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

This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients. 

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Sustainable Amidation Reactions – Recent Advances

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.

Contemporary Approaches for Amide Bond Formation

Despite being one of the most frequently carried out chemical reactions in industry, there is currently no amidation protocol that is regarded as safe, high yielding, environmentally friendly and inexpensive. The direct amidation of a carboxylic acid with an amine is viewed as an inherently good solution for developing such a protocol. Since the 1960s, there has been a gradual development in the use of silicon reagents for direct amidation. This review covers the methods published to April 2021 for silicon reagent mediated direct amidation of a carboxylic acid with an amine. This review also covers the use of polymeric SiO2 to promote direct amidation.

/pdf/silicon-compounds-as-stoichiometric-coupling-reagents-for-2m09trj7hh.pdf

Silicon compounds as stoichiometric coupling reagents for direct amidation

The condensation of carboxylic acids and amines mediated by silane derivatives provided a straightforward and sustainable method for amide bond formation with minimal waste. However, the detailed mechanism and structure-activity relationship of substrates, the topics that are of interest for both academic and industrial applications, were not clear. Herein, a systematic computational study was conducted to solve the two questions. We found that the two previously proposed mechanisms involving intramolecular acyl transfer or silanolate were less likely because the associated silanone intermediate and zwitterion adducts were too unstable with higher overall energy barriers. By comparison, the mechanism involving deprotonation of carboxylic acids, addition of carboxylates on silane reagents, dihydrogen formation to afford an acyloxysilane intermediate, carboxylic-acid-assisted addition of amines, and concerted proton transfer/amide formation, was found to be more favorable with overall energy barriers varying between 24 and 28 kcal mol-1 for the different calculated cases. Meanwhile, the dihydrogen formation and amide formation processes are both potential rate-determining steps. Energy composition, atomic charge, and distortion-interaction analyses indicated that the steric effect of silane reagents was more important than the electronic effect, making less bulky silane reagents more reactive. On the other hand, the dihydrogen formation process was mainly controlled by the electronic effect of the substituents of carboxylic acids and amines while the amide formation process was mainly influenced by their steric effect. As a result, less bulky, less acidic alkyl carboxylic acids are more reactive than unsaturated carboxylic acids, and less bulky, medium basic primary alkyl amines are more reactive than secondary alkyl amines and primary aryl amines. The related results provided deeper mechanistic insights into the amide bond formation mediated by silane derivatives and can act as a reference for further experimental design.

The mechanism and structure-activity relationship of amide bond formation by silane derivatives: a computational study.

A novel boron ester-catalyzed amidation reaction of carboxylic acids and amines with unprecedented functional group tolerance was recently reported. To gain deeper insights into this reaction, a computational study with density functional theory methods was performed in this manuscript. Calculations indicate that the amidation starts with the condensation of carboxylic acids with the boron ester catalyst. The resulting monoacyloxylated boron species further undergoes the carboxylic acid-assisted nucleophilic addition with amines to generate the amide product and a monohydroxyboron species. The condensation of the carboxylic acid with the monohydroxyboron species with the assistance of an amine regenerates monoacyloxylated boron species to finish the catalytic cycle. The rate-determining step is catalyst regeneration and the amine-coordinated monohydroxyboron species is the resting state in the catalytic cycle. The present results are consistent with the previous NMR study and the observed reaction orders of catalyst and substrates; it is expected to benefit further reaction optimization.

Boron Ester-Catalyzed Amidation of Carboxylic Acids With Amines: Mechanistic Rationale by Computational Study

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The mechanism and structure-activity relationship of amide bond formation by silane derivatives: a computational study.

Boron Ester-Catalyzed Amidation of Carboxylic Acids With Amines: Mechanistic Rationale by Computational Study