Dipolar Cycloaddition Reaction For Construction Of Nitrogen-containing Heterocycle

Nitrogen-containing heterocyclic molecular skeletons,especially five-membered and six-membered nitrogen-containing heterocyclic skeletons are commonly found in many biologically active natural products and pharmaceutical molecules.Synthetic heterocyclic skeletons have important applications in the field of pharmaceutical chemistry and pharmacology.The dipolar cycloaddition reaction has the advantages of short reaction time,high yield and high atomic economy.Therefore,it is of great significance to construct a nitrogen-containing heterocyclic skeleton through the dipolar cycloaddition reaction.In this paper,the cycloaddition reactions of 1,3-dipoles constructed by pyrrolidine and aromatic aldehydes,1,4-dipoles constructed by quinoline and alkynes with various dipolarophiles were studied to synthesize new nitrogen-containing heterocyclic compounds with potential drug activity.1.In the presence of acetic acid,the cycloaddition reaction of the 1,3-dipole formed by pyrrolidine and aromatic aldehydes with 4-arylidene-5-methyl-2-phenylpyrazol-3-one and 2-arylidene-N,N’-dimethylbarbiturates was studied.A series of 7’-(E)-benzylidenespiro[pyrazole-4,1’-pyrrolizines]and a series of 7’-arylidenespiro[pyrimidine-5,1’-pyrrolizines]with Z/E-isomers were synthesized.The three-component with N-phenylmaleimides and sequential oxidation with DDQ reaction gave 8-(E)-arylidenedihydropyrrolo[3,4-a]pyrrolizines in satisfactory yields.The structures of the thirty-two synthesized compounds were characterized by IR,NMR,HRMS,etc.and seven single crystal structurs were measured by X-ray diffraction method.2.In the presence of acetic acid,the cycloaddition reaction of the 1,3-dipole formed by pyrrolidine and aromatic aldehydes with 3-arylidene-indolinone and 2-benzylidenemalononitrile and ethyl-2-cyano-3-phenylacrylate was studied.A series of 7’-((E)-benzylidene)hexahydrospiro[indoline-3,1 ’-pyrrolizines]and a series of 7-((E)-benzylidene)-2,3-diphenylhexahydro-1H-pyrrolizine were synthesized.The structures of the twenty-seven synthesized compounds were characterized by IR,NMR,HRMS,etc.and three single crystal structurs were measured by X-ray diffraction method3.The cycloaddition reaction of the Huisgen 1,4-dipole formed by isoquinoline(quinolone)and dimethyl acetylenedicarboxylate with 4-arylidene-5-methyl-2-phenylpyrazol-3-one was studied.A series of spiro[pyrazole-4,1’-pyrido[2,1-a]isoquinoline]were synthesized.The reaction not only synthesized containing nitrogen complex heterocycles,but also had the advantages of simple reaction conditions and good yield.The structures of the twenty-nine synthesized compounds were characterized by IR,NMR,HRMS,etc.and three single crystal structurs were measured by X-ray diffraction method.