Synthesis Of Nitrones Via Conjugate Addition Of α-Halogeno Hydrazones

Nitrones are a kind of important and useful scaffolds in biology and medicine,which have antioxidant,antiproliferative,anti-inflammatory and antibacterial effects.Over the past decades,many important and efficient synthetic methodologies have been developed for the preparation of structurally diverse nitrones.However,there are some obvious problems with preparation of multi-functional nitroketone compounds,and the limitations of the above synthesis methods.So,it is highly demanded and urgent to develop novel strategies for preparing the multifunctionalized nitrones concisely and efficiently.α-Halohydrazone belongs to a class of synthons with wide and powerful synthetic functions,which can participate in many chemical transformations.On the basis of the previous advances on the synthetic methodology ofα-halohydrazones,we designed and explored the novel conjugation additions betweenα-halohydrazones and nitroso compounds,thus accomplished the efficient and concise preparation of highly functionalized nitrones bearing the potential biological activities.Clearly,the newly established conjugation additions work as the important organic synthetic foundations for the drug discovery of multifunctionalized nitrones.In this work,we employed the azadienes in situ formed fromα-halohydrazones act as electrophiles and nitroso compounds as nucleophiles to develop mechanistically new conjugation additions.So far,such a work has never been reported in the literature works.In this work,by using Na₂CO₃ as a base,the conjugation additions betweenα-halohydrazones and nitroso compounds proceeded readily and gave the nitrones with chemically new skeletons.The synthetic method features the novelty,simplicity as well efficiency and provides multifunctional nitrone compounds with biological activities.The main contents of this work are outlined as follows:（1）The model reaction ofα-halohydrazone with nitroso compounds was designed.The effects of base,solvent and other factors on the efficiency of the conjugate addition reaction were investigated,the possible reasons were analyzed,and the ideal reaction system was constructed.（2）Under the optimal conditions,a series of substrates was extended for the conjugate addition reaction.23 novel nitrones were synthesized in moderate to good yields（47-93%）.（3）The structures of the obtained nitrones were characterized by ~1H NMR,¹³C NMR and HRMS.The stereochemical configuration of the title products was determined by X-ray single crystal diffraction,and the mechanism of conjugated addition reaction betweenα-halohydrazone and nitroso compounds was speculated.