In the last few years, boric acid catalyzed carboxylic amide formation directly from carboxylic acids and amines has attracted considerable attention because it has emerged as a viable alternative route to the indirect methods of preparing carboxamides. The standard methods employ carboxylic acid derivatives such as acid halides, anhydrides or activating agents² such as DCC/HOBt, EDC, BOP-Cl.³ and others. These methods suffer from several disadvantages including environmental unfriendliness, poor selectivity, poor atom economy, poor step economy, and unsuitability for large-scale preparation.⁴

Recent developments employing boric acid as a green, inexpensive and readily available catalyst have significantly expanded not only the scope of the direct formation of carboxamides from carboxylic acids and amines in general,^5,6 but also its application to the synthesis of a wide spectrum of compounds of industrial interest. Carboxamides are key components of a number of valuable intermediates for the pharmaceutical and other industries. By far, the most notable application of boric acid catalyzed amidation has been the synthesis of medicinally useful carboxamides, including carriers for drug delivery,⁷ active pharmaceutical ingredients, and drug candidates.^8,9

Boric acid catalyzed amidation was featured in the preparation of sterically hindered N,N-disubstituted amides, which are used as drug delivery agents, in 45-55% yield (Figure 1).¹⁰ Mono-substituted a,β-unsaturated carboxamides such as N-furylmethylcinnamamides, which offer potential use as drug delivery agents and as biological models with antifungal and antiparasitic properties, were prepared by boric acid catalyzed amidation using a 2:1 cinnamic acid/amine molar ratio (Figure 1).¹¹

Bandichhor et al. employed this method to synthesize a number of active pharmaceutical ingredients (API).^8,9 When both primary and secondary amine functionalities are present in the same molecule, boric acid catalyzed amidation takes place chemoselectively at the primary amine functionality (Figure 2).⁸

The integrity of stereogenic centers either in the carboxylic acid and/or in the amine are preserved in the boric acid catalyzed amidation. No epimerization is observed under the studied experimental conditions (Figure 3).^4,8,12

Using the same procedure in a one step reaction, the dihydroxamic acid ligands can be prepared from N-methylhydroxylamine and 1,3-phenylene diacetic acid (Figure 4).¹³

The ability of boric acid to form an ester or a complex with hydroxyl functionality has provided higher catalytic activity in the direct amidation reaction involving carboxylic acids and amines. This discovery allows a wider range of molecule partners to be incorporated into a cooperative catalytic system for enhancing the direct amidation. A study of the kinetics of the boric acid catalyzed amidation of 4-nitrobenzoic acid with ammonia showed that the amidation activity was enhanced by adding the co-catalyst polyethylene glycol (PEG). The latter forms a hypothetical PEG-boric ester complex with boric acid. The molecular weights of PEG have little effect on the yield of the final 4-nitrobenzamide product (Figure 5).¹⁴ With PEG-400 as a co-catalyst, the optimal molar ratio between boric acid and PEG-400 in the amidation of 4- nitrobenzoic acid and ammonia was 1:(1.5-2.5).¹⁴

For the preparation of amides from sterically demanding carboxylic acids and amines, such as tris(alkylsubstituted cyclohexylamide) that is used as a material for molding,¹⁵ the catalytic activity of boric acid was enhanced when boric acid was converted in-situ to a boric acid ester. This conversion was achieved by means of a molecule bearing mono-hydroxyl or di-hydroxyl functional groups, such as cresol or tetrachlorocatechol prior to the addition of carboxylic acids and amines to the reaction vessel (Figure 6).^16,17

We believe that in the near future many more applications to the synthesis of important carboxamides using this boric acid catalyzed amidation will be reported.