Contemporary Approaches for Amide Bond Formation

Abstract

Amide bond construction has garnered significant interest in recent decades due to amides being one of the most prevalent functional groups among bioactive molecules. Out of the thirty‐seven new drugs approved by the FDA in 2022, eleven are small molecules containing at least one amide bond. Additionally, there are nineteen large molecules approved as new drugs, some of which have peptide structures, and therefore, also bear amide bonds. In recent years, multiple teams have embraced the challenge of developing more efficient methods for amide bond formation. This dedication has led to numerous publications appearing monthly in prestigious journals, showcasing significant advancements in this field. The primary goal of this review is to present the most viable strategies for constructing the amide bond. It is crucial to differentiate between amide bond formation and amide synthesis; hence, the focus is on describing specific methods for forming new C(O)−N bonds. In particular, this review concentrates on the methods developed within the last six years. There is a particular emphasis on new approaches that consider the thought process when selecting the starting materials and functional groups. This approach ensures coverage of all the most common chemical transformations that yield new amide bonds.

Deprotective Functionalization: A Direct Conversion of Nms‐Amides to Carboxamides Using Carboxylic Acids

“…Herein, we present the discovery of a general and simple deprotective functionalization protocol which deploys Nms‐amides for the synthesis of carboxamides. Despite considerable development of alternative approaches for the synthesis for carboxamides, [16] there is still continued high interest in further development [17–20] …”

Entschützende Funktionalisierung: eine direkte Umwandlung von Nms‐Amiden in Carbonsäureamide

“…Trotz der bedeutenden Entwicklung alternativer Ansätze zur Synthese von Carbonsäureamiden [16] besteht nach wie vor großes Interesse an der Weiterentwicklung [17–20] …”

“…Trotz der bedeutenden Entwicklung alternativer Ansätze zur Synthese von Carbonsäureamiden [16] besteht nach wie vor großes Interesse an der Weiterentwicklung. [17][18][19][20] Bei der Untersuchung der nukleophilen aromatischen Substitution von 1-Fluor-2-nitrobenzol mit einem sekundären Nms-Amid (1 a) beobachteten wir die unerwartete Bildung des symmetrischen Harnstoffprodukts 3 anstelle des erwarteten Produkts 2 (Schema 2). Wir vermuteten, dass das Nms-Amid (1 a) als Resultat einer Additions-Eliminierungs-Reaktion, die durch die Carbonatquelle (in diesem Fall Kaliumcarbonat) bei erhöhten Temperaturen ausgelöst wird, eine Spaltung der NÀ S-Bindung erfahren könnte.…”

Metal-Free Bisamidation of N-Tosylhydrazones with Carboxylic Acids Promoted by Tetrabutylammonium Iodide and tert-Butyl Hydroperoxide

“…Amide linkage, one of the prominent bonds abundant in nature, is equally important in synthetic organic chemistry due to their widespread presence in almost all sorts of molecules ranging from drugs and pharmaceuticals to cosmetics, pesticides, numerous biomolecules, etc . Apparently, the development of new and improved methods for amide bond formation is highly relevant and is an active area of research in methodology developments in organic chemistry . Conventional approaches toward amide bond formation include (i) the reaction between moisture-sensitive acid derivatives such as acid chloride/anhydride with amine and (ii) the coupling reaction between an acid and amine and well-known coupling agents like DCC, EDC, CDI, etc .…”