Synthesis Of Organocatalysts And Their Applications In Asymmetric Michael Additions

Objective:Due to the high enantioselectivity,green economy,easy to industrialize of asymmetric catalysis,organocatalysis is the most ideal method for many methods of asymmetric synthesis.Michael addition is the common reactions of growth carbon chain and synthesis the compounds containing multiple functional groups.In this paper,a series of substituted benzoyl thiourea catalysts were designed and synthesized based on the mechanism of hydrogen bond activation,and the catalytic activity was investigated of asymmetric Michael addition reaction of pyrazolone to nitroolefin;and the asymmetric double Michael addition reaction of angelica lactone to nitroolefin was developed by the existing catalyst in our laboratory.Methods:?1?Cinchona alkaloid,S-2-aminomethylpyrrolidine,substituted benzoyl chloride,N,N-dimethylaminocyclohexanediamine,potassium thiocyanate were used as the starting material,followed by Mitsunobu reaction,Staudinger reaction or the other reactions to give the unreported target catalysts.?2?The target catalysts were screened in the asymmetric Michael addition of pyrazolone to nitroolefin,by which the corresponding chiral compounds were obtained with high enantioselectivity;the reaction conditions were evaluated by screening the reaction solvent,temperature,catalyst loading to provide the optimization condition;complexes of the catalyst-substrate were analysed by Hartree-Fock calculation.?3?The existing catalysts in the laboratory were applied in the asymmetric double Michael addition of angelica lactone to nitroolefin.Under optimizing the reaction conditions the target compounds were obtained with high ee value and dr value.Results:?1?In this article,fourteen unreported substituted benzoylthiourea catalysts were designed and synthesized,and the structures were confirmed by HRMS,¹H NMR,¹³C NMR,and IR.?2?Catalysts 2a-2h can efficiently catalyze the asymmetric Michael addition reaction of pyrazolone with a series of nitroolefins,and obtained R?65^>99%ee?and S?77^>99%ee?configuration.?3?The effects of substituents on the performance of benzoyl thiourea catalysts were preliminarily determined by experiments and calculations.?4?Catalyst 4a can efficiently catalyze the asymmetric double Michael addition reaction of angelica lactone with a series of substituted nitroolefins to give adducts with promising ee value?63%⁹5%?and dr value?93:7^>99:1?.Conclusion:Fourteen novel substituted benzoyl thiourea catalysts based on hydrogen bond activation were obtained.The catalyst derived from cinchona alkaloid successfully catalyzed the asymmetric Michael addition reaction of pyrazolone to nitroolefins,and both the S and R configurations were obtained in high yield and enantioselectivity;the complex formed by the benzoyl thiourea catalyst having an electron-donating substituent and the nitroolefin has a large hydrogen bond energy,thereby having superior catalytic performance;the asymmetric double Michael addition reaction of angelica lactone to nitroolefins was successfully catalyzed by monothiocarbamate catalysts with high ee and dr values.