(3 + 3)cyclization Of ?-haloketones With Diazo Compounds To Access 4-pyridazinone Derivatives

Six-membered nitrogen-containing heterocyclic compounds are a very important class of compounds,which exist widely in natural products and drug molecules.The efficient construction of multifunctional six-membered heterocyclic framework is of great significance in modern organic synthesis.(3+3)Cyclization reaction is a practical method to efficiently construct a diverse sixmembered heterocyclic skeleton.This kind of reaction is usually the cyclization process between one highly active 1,3-dipole species and another relatively stable 1,3-dipole species.Oxyallyl cations are important 3-center 2-electron reactive intermediates,which are widely used in chemistry.They can be formed from easily available ketone precursors by a variety of strategies,and as highly active 1,3-dipoles can participate in cycloaddition reactions,mainly including(4+3)and(3+2)cycloaddition reactions.Related(3+3)cycloaddition reactions are rarely reported,especially the catalytic asymmetric(3+3)cycloaddition reactions are unknown.Diazo compounds are a class of relatively stable 1,3-dipole,and their participation in 1,3-dipole cycloaddition can rapidly construct heterocyclic skeletons containing two continuous nitrogen atoms.The reported related dipole cycloaddition reactions are mainly(3+2)cycloaddition reactions,and the related(3+3)cycloaddition reactions are rarely involved.In particular,catalytic asymmetric(3+3)cycloaddition reactions have not been reported.In this paper,the research progress of two kinds of 1,3-dipoles with different reaction properties is reviewed,namely,electrophilic oxyallyl cations with high reactivity and relatively stable diazo compounds with nucleophilic properties.The synthesis of 4-pyridazine derivatives based on the crossing(3+3)cycloaddition reaction between the two kinds of 1,3-dipoles was described.There are two parts:In the first part,a series of chiral organic small molecule catalysts were synthesized for the(3+3)cycloaddition reaction of ?-haloketones with diazomethylphosphonates.In this reaction,?-haloketone was used as a precursor to form oxyallyl cation intermediate in situ under alkaline conditions.We successfully achieved the first asymmetric(3+3)cycloaddition reaction based on oxyallyl cation and diazomethylphosphonate,providing a strategy of high diastereoselectivity,high enantioselectivity and high yield for the synthesis of optically pure 6-phosphonyl-4-pyridazineone derivatives containing two continuous tertiary carbon centers.In this method,bisphosphonimide derived from binnaphthol with unique spatial structure is used as chiral Br?nsted acid catalyst.Through control experiments and research results,a possible chiral control model was proposed.The absolute configuration of the product was determined by single crystal X-ray diffraction analysis.The obtained 4-pyridazineone products can be transformed into optically pure tetrahydropyridazine derivatives containing three continuous tertiary carbon chiral centers.The catalytic asymmetric(3+3)cycination reaction uses a challenging chiral Br?nsted acid catalyst buffer system with stoichiometric bases,which is rare in organic small molecule asymmetric catalytic systems and provides a new strategy for the development of catalytic asymmetric reaction systems for oxyallyl cations and diazophosphonates.This is not only the first successful asymmetric catalysis of(3+3)cycloaddition reaction involving oxyallyl cations,but also the first successful asymmetric catalysis of(3+3)cycloaddition reaction involving diazo compounds.This method has a wide range of substrates and novel catalytic system,which provides a basis for the study of biological activity and application transformation of chiral pyridazine derivatives.In the second part,a new strategy was designed and successfully developed for the formation of5,6-dihydro4-pyridazinone skeleton by(3+3)cycloaddition reaction with diazomethylphosphonates using ?-halogenone as precursor in the presence of trifluoroethanol and base.A series of multifunctional 6-phosphonyl-5,6-dihydro4-pyridazine derivatives were obtained with high chemical selectivity and yield.The 5,6-dihydro-4-pyridazinone product can be further dehydrogenated to access the corresponding 4-pyridazinone product under the promotion of potassium carbonate as a base,and the corresponding 4-pyridazinone product can be directly obtained from ?-haloketones and diazomethylphosphonates by one-pot method.At the same time,this method is also suitable for diazoacetate,that is,a series of multi-substituted 4-pyridazidone-6-carboxylate derivatives were synthesized by the one-pot method starting from ?-haloketones and diazoacetates.The obtained 4-pyridazineone compounds can be transformed into multifunctional pyridazine derivatives,which contain highly conjugated structures and can be used for the development of multifunctional optical materials.This is the first time to realize the(3+3)cycloaddition reaction between oxyallyl cations and diazoacetates.This reaction substrate has a wide range of application,mild conditions and simple operation,providing a new method for the efficient synthesis of these novel 4-pyridazine derivatives.