Direct Transamidation Reactions: Mechanism and Recent Advances

Abstract

Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or the need to use highly reactive carboxylic acid derivatives. In recent years, the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes their direct reaction with nitrogen nucleophiles difficult; thus, the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction because equilibrium is established. In this review, we present research on direct transamidation reactions ranging from studies of the mechanism to the recent developments of more applicable and versatile methodologies, emphasizing those reactions involving activation with metal catalysts.

Amide Synthesis by Transamidation of Primary Carboxamides

“…6 One of the most valuable alternatives is the formation of an amide bond via a transamidation reaction. 6c, 7 A characteristic of the amide bond is its high stability due to resonance. Indeed, the C-N bond has partial double-bond character because of orbital overlap between the nitrogen lone pair and the antibonding orbital of the carbonyl group (Scheme 1, A).…”

Mild, Metal‐Free and Protection‐Free Transamidation of N‐Acyl‐2‐piperidones to Amino Acids, Amino Alcohols and Aliphatic Amines and Esterification of N‐Acyl‐2‐piperidones

“…A recent survey estimates that the formation of the amide bond is one of the most prevalent chemical transformations conducted by industrial organic chemists. Thus the development of new methods for amides will have a major impact on chemical and biological sciences Typically, amides are prepared by the reaction of amines with activated carboxylic acids, esters, aldehydes, alcohols, hydration of nitriles, hydroamination of alkynes and aminocarbonylation . Alternately, amides can be prepared by transamidation, in which an amine is exchanged with a constituent of amides .…”

“…The high stability of amide linkages arising out of amidic resonance and comparable energetics of starting materials and products render transamidation a challenging task. Due to this, transamidation requires harsh reaction conditions, high temperature, prolonged reaction times and activating agents in stoichiometric/catalytic amounts . For the past two decades, great efforts have been made in this area to conduct transamidation at relatively milder reaction conditions , .…”

“…Due to this, transamidation requires harsh reaction conditions, high temperature, prolonged reaction times and activating agents in stoichiometric/catalytic amounts . For the past two decades, great efforts have been made in this area to conduct transamidation at relatively milder reaction conditions , . Though great headway has been achieved with primary amides,[4d], it is still elusive with secondary amides .…”

Amide Activation in Ground and Excited States

“…The amide functional group is one of the most generally used moieties both in synthetic organic chemistry and bioorganic chemistry [ 1 , 2 , 3 , 4 , 5 ]. They have been known and studied for more than a century and can be commonly found in peptides/proteins and biologically active compounds, as well as in a broad range of synthetic drugs and toxins as a key functionality [ 1 , 6 , 7 , 8 , 9 ].…”