Construction Of Cyclopropane Derivatives And Their Involvement In Tandem Cyclization Reactions

Cyclization reactions have always been a hot research topic for organic chemists.According to statistics,more than 50% of drug molecules have one or more heterocycles.Utilizing simple starting materials and inexpensive catalysts to synthesize multifunctional,structurally diverse,and complex cyclic compounds containing quaternary carbons,spiro rings,fused rings,etc.with atom economy,step economy,high efficiency and high selectivity remains an important scientific frontier and developing trend in this research field.In addition to various cycloaddition reactions,Friedel-Crafts cyclization reactions,electrophilic cyclization,and substitution cyclization,the rapid development of organocatalysis in recent years has provided many new ideas for further enriching the types of cyclization reactions.Intermolecular tandem cyclization is a new type of reaction,especially the new concept of activation of C-H bond and construction of C-C and C-N bonds.Tandem cyclization is an economical,efficient,green and environmentally friendly synthesis of heterocyclic compounds.It provides new strategies and approaches,so the intermolecular tandem cyclization has become a new opportunity and challenge for current organic chemistry methodological research.This paper mainly studies base catalyzed and metal catalyzed tandem cyclization reactions.Cyclopropane derivatives are a class of important organic synthesis intermediates,and their skeleton structures are widely found in drugs and biologically active molecules.We have developed an efficient and highly diastereoselective route for the synthesis of spiro-cyclopropanes via a base induced annulation reaction of2-arylidene-1,3-indanediones and dimethylsulfonium ylides.We systematically studied from the initial experimental design,screening conditions（catalysts,solvents,temperature,etc.）,substrate universality,gram-scale reaction and derivatization reaction,the structures of all products were confirmed by NMR,MS and X-Ray,and the reaction yields were up to 97% and 20:1 d.r..The pyrazole scaffold,a vital azaheterocycle framework,has remarkable medicinal properties ranging from antitubercular,anti-inflammatory,antifungal,antibacterial,anticancer,antiviral,antidiabetic,anti-mycobacterial,anesthetic and analgesic properties,in addition to its diverse biological activities.Using a base-catalyzed tandem cyclization strategy,we developed a metal-free in situ generated tosyldiazomethane（Ts DAM）and（Z）-aurones as starting materials to prepare polysubstituted pyrazoles.The method specifically involves a tandem reaction mechanism of 1,3-dipolar cycloaddition in an aqueous system and cleavage of C-O bonds in an acidic environment to achieve aromatization.We also systematically studied through the initial protocol design,screening conditions（base,solvent,temperature,etc.）,substrate universality,gram-scale reactions and derivatization reactions,and all products were confirmed by NMR,MS and X-Ray,and the reaction yields were up to 98%.Pyrimidine and imidazole,which usually display significant bioactivities in numerous biologically active compounds,founded in a large number of medicinal compounds and natural biological products.The development of novel strategies for the efficient synthesis of these heterocyclic compounds is still important in the field of synthetic chemistry.We have developed a new method for the synthesis of substituted pyrimidines and 2H imidazoles by Cu（I）-catalyzed 2H azirine ring expansion and radical induced tandem cyclization with oxime ethers.The strategy has mild reaction conditions and broad substrate scope,and allows rapid assembly of the target products.In addition,the method also describes the selective cleavage of C-N bond or C-C bond of 2H azirines with [3+2] or [3+3] annulation in switchable way.