Direct Amide Coupling of Non‐activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride

Abstract

Amidst the green: A green, mild and effective protocol for the direct formation of secondary and tertiary amides from non‐activated carboxylic acids and amines in good to excellent yields by employing ZrCl4 as the catalyst is presented (see scheme). The amide coupling protocol proved to be suitable for scaled up syntheses, and the mild reaction conditions conserve the enantiopurity of chiral starting materials.

Catalytic amide formation from non-activated carboxylic acids and amines

“…The best result was obtained with RAL and palmitic acid (50% yield) at 40 15 ºC for 7 days with a 2:1 ratio of acid to amine, and a catalyst loading of 2000 lipasic units of enzyme to 1 mmol carboxylic acid. A clear correlation between the length of the carbon chain in the carboxylic acid substrate and product yield was observed; only 25% yield of the product was obtained with acetic acid 20 (Scheme 6).…”

“…However, these types of catalysts commonly require removal of formed water as well as elevated temperatures in order to enable high yields of amide product. Both heterogeneous and homogeneous systems have been developed for boron-based 15 catalysts.…”

“…10 As mentioned above, it is well-known that amides can be formed by the thermal treatment of a carboxylic acid and an amine without any catalyst present, generally at reaction temperatures of >140 ºC. 11 Recently, it was shown that a significant amount of the 15 amide product can be formed even at lower temperatures, usually with azeotropic removal of water. 12,13,14 The yields of the thermal amidation reaction is highly substrate dependent, as well as dependent on temperature, substrate concentration, solvent and other reaction parameters.…”

“…13 For comparison, the structurally similar N-benzylphenylacetamide 25 was formed in only 13% yield or less, when phenylacetic acid and benzylamine were allowed to react in THF at 70 ºC at a concentration of 0.4 M and a reaction time of 24 hours. 15 The literature on thermal amidation is not covered in this review unless the non-catalysed reaction is specifically mentioned by the 30 authors. 35 …”

“…Prasad et al reported on the kinetic resolution of racemic 2-ethylhexyalmine in the amidation reaction with six different carboxylic acids, using CAL-B immobilized on accurel as catalyst at 90 ºC under 15 solvent free conditions and vacuum. 52 The amides were obtained in 40-45% yield with >99% ee employing a catalyst loading of 120 mg/mmol carboxylic acid and 2 equivalents of the amine (Figure 2).…”