Organocatalytic Asymmetric 1,4 And 1,6-Conjugate Addition Reaction Of Azadienes And Aza-p-Quinone Methides

Benzofuran derivatives are an important class of heterocyclic compounds,which are found in natural products and biologically active molecules.Therefore,it has a very wide range of applications.In view of the original driving force of the aromatization of azadiene,these compounds are often used to synthesize many benzofuran derivatives with potential pharmacological and biological activities.Although azadienes have been widely used in the synthesis of benzofuran derivatives in the recent years,the chiral phosphoric acid catalyzed asymmetric 1,4-conjugate addition reactions of thiazolone,1-naphthol and azadiene have never been reported.In addition,this type of reaction is of great significance for the construction of benzofuran derivatives containing quaternary carbon and tertiary carbon stereo centers.Aza-p-quinone compounds are widely distributed in natural products and drug molecules and are very powerful tools for the synthesis of nitrogen-containing chiral compounds.However,there were still few studies on propargyl aza-p-quinone methides in recent years and they were limited to asymmetric 1,8-conjugate addition and cycloaddition reactions.In this context,our research group used propargyl aza-p-quinone methides and N-aryl-3-oxobutanamides as raw materials and synthesized active propargyl compounds containing quaternary carbon chiral centers through asymmetric1,6-conjugate addition for the first time.The specific research work is as follows:Part I: In this work,we realized a chiral phosphoric acid catalyzed asymmetric1,4-conjugate addition reaction of azadienes and thiazolones.Firstly,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 solvent,and determined the best reaction conditions.On this basis,we carried out a substrate expansion for the reaction.The experimental results show that the method has good applicability to different substituted azadienes and thiazolones,and the products were obtained in 71-99% yields with 70-96%ee and 8:1->20:1 dr.We have successfully synthesized a series of sulfur-containing tetra-substituted benzofuran compounds with high enantioselectivity and diastereoselectivity.At the same time,the report not only successfully solved the problem of constructing a sulfur-containing tetra-substituted carbon stereocenter,but also provided a novle,efficient and simplified method for expanding the asymmetric nucleophilic addition reaction of thiazolones.Part II: In this work,we realized the asymmetric 1,4-conjugate addition reaction between azadiene and 1-naphthol catalyzed by chiral phosphoric acid.Firstly,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 solvent,and determined the best reaction conditions.Finally,the optimal reaction conditions for the reaction were determined.The results of substrate expansion show that the method has good applicability to different substituted azadienes,and the products were obtained in73-99% yields with 70-98% ee.This synthesis strategy can not only obtain various optically active triarylmethanes effectively,but also realize the para-selective asymmetric reaction of 1-naphthol successfully.Part III: In this study,we realized the asymmetric 1,6-conjugated addition reaction of aza-p-quinone methides and N-aryl-3-oxobutanamides catalyzed by chiral phosphoric acid for the first time.Firstly,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 solvent,and determined the best reaction conditions.The test results of the versatility of the substrate show that this method can generate a series of 1,6-conjugated addition products with good yields(66-94%)and stereoselectivity(70-95% ee,9:1->20:1 dr).This catalytic strategy not only realizes the site and stereoselective 1,6-conjugation addition reaction of propargyl aza-p-quinone methides for the first time,but also provides a credible access to alkyne substituted quaternary carbon stereocenters.