Study On Synthesis Of Spirocyclic Compounds By Cycloaddition Reaction

Since the 60s and 70s of the twentieth century,biologists and pharmacologists have discovered that compounds with spirocyclic structures were accounted for a large proportion of compounds with biological activities which are isolated from natural products.Due to the special structure,spirocyclic compounds usually have a variety of biological activities.So compounds containing spiro structure are often become the important source of lead compounds in medicinal chemistry.Now,the synthesis and application of these compounds have become a hot spot in organic synthesis and drug synthesis all over abroad.Cycloaddition reaction is a bimolecular reaction of the two conjugated systems to form a cyclic molecule,and is an important method for the synthesis of monocyclic and polycyclic compounds.In this thesis,a series of spiro compounds were synthesized by cycloaddition reactions.These reactions have the simple reaction conditions and easy processing,which would enrich the synthetic method for spiro compounds.1.In the first chapter,we studied the reaction of azomethine imines to form spiro compounds in acetonitrile by 1,3-dipolar cycloaddition.Without using any catalyst,azomethine imine reacted with 2-arylideneindandione and 3-phenacylideneoxindoles to give spiro compounds with two diastereoisomeric centers.Additionally,azomethine imine reacted with 4-arylidene-3-methyl-5-phenylpyrazolone in the presence of triethylamine as the basic catalyst to afford spiro compounds with multiple chiral centers.Although the synthetic spiro compounds have multiple chiral centers,the reaction has a high diastereoselectivity.All products were characterized by IR,1H NMR,13C NMR,HRMS spectroscopy.The single crystal structures of six products were determined by X-ray diffraction method.2.We systematically investigated the domino reactions of 4-arylidene-3-methyl-5-phenylpyrazolones with a series of vinyl malononitriles.In the presence of triethylamine as basic catalyst,pyrazolone reacted smoothly with various vinyl malononitriles to give spiro[phenanthroline-7,4'-pyrazoles]and spiro[phenanthrene-2,4'-pyrazole].The reaction usually showed high yields and good diastereoselectivity.All products were characterized by IR,1H NMR,13C NMR,HRMS spectroscopy.The single crystal structures of six products were determined by X-ray diffraction method.3.The synthesis of two pharmaceutical intermediates were carefully studied by using trimethoprim as the key starting material.Through the sequential demethylation of trimethoprim,hydrolysis and other processes,two pharmaceutical intermediates were efficiently prepared in good yields,which will be employed for preparation of new chemicals.All products were characterized by 1H NMR spectroscopy.