Asymmetric Mannich Reaction Of C-Alkynyl N,O-Acetal Catalyzed By Organic Catalyst:Synthesis Of Chiral β-ketopropargylamine

Objective:Chiral ketone-substituted propargylamine derivatives are important multifunctional compounds in organic and pharmaceutical synthesis,which are widely used in the synthesis of bioactive molecules and multifunctional amino derivatives.However,due to the limited synthetic methods,we are committed to developing a simple and efficient method to synthesize chiral β-ketopropargylamine.Methods:Firstly,we synthesized N,O-acetal and β-keto acid according to the methods reported in the literature.Secondly,in order to obtain the optimal conditions,we use template substrate to screen the solvents,catalysts,additives,temperature etc.Thirdly,under the optimal conditions,we expanded the range of substrates to investigate the applicability of the reaction.After that,we carried out large-scale and transformation experiments to explore the practicability of this reaction.Finally,we exploredthe reaction configuration and reaction mechanism.Results:Through theoptimizing of various reaction conditions,the best reaction conditions for C-alkynyl N,O-acetalla and β-keto acid 2ain the model reaction were established,which using methyl cyclopentyl ether(MCPE)as solvent,The chiral phosphoric acid of 3,3’-(2,4,6-triisopropyl)-H8 BINOL framework was used as catalyst,5A molecular sieve was used as additive,and the optimum reaction temperature was-10℃.Under optimal conditions,chiral propargyl amines with better enantioselectivity can be synthesized from various substituents of C-alkynyl N,O-acetal and β-ketoic acid.In the large-scale synthesis and transformation of chiralβ-ketone propargyl amine,93%yield and 90%enantioselectivity can be obtained when the amount of reactants is increased by 20 times.The chiral β-ketone propargyl amine can obtain the conversion product with better yield and enantioselectivity.Conclusion:We have developed a simple and efficient method for the synthesize ofβ-ketoalkynylamine by asymmetric Mannich reaction of β-keto acid and C-alkynyl N,O-acetal catalyzed by chiral phosphoric acid.The chiral propargyl amine and its derivatives were obtained with high yield(up to 97%)and excellent enantioselectivity(up to 97:3 er).And the scheme has a wide range of substrate universality and practical application value.