Design And Synthesis Of Sulfonamide Organocatalysts And Their Applications In Asymmetric Mannich Reaction

Abstract:In last decades, chemists have witnessed a spectacular advancement in the field of asymmetric catalytic reactions based on metal-free organic molecules. In many cases, these small compounds as organocatalysts provided extremely high enantioselectivity. Organocatalytic reactions have become powerful tools for the construction of skeletons in complex molecules. Mannich reaction is one of the most important reactions for the formation of carbon-carbon bonds. In recent years, asymmetric Mannich reactions catalyzed by organocatalysts have been studied widely and thoroughly, and it has been successfully applied in the synthesis of some natural products and drug intermediates. However, the articles about asymmetric synthesis of biological and pharmaceutical compounds via Mannich reaction have been rarely reported.In this thesis, we have designed and synthesized a series of primary amine (Cat.30-32) and secondary amine (Cat.36-38, Cat.42-44) sulfonamide organocatalysts starting from L-proline, L-alanine and L-phenylalaine and applied them in asymmetric Mannich reaction for one-pot synthesis of2-aryl-2,3-dihydro-4-quinolones. These catalysts have been screened. And good reactivity and enantionselectivity could be obtained when using the secondary amine sulfonamide catalyst30and primary amine sulfonamide catalyst36. The effects of solvent, reaction temperature and catalyst loading on the reaction were further investigated and it was found that good results could be obtained when the reaction proceeded at-20℃in methanol with20mol%catalyst loading. The reaction scope of substrates was also explored under the optimal condition and high enantioselectivity and high yields were obtained. Specifically, the prolinamide catalyst30gave the Mannich products in high yields (up to92%) and high enantioselectivity with up to69%ee of the (s)-isomer. Meanwhile, the primary amine sulfonamide36was also identified as a good catalyst for this reaction giving the (R)-enantiomer in up to74%ee. This research finding might pave the pathway for the enantioselective synthesis of2-aryl-2,3-dihydro-4-quinolones and further investigation of their biological activities.