C-N Bond Cleavage-based Transformation Reactions Of Amide Pharmaceutical Intermediates

In recent years,great attentions foused on the breakage of C-N bonds in amide compounds and its applications on the cross-coupling reactions.Given the central position of amides in organic chemistry and biology,these new methods are of considerable influence.With the discovery of several classical non-planar bridged lactams,the field of twisted amides has growed rapidly.Two well-known twisted amides,prepared by Kirby group and Stoltz group independently,are 1-aza-2-adamantanone and 2-quinuclidonium tetrafluoroborate,and the twisted angle of these two compounds are close to 90°.This thesis focuses on the reactions of non-bridged twisted amides based on C-N bond cleavage and explores its use in pharmceuticals.This thesis is divided into four chapters:1.Intermolecular Friedel-Crafts acylation with twisted amides by C-N bond cleavage.In this chapter,we used N-acyl-glutarimide as substrate,benzene as solvent,and trifluoromethanesulfonic acid?TfOH?as catalyst at room temperature for 15 hours to obtain ketones in moderate to excellent yield.A total of 21 ketones were obtained under optimized reaction conditions?50-95%yield?.This reaction demonstrates high functional group tolerance,obviating the need for preformed sensitive organometallic reagents and expensive transition metal catalysts.Conceptually,this acid-promoted reaction of twisted amides provides more options for acylating reagents under mild,metal-free conditions.2.Sc?OTf?₃-catalyzed syntheses of anhydrides from twisted amides.Sc?OTf?₃ catalyst in the presence of water was used to synthesize anhydrides in one step from two molecules of N-acyl-glutarimides without external nucleophiles,and 6 anhydrides were obtained in 58-87%yield.The success of reaction indicates that twisted amides with the glutarimide scaffold are more reactive than carboxylic acid anhydrides.Mechanistic studies reveal that the coordination of the catalyst is critical to the challenging C-N activation step.This process further highlights the utility of twisted amides in organic synthesis.3.Transamidation of N-acyl-glutarimides with amines.In this chapter,we used N-acyl-glutarimide as substrate,triethylamine as base,dichloromethane as solvent,and the reaction with amine at room temperature for 15 hours afforded 22 transamidation products?60-98%yield?.A wide range of amide with different functional groups,including electrophilic substituents that would be problematic in metal-catalyzed transamidation conditions,are tolerated under the optimized reaction conditions.Mechanistic experiments implicate the amide bond-twisting,thermodynamic stability of the tetrahedral intermediate and leaving group ability of glutarimide as the factors controlling the reactivity of this process.4.Metal-free transamidation of secondary amides via C-N bond cleavage.In this chapter,we carried out the transamidation reaction at room temperature using N-acyl-N-Boc-amine and N-acyl-N-Ts-amine as substrates,respectively.A total of 38 transamidation products were obtained under the optimized reaction conditions?65-98%yield?and all new compounds were verified by NMR and HRMS.The combination of rational modification of the amide bond with nucleophilic addition mechanism,and the thermodynamic collapse of the resultant tetrahedral intermediate constitutes a two-step procedure to accomplish a challenging transamidation of secondary amides under mild conditions.