To Catalyze or not to Catalyze? Insight into Direct Amide Bond Formation from Amines and Carboxylic Acids under Thermal and Catalyzed Conditions

Abstract

Kinetic studies show that the direct formation of amides from amines and carboxylic acids without catalyst does occur under relatively low temperature conditions, but is highly substrate dependent. Boric and boronic acid-based catalysts improve the reaction, especially for less reactive acids, and initial results indicate that bifunctional catalysts show even greater potential.

Catalytic amide formation from non-activated carboxylic acids and amines

“…The amidation of oleic acid was complete after 6 hours of reaction time, using molecular sieves as water scavenger and the oleamide product was isolated by recrystallization in 79% yield. However, the catalyst loading for 70 the new protocol was slightly higher compared to the MIBK protocol: 35 mg/mmol substrate. 20 Novozym® 435 was employed in a continuous plug flow reactor to synthesise oleamide from oleic acid and ammonium 75 carbamate in 2-methyl-2-butanol.…”

“…The highly selective actions of enzymes under ambient conditions, as in most crucial biological processes, have inspired many research groups to utilize biocatalysts for synthetic purposes. Not surprisingly, enzymatic systems have been applied for the catalytic formation of a range of different amides and their 70 derivatives.…”

“…20 The authors demonstrated that 4-methyloctanoic acid could be resolved by turning it into the primary amide using Novozym® 435 (20 mg immobilized enzyme per 1 mmol substrate, Scheme 12). An excess of ammonium carbamate was used as source of ammonia, resulting 70 in 52% conversion and 95% ee in favour of the (R)-enantiomer. The ee was determined by measurements on the remaining unreacted carboxylic acid.…”

“…In addition, there are several examples of highly selective kinetic resolution and even an example of dynamic kinetic resolution. A drawback with enzyme-based catalysts is the pre-determined preference for either the (R)-or (S)-isomer, which can be of concern if the opposite enantiomer is the synthetic 70 target. Moreover, the synthetic scope is often limited to substrates with similar structures and the reaction times are sometimes in terms of days.…”

“…In recent time, the direct catalytic amidation of non-activated carboxylic acids has attracted more attention, with an increasing number of groups focusing on this area of research. Although 70 several reviews cover parts of the material presented herein, 10 there is to the best of our knowledge none which compiles all types of catalytic methods for direct amidation. Thus, the aim of this review is to provide an easily accessible and comprehensive overview of synthetically relevant literature on all types of 75 catalysts for direct amidation, ranging from biocatalysis, Lewis acid catalysts based on boron reagents and different metal complexes, as well as other catalyst types.…”