Investigations On The Functional Group Transformations Of N-benzyl-N-Boc Amides Under Transition Metal-free Conditions

Amide is one of the most significant functional groups in organic chemistry and widely used in medicine,agriculture,and industry,especially in natural product synthesis.Moreover,it is the basic unit for the construction of polypeptides and widely exists in organic intermediates.The functional group conversion reaction of amide has vital research value in all fields of organic chemistry.However,due to the resonance effect in amide groups,it is inert in terms of its chemical properties and not easy to be broken or functionalized,which usually requires harsh experimental conditions to break C-N rotation barriers.On account of the limitation in organic synthesis,drug development and material science application,how to effectively activate the inert amide bond has become a major challenge in the field of chemical sciences in recent years.The breakthrough came with Garg and Szostak group,who reported a nickel-catalyzed and palladium catalyzed C(O)-N activation,which provided a new idea for the transformation of amide group.In this context,it was a significant task to study the activation of amides and functional group conversion of inert amides under transition metal-free condition.In the paper,the reaction of N-benzyl-N-Boc amides with alcohols,sugars and amines were systematically studied under transition metal-free.This paper specifically included the following aspects:1.N-benzyl-N-Boc amides were converted to the corresponding esters by treatment with a range of alcohols under the catalysis of Cs₂CO₃ catalyst.At room temperature,using 0.2 equiv.cesium carbonate as the catalyst and dimethyl sulfoxide as the solvent,N-benzyl-N-Boc amides reacted with various alcohols through intermolecular nucleophilic substitution reaction to yield various ester efficiently.This method exhibits broad substrate scope and represents a practical alternative to existing esterification strategies.Using this strategy to synthesize the crown ether derivatives bearing ring ester structure and modify the natural products with biological activity.2.Sugar is an important component in biology,medicine,and human body.Glycoconjugates play an important role in life science and are formed by sugar covalent linked to proteins,peptides,antibodies and small molecules.Glycoconjugates were obtained with wide substrate universality and excellent yields by optimization condition of catalysts,solvents and so on.Using Li Ot Bu as the catalyst and N,N-dimethylformamide as the solvent,N-benzyl-N-Boc amides reacted with various sugar derivatives to synthesis corresponding glycoconjugates.3.The transamidation of N-benzyl-N-Boc amides was studied under transition metal-free and base-free conditions.A series of amides were synthesized in good to excellent yields through the high reactivity of N-Boc amide via nucleophilic substitution reaction.Notably,chiral amino-acid-derived nucleophiles and amides bearing an epimerizable stereocenter preserves enantiopurity under the base-free condition.The practical value of this method was demonstrated through the synthesis of moclobemide and post-transformation of drugs,which had the potential application value in drug synthesis.4.In the first part of our work,we achieved a small amount of n-hexaldehyde by-product for the esterification of amides during a catalytic transition metal system.According to Goswami and Appe groups reported the catalytic system,we studied the the transfer dehydrogenation of secondary alcohols using divalent nickel.On this basis,we studied the oxidation reaction of alcohols catalyzed by cheap metal nickel.In addition,a simple and efficient method for the synthesis of ketone and aldehyde was successfully studied under base-free condition.The efficient oxidation reaction was occurred by using cheap divalent nickel salt as catalyst and acetone as hydrogen acceptor.Notably,this methodology could avoid the synthesis of aldehyde by-products under base-free condition.Kinetic isotope effect(KIE)studies were performed in an effort to gain more insights into the reaction mechanism,which lead us to suggest that?-hydride elimination is rate-limiting step in the catalytic process.