Studies On The Cyclization Reaction Of 2-Isocyanobenzaldehydes With Various Nitrogen Sources

Isocyanides are an important class of organic synthesis intermediates with active chemical properties and a wide range of reaction types,and are widely used in the synthesis of a variety of nitrogen-containing compounds.In this field,o-functionalized aryl isocyanides can finely modulate the reactivity of isocyanides and have been widely used in the synthesis of important nitrogen source blocks and various nitrogen-containing thick heterocycles.As a member of the o-functionalized aryl isocyanides family,2-isocyanobenzaldehydes have both aldehyde and isocyano basic structural units,which can not only be used as nucleophiles and electrophiles,but also as 1,5-dielectrophiles and 1,4-dipoles,undergoing many types of chemical reactions.However,although the synthesis of 2-isocyanobenzaldehydes has been reported,studies on the properties and applications of this class of compounds have never been developed.Therefore,it is highly desirable to investigate the properties and applications of this class of compounds.This thesis focuses on the development of novel tandem cyclization reactions with various nitrogen-derived nucleophiles using 2-isocyanobenzaldehydes as starting materials,and develops a number of important nitrogenous heterocycles such as quinazolines,hydrogenated quinazolines,quinazolinones,indolo[1,2-c]quinazolines,imidazo[1,2-c]quinazolines and benzodiazepines.A new strategy for the facile and efficient synthesis of a number of important nitrogenous and dense heterocycles.The specific studies are as follows:1.A three-component coupled cyclization reaction of amines,2-isocyanobenzaldehydes and trifluorodiazoethane was successfully achieved under the catalysis of Ag₂CO₃.This reaction provides a new method for the construction of trifluoromethyl-containing dihydroquinazolines in one step under simple and mild conditions.More importantly,the use of trifluorodiazoethyl-substituted dihydroquinazolines as synthesis substrates allowed both the preparation of trifluoromethyl-substituted indolo[1,2-c]quinazolines in high yields via TBHP/KI-mediated intramolecular cyclization and aromatization processes,and the Ag BF₄-catalyzed 1,2-aryl migration,carabine expansion and further hydrolysis processes to achieve the efficient synthesis of trifluoromethylindolines.2.A series of structurally diverse thickened quinazoline derivatives were prepared by the successful bicyclization reaction of 2-isocyanobenzaldehydes with various amphiphilic nucleophiles under the conditions of PPTS as a catalyst.The reaction is not only simple and efficient,forming two rings and three new bonds in one step,but also has the advantages of easy availability of raw materials,mild conditions,a wide range of substrates,good tolerance of functional groups,high reaction efficiency,high product yields,only water and hydrogen as by-products,and minimal solvent usage.This lays the foundation for the synthesis of2-isocyanobenzaldehydes in nitrogenous heterocycles compounds.3.The aminobenzylation/cyclization of 2-isocyanobenzaldehyde was successfully achieved by us with the co-facilitation of Na N（Si Me₃）₂/Cs TFA.A variety of toluene derivatives,benzyl compounds and 2-isocyanobenzaldehydes were able to achieve such tandem reactions as described above,and 4-benzyl-substituted dihydroquinazoline and quinazoline derivatives were prepared in moderate to high yields.This aminobenzylation/cyclization reaction exhibited remarkable chemoselectivity and excellent functional group tolerance.Furthermore,Using the dihydroquinazoline obtained above as a synthetic substrate,a variety of complex heterocycles including iminoquinazolines,dihydroindolo[1,2-c]quinazolines and dihydro-8H-isoquinolo[2,3-c]quinazolines were constructed,demonstrating the potential of this strategy for synthetic applications.4.Under metal-free catalytic conditions,we have achieved an efficient synthesis of heptadruplex benzodiazepines using 2-isocyanobenzaldehyde as a 1,4-dipoles and azomethine yelides in a[4+3]cycloaddition reaction.This method not only extends the reaction mode of2-isocyanobenzaldehyde with a wide range of substrate applicability and functional group tolerance,but also provides new ideas for further application of 2-isocyanobenzaldehyde as a1,4-dipoles in the synthesis of other heterocyclic compounds.5.A series of 4-substituted quinazolin-2（1H）-ones and 2-aminoquinazoline-3-oxides were prepared by the successful tandem cyclization of o-acylaryl isocyanides with azide and two molecules of hydroxylamine,respectively,using Pd（OAc）₂as catalyst.The reaction conditions were mild and did not require complex ligands.For all kinds of substituted o-acylaryl isocyanides the reaction can be applied.In addition,the heterocycles prepared above were used as synthetic substrates to enable the preparation of a variety of heterocyclic compounds with important potential applications in biochemistry and medicinal chemistry through functional group introduction and transformation strategies.