Thiourea Catalysts Derived From Cinchona Alkaloids And Their Application To Nitro-Mannich Reaction And Vinylogous Mannich Reaction

Asymmetric organocatalyst has developed dramatically in recent years.Among them,Mannich reaction have become a convenient and efficient procedure for constructing carbon-carbon bonds.In addition,it is well known that cinchona alkaloids are one of superior chiral skeleton and they are one of inexpensive and accessible chiral resources.Thiourea,it is alkaline,can form a hydrogen bond between the substrates,it can activate substrates.Therefore,It is of great significance that developing the kinds of bifunctional thiourea catalyst systems to catalyze the Mannich reaction and obtained valuable optically pure amine compounds.In this thesis,we developed two different kinds of bifunctional thiourea catalysts derived from cinchona alkaloids and applied them to nitro-Mannich reaction and vinylogous Mannich reaction.The specific research work as following:1.We have developed a highly enantioselective asymmetric nitro-Mannich reaction of aryl?-ketoester-derived N-Ts ketimines and nitromethane catalyzed by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine.A set of optimal reaction conditions were identified by screening the catalysts,temperatures,solvents,additives and catalyst loadings:catalyst?5 mol%?,5?MS?40 mg?used as additive and PhF used as solvent at room temperature 28 h.A variety of aryl?-ketoester-derived N-Ts ketimines were investigated,and corresponding substrates'reactivity are very good,and good experimental results are obtained?up to 99%yield and 99%ee?;We also tried to use nitroethane in place of nitromethane,and the product obtained in the middle result?72%yield,97:3 dr,45%ee?;When the N-Ts was replaced in other sulfonyl groups,the corresponding products can give the excellent yields?83%/90%?and middle enantioselectivities?68%/48%?;When alkyl groups were in place of aryl groups,it can give the product in 42%yield with 15%ee.In addition,To explain the stereoselectivity of the reaction,a catalytic mechanism was demonstrated tentatively.2.An efficient enantioselective vinylogous Mannich reaction of N-Boc aminosulfones with noncyclic?,?-dicyanoolefins has been realized by an extraordinary bifunctional thiourea-ammonium salt phase transfer catalyst derived from quinine.Through the screening of catalysts,we found that the quaternary ammonium salt phase transfer catalyst with a sterically hindered 3,5-di-tertbutyl benzyl moiety showed the best results.Subsequently,a series of reaction conditions including bases,solvents,reaction temperatures and aqueous solution of base were screened,the optimal reaction conditions were identified:catalyst?10 mol%?,K₃PO₄?5 equiv.?,m-xylene used as solvent,the reaction temperature of-30°C and 48 h.A wide range of N-Boc aminosulfones as well as?,?-dicyanoolefins were investigated,and corresponding substrates'reactivity are very good,and satisfactory results was obtained?up to 99%yield and 98%ee?.The optically active product was easily converted into the corresponding amino ketone in good yield by using KMnO₄ at slightly elevated temperatures without loss in the enantioselectivity.