Catalytic dehydrative amide bond formation using aqueous ammonia: synthesis of primary amides utilizing diboronic acid anhydride catalysis

Oct 23, 2026

Catalytic dehydrative condensation of carboxylic acids with aqueous ammonia is developed using a diboronic acid anhydride (DBAA) catalyst to synthesize primary amides. The study addresses the lack of successful direct catalytic amidations employing inexpensive and safe aqueous ammonia without harsh pre-activation. Primary amides are positioned as key functional groups for pharmaceuticals and natural products. Optimization evaluates ammonia amount, catalyst loading, and solvent effects, demonstrating markedly improved yields under appropriate conditions.

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Catalytic dehydrative amide bond formation using aqueous ammonia

Background and importance of primary amides

Catalyst development and mechanism rationale

Reaction concept and initial optimization

ChemComm | | Published on 26 May 202 | 3 | | --- | --- | --- | | | COMMUNICATION | | | | | | Licence and permissions Cite this: Chem. Commun., 2023, 59, 7391 Received 28th April 2023, Accepted 20th May 2023 DOI: 10.1039/d3cc02071a[rsc.li/chemcomm](rsc.li/chemcomm) Catalytic dehydrative amide bond formation using aqueous ammonia: synthesis of primary amides utilizing diboronic acid anhydride catalysis† Naoya Takahashi,a Hinata Iwasawa, b Tatsuhito Kinashi,a Kazuishi Makino a and Naoyuki Shimada *b Although aqueous ammonia is an inexpensive and readily available safe source of ammonia, there have been no successful studies on direct catalytic dehydrative amidations of carboxylic acids with aqueous ammonia. In this study, we report a catalytic methodology for the synthesis of primary amides through diboronic acid anhydride (DBAA)-catalyzed dehydrative condensation of carboxylic acids with aqueous ammonia as the amine substrate. Primary amides are important functional groups present in many pharmaceuticals and natural products (Fig. 1A) .1 Furthermore, they are known as building blocks that can be used for various transformations in organic synthesis.2 Representative synthetic methods for primary amides include hydration of nitriles,3 rearrangement of aldoximes,4 aminolysis of esters,5 and oxidative amidation of aldehydes6 and alcohols7 (Fig. 1B) . Recently, various catalytic methods have been developed for the synthesis of primary amides.3,4b,6a,c,7 Although the amidation of carboxylic acids with ammonia equivalents is one of the most direct synthetic methods of primary amides, this approach conventionally requires harsh conditions such as high temperature and high pressure8 or pre-activation of carboxylic acids for conversion into acid chlorides9 or active esters.10 Therefore, the synthesis of primary amides via direct catalytic amidation of carboxylic acids with ammonia is an important research topic. Various catalytic dehydrative amidation methods utilizing primary or secondary amines as substrates have been reported so far.11 Particularly following the pioneering a Laboratory of Organic Chemistry for Drug Development and Medical Research Laboratories, Department of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minatao-ku, Tokyo 108-8641, Japan b Laboratory of Organic Chemistry for Molecular Transformations, Department of Chemistry and the Institute of Natural Sciences, Nihon University, 3-25-40 Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan. E-mail: [shimada.naoyuki@nihon-u.ac.jp](shimada.naoyuki@nihon-u.ac.jp) † Electronic supplementary information (ESI) available: Experimental details, characterization data, copies of 1H-and 13C-NMR spectra for all new compounds. See DOI: [https://doi.org/10.1039/d3cc02071a](https://doi.org/10.1039/d3cc02071a) work of Yamamoto [et al.](et al. in 1996)[ in 1996](et al. in 1996), 12 various aromatic or aliphatic boronic acid catalysts have been developed to date.13 Recently, organomultiboron compounds such as 1,3-dioxa-5-aza-2,4,6-triborinane (DATB),14 diboron,15 and gem-diboronic acid (gem-DBA)16 have also been used as catalyst for amidation reactions. However, there are no reports on the synthesis of primary amides using organoboron catalysis. Presently, primary amides are synthesized using biocatalysts such as enzymes17 or bacteria18 and metal catalysts of titanium,19 zirconium,20 and magnesium.21 Nevertheless, all these methodologies require harmful ammonia gas or ammonia equivalents such as ammonium salt or urea, which produce by-products. To the best of our knowledge, there has been no report on the catalytic dehydrative amidations using aqueous ammonia, which is inexpensive, readily available, and safe.22 We have developed a diboronic acid anhydride catalyst (DBAA) (1)23 with a B–O–B skeleton incorporated into the molecule based on the recently reported activation mechanism of the boronic acid-catalyzed amidation reaction.24 DB

FAQs

What is the main goal of the study?

To establish a DBAA-catalyzed dehydrative condensation method that converts carboxylic acids and aqueous ammonia into primary amides.

Why is aqueous ammonia used in this catalytic approach?

It is inexpensive, readily available, and safe, and the method aims to avoid the harsh conditions or ammonia-equivalent by-products used in conventional routes.

How does the DBAA catalyst enable dehydrative amidation?

DBAA activates the carboxylic acid electrophilically through intermolecular covalent B–O bond formation driven by dehydration involving the carboxylic acid hydroxyl group.

Oct 23, 2026

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