituted-Quinazoline 3-Oxides,the reaction of 2,4-disubstituted-quinazoline 3-oxides show some specialization and originality to some extent.