Studies On The Synthesis Of Mannich Bases Catalyzed By Hafnium Triflate

Study found many compounds which contain Mannich bases（β-aminoketone）structure,has important applications in the medical field because of its various biological activities such as anti-inflammatory analgesic,anti-cancer,anti-psychotic,antihypertensive and so on.In addition,it is widely used in materials such as fabric dyes and polymer chemistry.Therefore,the catalytic synthesis of Mannich bases is one of the hotspots in organic chemistry research.In recent years,a large amount of Br?nsted acid and metal Lewis acid have been used for the catalytic study of the Mannich reaction.It is worth noting that the tetravalent salts of titanium and zirconium which metal belong to IVB,have a good catalytic effect on the Mannich reaction.In the previous study of Kabachnik-Fields reaction,our group found that the hafnium（IV）salt（which metal belong to IVB）showed better catalytic activity than the zirconium（IV）salt.The reaction mechanism is similar to the Mannich reaction.Therefore,we speculate that the hafnium（IV）salt has a strong catalytic effect on the Mannich reaction.The chapter two and three of the paper focus on the studies of 1)the Mannich reaction and its mechanism catalyzed by Hf（OTf）₄,2)synthesis method and mechanism of N-protected Mannich bases by three-component reaction.The detailed research results are summarized as follows:In the second chapter,the Mannich reaction catalyzed by Hf（OTf）₄ has been studied.The reaction of benzaldehyde,aniline and acetophenone in acetonitrile was first used as a model.By comparing the catalytic activities of zirconium（IV）salts and hafnium（IV）salts,Hf（OTf）₄ was determined as the best catalyst.Sixteen Mannich bases which aryl ketone was used as substrate were synthesized in high yield.After optimization of reaction solvent,reaction temperature and the amount of catalyst.Subsequently,the regioselectivity of the reaction which alkyl ketone was used as substrate was studied.The reaction site of asymmetric ketone was methyl which small steric hindrance.Twelves kind of Mannich bases were synthesized to verify the regioselectivity.When studied the stereoselectivity of the reaction which alkyl ketone was used as substrate,cyclohexanone and cyclopentanone was used as the substrate.In the solvent-free system,Hf（OTf）₄ has less effect on the stereoselectivity.In the solvent system,the reaction was not stereoselective when there have not catalyst.After added Hf（OTf）₄,the anti-structured Mannich bases was obtained mainly.The results were opposite when cycloheptanone was used as substrate,the stereoselectivity of the reaction in the system of the solvent,the syn-structure of Mannich base was mainly obtained.When increases the amount of Hf（OTf）₄,it tends to obtained a anti-structured.Hf（OTf）₄ was added to the solution of MeOH-d₄ which have acetophenone or cyclopentanone to induce H-D exchange reaction.It was found that Hf（OTf）₄ had a strong activation effect on carbonyl group and could transform ketone form into enol which was more conducive to the reaction,the reaction mechanism was verified..In the third chapter,the synthesis of N-protected Mannich bases catalyzed by Hf（OTf）₄ has been studied.First studied the Mannich-type reaction.Hf（OTf）₄ can catalyze the condensation reaction of N-acyl imide and acetophenone to obtain N-protected Mannich bases.Subsequently,the catalytic activity of metal Lewis acid which located in IVB was screened by three-component reaction of benzaldehyde,acetophenone and benzyl carbamate.It was found that only HfCl₄ and Hf（OTf）₄ had catalytic effect,and Hf（OTf）₄ had better catalytic effect.Then the reaction solvent,reaction temperature and the amount of catalyst were optimized,the method was extended to ethyl carbamate and benzenesulfonamide.Twenty-three N-protected Mannich bases were synthesized in high yield,which verified the versatility of the method.In addition,the mechanism of three-component reaction has been shudied,is aldol condensation and aza-Michael addition cascade reaction.