Asymmetric Organocatalytic Michael Addition Reaction Of Enoyl-pyridine-nitrogen Oxide And 1-azadienes

Pyridine compounds are a class of nitrogen-containing heterocyclic compounds and a ubiquitous structural part of drugs that exist widely in nature.The pyridine skeleton structure exists widely in drug molecules,it has a variety of important pharmacological and physiological activities.Although there have been many studies on the synthesis of pyridine skeleton compounds,these synthetic methods still have disadvantages such as large amount of catalyst and narrow substrate range.Therefore,the development of new synthetic methods is still a major challenge faced by organic chemists.Our group continues to conduct research on pyridine nitrogen oxides and chooses 5H-oxazol-4-ones as the nucleophile.Under the action of organic catalysts,we have successfully constructed a new framework with both pyridine nitrogen oxides and five-membered nitrogen heterocycles,and the method has good enantioselectivity and diastereoselectivity.Benzofuran derivatives are ubiquitous in natural products and pharmacologically active substances,and the dense ring structure containing nitrogen and oxygen atoms is a common group in pharmacologically active compounds.Therefore,it is of great significance to develop an effective synthetic strategy to synthesize heterocyclic compounds containing benzofuran skeleton.Due to the driving force of aromatization,benzofuran-derived azadiene exhibits high reactivity in organic synthesis.Although many1,4-conjugated addition and cycloaddition reactions of azadiene have been reported,these synthetic methods still have shortcomings such as limited types of substrates and few catalytic systems.In this context,based on previous work,our group actively explored the organically catalyzed asymmetric Michael addition reaction of azadiene compounds with2-naphthol,and constructed chiral triaryl heterocyclic compounds successfully containing benzofuran skeletons with different configurations,which have high yield and stereoselectivity.Part I: This part reported the asymmetric Michael addition reaction of enoyl-pyridine-nitrogen oxide and 5H-oxazol-4-ones catalyzed by chiral thiourea catalysts.First of all,we screened the catalyst.After determining the best catalyst,we optimized a series of reaction parameters such as the type of solvent and the amount of catalyst,and determined the best reaction conditions.Then,the suitability of the substrate was investigated.The method was well compatible with 5H-oxazol-4-ones and the different substituted pyridine nitrogen oxides,the target product was obtained in 62-99%yield with 84->99% ee,>20:1 dr.We have constructed a pyridine compound containing a quaternary carbon chiral center successfully through this synthetic method.This target product may be further transformed into some pharmaceutical intermediates,which has potential application value in the industrial field.Part II: This part reported the asymmetric Michael addition reaction of azadiene and2-naphthol catalyzed by chiral thiourea catalysts.First of all,we screened the catalyst.After determining the best catalyst,we optimized a series of reaction parameters such as the type of solvent,the amount of solvent,the amount of catalyst,reaction time,temperature and so on,and determined the best reaction conditions.Next,the suitability of the substrate was investigated.The method was compatible with the different substituted azadienes and 2-naphthol,and the yield of the target product was 60-99% and the ee value was 74-96%.When the thiourea catalyst plays a mediating role,we can construct a chiral triaryl heterocyclic compound with high yield and high stereoselectivity of R configuration containing benzofuran skeleton through this synthetic method.Part III: This part reported the asymmetric Michael addition reaction of azadiene and2-naphthol catalyzed by chiral phosphoric catalyst.First of all,we screened the catalyst.After determining the best catalyst,a series of reaction parameters such as the type of solvent,the amount of solvent,temperature were optimized and the best reaction conditions were determined.Then,the suitability of the substrate was investigated.The method was compatible with the different substituted azadienes and 2-naphthol,and the yield of the target product was 54-86% and the ee value was 61-99%.When the chiral phosphoric acid catalyst plays a mediating role,we can construct a chiral triaryl heterocyclic compound with high yield and high stereoselectivity of S configuration containing benzofuran skeleton through this synthetic method.It is worth noting that this strategy provides a new method for obtaining a variety of optically active triarylmethanes in an asymmetric catalytic manner.In summary,we have successfully developed an organocatalyst-controlled enantiodivergent Michael additions of azadienes with unprotected 2-naphthols.