The importance of the amide functional group emerges from their presence in many crucial compounds such as proteins, fabrics, fertilisers, insecticides, plastics, drugs, and in a vast number of synthetic structures. As a consequence, the development of new methods for the efficient synthesis of amides is of vital importance. Traditional methods for the production of amides require the transformation of the acid into the corresponding acid chloride or the use of coupling reagents. Although these methods produce amides under mild reaction conditions and in good yields, the use of stoichiometric amounts of a coupling reagent is required, leading to the generation of one equivalent of waste and a low-atom economy process. Besides, the removal of the corresponding by-product can be tedious, increasing the cost of the transformation. The direct synthesis of amides from unactivated carboxylic acids is an important transformation that has been less exploited and studied. Secondary and tertiary amides can be obtained by the thermal condensation of the acid and the amine, but the competing acid-base reaction makes this coupling challenging. The direct synthesis of primary amides using this methodology is more challenging due to the low nucleophilic nature of the nitrogen source, and as a result coupling reagents are often required. The most common nitrogen sources employed for the synthesis of primary amides are ammonia, ammonium salts, carbamates and urea. In order to avoid coupling reagents the use of a catalyst is an attractive approach to obtain primary amides directly from the carboxylic acid. Our aim was to expand the repertoire of amidation reactions by developing a novel and simple methodology. A new method for the efficient synthesis of primary amides directly from unactivated carboxylic acids is described. This protocol does not require the employment of coupling or activating reagents, or the use of ammonia or amines that are commonly needed. This transformation is achieved using Mg(NO3)2 6H2O or imidazole as low-cost, non-toxic and readily available catalysts, and urea as a stable and easy to manipulate nitrogen source. Overall, these advantages make this protocol very attractive to be applied in industrial processes.

Magnesium salts and imidazole: Cost-effective and sustainable catalysts for the efficient synthesis of primary amides from unactivated carboxylic acids

256th National Meeting (2018)

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