Studies On The Methodologies Of Reductive Fuctionalization Of Amides Based On Amide Activation And Transition Metal Catalyzed The Breaking Of C-N/C-C Bond Of Amide

Amides are a class of important compounds,which play an important role in medicine,materials,the origin of life and other fields.Because of the resonance effects between the vicinal nitrogen lone pair and the vacant ?*c=o orbital,the reactivity of amide carbonyl group is very low.It usually needs to be converted into thioamides and other activated forms to react with nucleophilic reagents,usually through several steps.Therefore,it is of great significance and challenge to develop a steps-economic amide conversion method.The C-N bond of amide has high bond energy due to the conjugate stabilization,and the amine released after C-N bond breaking process will reduce the activity of metal catalysts.Metal-catalyzed cleavage of amide C-N bonds has been rarely reported until now.Therefore,it is very important and challenging to develop metal-catalyzed methods to construct C-C or C-O bonds by breaking C-N bonds.Based on the study of direct conversion of amides to construct C-C bonds by trifluoromethanesulfonic anhydride(Tf2O)activation and Iridium catalytic reduction,this dissertation further develops the step-economic methodologies of transforming amides to form C-C bonds and chiral C-C bonds.In addition,this dissertation also develops the methodologies of transition metals catalyzed breaking amide C-N bonds to form C-C bonds and C-O bonds.The results of this dissertation are as follows:1.Developed a method for direct reductive trifluoromethylation of secondary amides(Chapter 2)Based on the strategy of amide activation by Tf2O,we developed the metal-free method of preparing a-triflucromethylamines through reaction of secondary amide and nucleophilic trifluoromethylation reagent TMSCF3,and the method is also extended to the catalytic pathway using[Ir(COE)]2Cl2/TMDS as catalytic reduction reagent.This is the first report of direct preparation ?-trifluoromethylamines from secondary amide.The reaction can be carried out under relatively mild conditions at room temperature without adding strong corrosive acids such as HF to activate imine intermediates.The reaction is suitable for aryl amide and alkylamide,and compatible with ketone,ester,OAc,olefin and other functional groups.This method provides a new way for the synthesis of a-trifluoromethylamine,which plays an important role in medicine.2.The studies on the direct reductive alkynylation of the amide(Chapter 3)2.1 Developed a method for direct alkynylation of amides/lactams(section 3.1)The tertiary amide transformed into active intermediate by Tf2O in situ activation,which followed by successive addition of a Grignard reagent and an organometallic reagent(RMaX or RLi),resulting in the formation 2of 3-amino-1,4-diacetylene containing N heteroquaternary carbon center.The method is very efficient and the yield is up to 96%.The reaction conditions are mild and can be carried out at room temperature.Meanwhile,the reaction can obtained moderate to high yield for both linear amide and lactam,and both alkynyllithium reagent and alkynyl Grignard reagent can be used as a Nucleophile.Moreover,the reaction can be well compatible with many functional groups such as ether,halogen atom,CF3,alkyl Cl,pyridine heterocyclic,and amine.This part of the work is under manuscript preparation.2.2 Preliminarily developed a method for Iridium-catalyzed asymmetric reductive alkynylation of secondary amides(section 3.2)Based on the strategy of[IrCl(COE)2]2/Et2SiH2 catalyzed reduction of secondary amides,we developed a highly efficient and universal method of asymmetric alkynylation of secondary amides to prepare chiral ?-alkynylamines.This method uses protected L-Proline as chiral catalyst,acetylene copper reagent as nucleophilic reagent,and L2 or L3 ligand to regulate chirality.The method has high enantioselectivity and excellent yield.The method is compatible with fuctional group such as Me,MeO,CF3 and F,and is also adapted to substrates such as thiophene heterocycles and naphthalene.Moreover,this method is not only applicable to N-Ph amide,but also to N-alkyl amide.3,The studies on transition metal catalyzed cross coupling of amide3.1 Developed a method for Ni-catalysed esterification of amides by C-N bond activation(Section 4.1)Based on the strategy of Ni-catalyzed amide C-N bond activation,we developed the catalytic synthesis method for preparing esters from amide and alcohol.The method uses cheap metal Ni as catalyst,L1 as ligand and alcohol as nucleophilic reagent.The method shows mild conditions(room temperature),high efficiency(up to 99%yield),wide range of substrates(aryl and alkyl can be adapted),and good compatibility of functional groups(nitro,ester,ketone,olefin,halogen,etc.).Meanwhile,the chiral center in the substract will retain during the transformation of the direacting group.3.2 Developed a method for Ni-Catalyzed cross-coupling of aryl N-acylpyrrole-type amides with organoboron reagents(Section 4.2)Based on the activation strategy of amide C-N bond,we developed a method of Ni-catalyzed cross-coupling of N-acyl pyrrole amide with organicboron reagents to afford ketones.The success of this method relies on th e discovery of a new chelating bis-NHC(N heterocyclic carbene)ligand.The feature of this method include:(1)The easily prepared novel bidentate NHC ligands with high efficiency;(2)Good functional group compatibility,which is compatible with ketones,esters,amines and heterocycles;(3)Mild conditions and gram-level preparation.3.3 Developed a method for Ni/Pd-catalyzed cross coupling of alkyl N-acyl pyrrole amides with organicboron reagents(Section 4.3)Based on the strategy of amide C-N bond activation,we developed a method of Ni-and Pd-catalyzed cross-coupling of alkyl N-acyl pyrrole amide with organoboron reagents to afford ketones.Meanwhile,for N-acyl indole amides,we obtained by-products olefins.The reaction has two conditions,Ni(COD)2/L3 combination and Pd-L6 combination,which are complementary and both show good substrate scope and functional group tolerance.For example,the method is compatible with ketones,esters,olefins,CF3 and other functional groups,and is applicable to heterocyclic substrates and complex substrates such as cholic acid amide,cholesterol derivative amide and estrone borate.The formation of olefin by-product may undergo an oxidative addition of C-N bond,followed by CO removal,and finally the elimination of ?-H.This method enriches the field of the coupling reaction of alkyl electrophiles and C-N bond activation.3.4 Developed a method for Ni-catalyzed decarbonyl cross coupling of N-acyl pyrrole amides with organicboron reagents(Section 4.4)Based on the strategy of amide C-N bond activation,we developed a method of Ni-catalyzed decarbonylation cross-coupling of N-acyl pyrrole amide with organic-boron reagent.This reaction uses Ni(COD)2 as catalyst,L1 as ligand,and is proceeded under heating conditions.This method provides a new way to synthesize heterocyclic biaryls from amides.The reaction process is novel and undergoes successive breaking of C-N bond and C-C bond.The reaction shows good substrate scope and moderate functional group tolerance.For example,the method is compatible with esters,sulfonyl and other functional groups,and is applicable to heterocyclic substrates.This method can be applied not only to aryl and alkyl N-acyl pyrrole amides or borate esters,but also to N-acyl pyrazole,N-acyl indole and N-acyl carbazole amides.The method can also be applied to synthesis of polyaromatic hydrocarbons by orthogonal coupling.