Synthesis Of Some Nitrogenous Heterocyclic Small Molecule Compounds By Series Reaction

N-heterocycles, which exist in a wide range of natural products with remarkable biological activities, occupy thirty percent of the heterocyclic compounds. Thus, the development of efficient methods for the construction of N-heterocycles has attracted continuous interest in organic synthesis.Tandem reaction is an effective strategy employed in diversity-oriented synthesis. Compared with the conventional multi-step synthesis, the tandem reaction simplifies the operation process without the separation and purification of intermediates, which is particularly prominent for the sensitive, unstable intermediates; Meanwhile, it is environmental friendly owing to avoiding the waste of raw materials and solvents; In addition, it also exhibits high efficiency for bonds formation and easily achieves molecular diversity and complexity.The thesis is mainly focused on the tandem reactions for the generation of some N-heterocyclic small molecule compounds based on2-alkynylbenzaldehyde and its derivatives.Firstly, based on the electrophilicity and [3+2] cyclization characteristics of isoquinolin-2-ium-2-ylamide intermediates, a mild and efficient route to N-pyrazolo[5,1-α]isoquinolines via a C-H activation of tertiary amine is developed. An enamine species generated from oxidation of tertiary amine in the copper-oxygen system participates in the electrophilic cyclization process. Subsequent exploration showed that the N-sulfonylketenimine intermediate could also react with isoquinolin-2-ium-2-ylamide through a [3+2] cycloaddition process.Secondly, a facile synthetic protocol for the construction of benzazepine and benzoxepine derivatives through a copper(I)-catalyzed reaction of2-(2-ethynylphenyl)-l-tosylaziridine or2-(2-ethynylphenyl)oxirane with sulfonyl azides is disclosed. The ketenimine is the key intermediate during the reaction process. Additionally, a copper(I)-catalyzed three-component reaction of2-(2-ethynylphenyl)-oxirane, sulfonyl azide, and2-isocyanoacetate affords the3’,5’-dihydro-1H-spiro[benzo[d]oxepine-2,4’-imidazoles] in good yields. The molecular diversity and complexity could be easily introduced via a simple operation.Subsequently, the cascade reaction of2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides an efficient route for the generation of fused benzoindolines. A ketenimine species and6π-electrocyclization are believed to be involved in the transformation. Based on the above results, another approach for the construction of benzoindoline scaffold via a copper(Ⅱ)-catalyzed tandem reaction of1-bromoethynyl-2-(cyclopropylidenemethyl) arenes with allylic sulfonamides is developed. The transformation is a four-step cascade involving Ullmann coupling, aza-Claisen rearrangement,6π-electrocyclization, and intramolecular rearrangement. The reaction mechanism is further confirmed by control experiment and DFT calculation.Finally, a palladium-catalyzed reaction of1-bromo-2-(cyclopropylidenemethyl) benzene and2-alkynylbenzenamine is explored, which generates2-(naphthalen-2-yl)benzenamines and5H-indeno[1,2-c]quinolines via6-endo and5-exo cyclization, respectively. The regioselectivity for the final outcome could be tuned by phosphine and N-heterocyclic carbene ligands.