Studies On The Reductive Transformation Of Amides And Reductive Amination By Iridium-Catalyzed Reaction

As cheap and stable carbonyl compounds,amides are commonly used in the field of organic synthesis and pharmaceutical intermediates.It is also widely found in nature,for example,the main structure of proteins is polypeptide.In addition,amide group is often used as the protective group of amine and the orientating group of C-H activation.Owing to the high stability of the structure of amide,however,the transformation of amide group has always been a difficult problem.Consequently,it is of great significance to develop high-efficiency methods for direct activation of amide.With the development of the society,the pollution of environment have attracted more and more attention from people.It also puts forward new tasks for chemical parctitioners,which include not only the synthetic method of better chemical selectivity,but also the high efficiency and better atom economy.Transition metal catalysis provides the possibility for these two aspects.Thersfore,developing metal catalyzed method to achieve amide transformation is of great significance.In recent years,our group has been based on Trifluoromethanesulfonic anhydride(Tf2O)to activate amide,and also accumulated rich experience in this research field.Meanwhile,there are some explorations for metal catalyzed activation of amide.and has some exploration for metal catalysis.This dissertation is based on previous works,we further debeloped metal catalyzed transformation of amide,and applied metal catalyst to reaction of reductive amination.Finally,we developed the method for amine production by metal catalyzed amide reduction or reductive amination,and applied these methods to synthesize drug molecules.The main results and observations from these studies are listed as follows.1.Developed a reduction reaction of amide to amine by metal catalyzed hydrosilylation(Chapter 2).(?).We developed a method for reduction of tertiary amide by iridum catalyst and Lewis acid,B(C6F5)3 bis-catclytic system.Based on the previous research,an enamine or a N,O-hemiaminal was suggested as the possible reaction intermediate.Therefore,according to the theory of frustrated Lewis Pairs "FLPs",B(C6F5)3 was found to be highly effective under the synergistic catalytic effect of iridium catalyst.By using this bis-catalytic system,tertiary amides are easily reduced to the corresponding amines under mild conditions.This method also exhibits excellent chemoselectivity and high yields with a broad substrate's scope.A combination of the above feature with the excellent functional group tolerance and mild condition of the reaction provided a valuable tool for the synthesis of the amine and pharmaceutical molecules.(?).A new type of ionic metal iridium catalyst was developed to catalyze the reaction of hydrated reductive amides(tertiary amides or secondary amides)as amines.Using this ionic metal iridium complex,it plays two important roles,activating both silane and amides.The reduction systems,not only the reaction condition was mild,but also it rate was fast.In addition,it can also remain unchanged for amide carbonyl a-site and N-? site.Finally,this reaction systems can also used to synthesize a large number of drug molecules.2.Iridium-Catalyzed Reductive Functionalization of Tertiary Amides(alkylation and cyanylation)(Chapter 3)The selective reduction of functional groups of tertiary amides catalyzed by NHC ligands has been developed,resulting in the formation of N-a position alkyl or cyano substituted amines.By modifying the catalyst ligand and using the ligand's steric effect,the reduction reaction is controlled to stay in the intermediate,and then the N-a substituent product is obtained by using different nucleophilic reagents.For instance,Grignard reagents or TMSCN,Finally,This method is then successfully applied in the concise synthesis of(±)-Cetirzine.But this system can only transform the tertiary amide substrate,and secondary amides needs further exploration.4.Study on Reductive Amination through Iridium Catalytic Hydrogenation(Chapter 4)The catalytic hydrogenation of iridium catalyzed by metal iridium has been developed,and the ionic metal iridium catalyst's properties of Lewis acidity and high efficient hydrogen activated provide an efficient way for the direct reductive amination.The reaction can be completed at room temperature and 1 atm pressure for aldehydes and amines.For ketones and amines,pressure is increased to only 10 atm.In addition,some other groups(nitro,nitrone,hydroxylamine,ketone,etc.)were also found to be reductive by use this catalytic system.