The Catalysts Derived From Cinchona Alkaloids And Their Application To Aza-Henry Reaction And Mannich Reaction Of Trifluoromethyl Ketimines

In recent years,the asymmetric catalysis of organic small molecules has attracted more and more attention.Mannich reaction is known to be one of the most efficient ways to build C-C bonds.Molecules containing trifluoromethyl groups can effectively improve biological activity,metabolic stability,lipophilicity and binding affinity,so compounds containing trifluoromethyl are widely used in drugs,materials and agricultural products.As the dominant framework of chiral catalysts,cinchona is a cheap and readily available chiral source.Due to its characteristic that its structure is easy to modify,it is of great significance to develop a bifunctionalized catalyst system derived from cinchona to catalyze the synthesis of valuable optically pure compounds by asymmetric Mannich reaction.In this paper,two different types of bifunctionalized cinchonine-derived catalysts were successfully applied to the asymmetric aza-Henry reaction of non-cyclic trifluoromethyl ketimines and the asymmetric Mannich reaction of non-cyclic trifluoromethyl ketimines and phenylthiophenols.The specific research work is as follows:1.A bifunctional phase transfer catalyst derived from cinchonine was synthesized and successfully applied to the asymmetric aza-Henry reaction between N-Boc ketimines derived from trifluoromethyl acetophenone and nitromethane.Through the optimization of catalyst,base,solvent,temperature and amount of catalysts,the optimal reaction conditions were determined:5 mol%catalyst,LiOH·H₂O as the base,toluene as the solvent at-20?for 18 hours.The scopes of substrates were further expanded,and the substrates with electron-withdrawing substituents and electron-donating substituents were tried respectively,and the products were obtained with good yield and high enantioselectivity?up to 98%yield,up to 96%ee?.Finally,we tried to transform the nitro group to the amino group,and then further cyclization to obtain imidazoline-2-ketone compounds.We confirmed the absolute configuration of the product by single crystal diffraction,and the absolute configuration final product was S.2.A series of squadrhamide catalysts derived from cinchonine were synthesized and used to catalyze the asymmetric Mannich reaction between non-cyclic trifluoromethyl ketimines and phenylthiophenols.The optimal reaction conditions were determined by selecting the type of catalysts,solvent,temperature,additive and amount of catalyst.Through the optimization of the catalysts,it can be concluded that the enantioselectivity of quinine skeleton and squadrhamide fragment to this reaction is very important.Finally,we selected quinine-derived squadrhamide as the optimal catalyst,m-xylene as the solvent,and 20 mg of 3?MS as the additive,at-40?reaction approximately for 5 min,the products were obtained in 94%yield and 94%ee.It is worth noting that when the substrate is replaced by methyl group,products were obtained in medium enantioselectivity;when the substrate is replaced by other electron-withdrawing or electron-donating substituents,the products were obtained in good yields with high enantioselectivities?96%yield,99%ee?.We investigated the scope of substrates,respectively tried phenylthiophenols and ketimines with different substituents,and the experimental results showed that the substituents had no obvious effect on the activity of the reaction.Finally,in order to verify the feasibility of the method,we carried out a gram-scale reaction and the product was obtained in good yield and high enantioselective.In order to explore the catalytic mechanism,we propose a possible transition state model.The product is S configuration by single crystal diffraction.