Amide bond formation: beyond the myth of coupling reagents

Abstract

Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of "acronym" based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 references).

Metal-catalyzed nitrile hydration reactions: The specific contribution of ruthenium

“…and 25-26, the requirement of rather elaborated phosphine ligands makes them unappealing face to practical applications. In this context, the arene-ruthenium(II) complexes [RuCl 2 (η 6 -arene){P(NMe 2 ) 3 }] (arene = C 6 H 6 , p-cymene, 1,3,5-C 6 H 3 Me 3 , C 6 Me 6 ), described by Cadierno,, represent more simple and competitive alternatives since they make use of the commercially available and inexpensive ligand tris(dimethylamino)phosphine. All these complexes are able to operate in pure water under neutral conditions.…”

“…Amides are commonly prepared by the reaction of activated carboxylic acid derivatives (acid chlorides, anhydrides and esters) with amines including ammonia [2], or by direct union of the acids with the amines assisted by coupling reagents, such as carbodiimides or 1H-benzotriazole derivatives [3].…”

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18 O-labeling

“…Native chemical ligation has teamed with solid phase peptide synthesis to target an increasing list of complex problems, whereas α-keto acid-based methods (18,19) and umpolung amide synthesis (UmAS) (20) are beginning to target others. Historically, improvements to dehydrative amide synthesis have received the lion's share of effort, and this is justified by the broad inventory of carboxylic acids available commercially and synthetically (21). Aside from the need to greatly generalize any one of these developments, it remains a challenge to routinely incorporate chiral nonnatural amino acids.…”

Ruthenium-Catalyzed Amide-Bond Formation

“…All these facts clearly show the importance and prevalence of amides in synthetic organic chemistry. In general, traditional approaches for amide synthesis rely on the use of activated carboxylic acid derivatives and amines, processes which often require stoichiometric amounts of coupling reagents and suffer from the inherent drawback of producing large amounts of waste products along with the desired amide [1,2,6,7].…”