The amide bond represents the most fundamental functional group in numerous areas of chemistry, such as organic synthesis, drug discovery, polymers, and biochemistry. Although typical amides are planar and the amide N–C(O) bond is notoriously difficult to break due to nN→π⁎C=O resonance, over the past 5 years remarkable breakthroughs have been achieved in the activation of amides by complementary mechanisms that ultimately hinge on ground-state destabilization of the amide linkage. In this review, we present an overview of the main reactivity manifolds employed in the activation of amides by selective N–C(O) cleavage pathways along with their main applications in catalytic as well as stoichiometric synthesis. This cutting-edge platform clearly demonstrates how to harness the power of amidic resonance to achieve a host of previously elusive transformations of amides and holds the promise to change the landscape of how chemists perceive the traditionally unreactive amide bonds into readily modifiable linchpin functional groups that can be readily triggered for the desired reactivity.

Amide Bond Activation: The Power of Resonance

Amide bond forming reactions are critical for both polypeptide synthesis and medicinal chemistry. Most current approaches for amidation employ stoichiometric activating agents, but such methods are neither atom economical nor synthetically elegant. Catalytic approaches for amidation are potentially green and more ideal substitutes for current standard methods and thus are the subject of this review. Such methods face significant thermodynamic and kinetic barriers and have, as a result, historically conceded the use of elevated temperatures and dehydrating agents or lacked broad and relevant substrate scopes from the perspective of peptide chemistry. Recent advancements in methods for both direct amidation (the coupling of a carboxylic acid and an amine) and indirect amidation (the coupling of other partners resulting in an amide bond) based on aryl boronic acids, transition metals and organocatalysis for the former and ester amidation and redox‐coupled amidation for the later, address these previous shortcomings and are examined therein.

Recent developments in catalytic amide bond formation

Abstract In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.

Challenges and Breakthroughs in Selective Amide Activation

Diboronic Acid Anhydride-Catalyzed Direct Peptide Bond Formation Enabled by Hydroxy-Directed Dehydrative Condensation.

A range of environmentally friendly solvents was evaluated in the Suzuki–Miyaura coupling of amides in an attempt to provide the first solvent selection guide for the powerful C–C coupling by amide...

Green Solvent Selection for Suzuki–Miyaura Coupling of Amides

A chemoselective and catalytic transamidation for peptide synthesis is described. Transamidation under Zn catalysis is chemoselectively achieved by amino acid amide/peptidic amide derivatization wi...

Zn-Catalyzed Nicotinate-Directed Transamidations in Peptide Synthesis

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Zn-Catalyzed Nicotinate-Directed Transamidations in Peptide Synthesis