Copper‐Catalyzed Direct Amidation of Carboxylic Acids and Anilines via CS 2 Activation

A green, microwave‐assisted methodology for the selective direct amidation of carboxylic acids with amines, using montmorillonite K10 as a heterogeneous catalyst, has been developed. This is an efficient transition‐metal‐free, montmorillonite‐K10‐catalyzed direct amidation of carboxylic acids. The method is compatible with sterically hindered α‐branched, aliphatic, benzylic, aromatic, unsaturated and conjugated carboxylic acids. Moreover, chiral integrity of substrates remained unchanged after the reaction.

Unlike other metal fluorides, catalytic titanium tetrafluoride enhances the direct amidation of aromatic and aliphatic carboxylic acids and N-protected amino acids in refluxing toluene. While aromatic acids were converted to amides with 10 mol% of the catalyst within 24 h, aliphatic acids underwent a faster reaction (12 h), with lower catalyst loading (5 mol%). This protocol is equally efficient with alkyl and aryl amines providing a variety of carboxamides and peptides in 60-99% yields.

Direct amidation of carboxylic acids with amines holds significant importance; therefore, catalytic processes involving boronic acids have undergone extensive investigation. However, studies focused on the amidation of aromatic carboxylic acids remain limited. In this study, we introduce a fluorescence-based screening methodology employing an anthracene derivative probe, facilitating the rapid evaluation of various amidation catalysts. Using this approach, boronic acids were evaluated for their catalytic potential. Our findings reveal that 2-hydroxyphenylboronic acid (C7), previously deemed inefficient for aliphatic acids, effectively catalyzes the amidation of aromatic acids. The catalysts identified through this method consistently achieved high yields, reaching up to 98% across a broad spectrum of substrates.

Ammonia-borane serves as an efficient substoichiometric (10%) precatalyst for the direct amidation of both aromatic and aliphatic carboxylic acids. In situ generation of amine-boranes precedes the amidation and, unlike the amidation with stoichiometric amine-boranes, this process is facile with 1 equiv of the acid. This methodology has high functional group tolerance and chromatography-free purification but is not amenable for esterification. The latter feature has been exploited to prepare hydroxyl- and thiol-containing amides.

Secondary and tertiary amides are formed in high yields, in an efficient and environmentally benign titanium(IV) isoprop­oxide catalyzed direct amidation of carboxylic acids with primary and secondary amines.

Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.

The synthesis of amides is of huge importance in a wide variety of industrial and academic fields and is of particular significance in the synthesis of pharmaceuticals. Many of the well established methods for amide synthesis involve reagents that are difficult to handle and lead to the generation of large quantities of waste products. As a consequence, there has been a considerable amount of interest in the development of new approaches to amide synthesis. Over the past few years a wide range of new reagents and catalysts for direct amidation of carboxylic acids have been reported. In addition, the interconversion of amide derivatives through transamidation is emerging as a potential alternative strategy for accessing certain amides. This microreview covers recent developments in the direct amidation of carboxylic acids and the interconversion of amides through transamidation. The advantages and disadvantages of the various methods are discussed, as well as the possible mechanisms of the reactions.

Review: 66 refs.

Direct amidation of carboxylic acids is a fundamental transformation in organic synthesis and plays a pivotal role in the construction of amide bonds that are ubiquitous in pharmaceuticals, natural products, and materials. Despite its importance, many of the reported catalytic methods rely on expensive, moisture-sensitive, or inefficient reagents, thereby limiting their practical utility. In this study, we introduce sodium hexafluoroaluminate (cryolite, Na3AlF6) as a cost-effective, recyclable, and environmentally benign catalyst for direct amidation. Using 10 mol% cryolite, a broad range of aromatic and aliphatic carboxylic acids were converted into the corresponding amides in moderate to high yields (46–97%). Notably, the method requires no specialized additives or chromatographic purification, further enhancing its synthetic practicality. Beyond amidation, cryolite also proved to be highly effective in esterification reactions, affording esters in up to 90–92% yield within 24 hours when employed in either toluene or the reacting alcohol as solvent. The catalyst is inexpensive on a per-mole basis, widely available, and easy to handle, and it can be recycled without significant loss of activity, underscoring its potential for sustainable applications. These attributes position cryolite as a robust and attractive alternative to conventional transition-metal-based catalysts. To the best of our knowledge, this work represents the first demonstration of cryolite as a catalyst in organic synthesis, providing a practical, scalable, and green approach to both amide and ester bond formation.

Pyridine‐borane complex was widely used as a reducing agent, but the exploration of such reagent as a catalyst for amidation of carboxylic acids are still unknown. Here we reported the first example of direct amidation of carboxylic acids catalyzed by pyridine‐borane complexes. This protocol features a low catalyst loading (0.2–10 mol %), broad substrate scope, good functional group compatibility, and affording the amides in high yields.

The development of a highly efficient and simple protocol for the direct amidation of carboxylic acids is described employing ynoates as novel coupling reagents. The transformation proceeds in good to excellent yields via in situ α-acyl enol ester intermediates formation under mild reaction conditions. This useful method has been demonstrated for a range of substrates to provide a succinct access to structurally diverse amides, including key intermediates of glibenclamide, tiapride hydrochloride, and nateglinide, and can be conducted on a mole scale.

Repurposing n-butyl stannoic acid as highly efficient catalyst for direct amidation of carboxylic acids with amines

Sulfonated reduced graphene oxide as a highly efficient catalyst for direct amidation of carboxylic acids with amines using ultrasonic irradiation

The ortho‐iodo arylboronic acid shown in the scheme efficiently promotes the direct amidation of carboxylic acids, which allows convenient formation of a wide range of carboxylic amides.

Ru-catalyzed direct amidation of carboxylic acids with N-substituted formamides