Efficient iron-catalyzed direct acylation of amines with carboxylic acids and esters under oxygenated conditions

Abstract

Amides are ubiquitous in natural and synthetic compounds, and amidation is by far the most prevalent reaction in medicinal chemistry. In addition, atom-economical procedures for the direct amidation of esters or acids with amines are in high demand. Encouraged by the abundance and low toxicity of iron compounds, we envisaged that a new iron-catalyzed protocol for the acylation of amines with both esters and carboxylic acids could be designed if the iron catalyst was combined with dioxygen. Several experiments were carried out in order to define the iron source and to evaluate the effect of molecular oxygen, additives and different reaction media. A number of substrates were then reacted under optimized conditions, and experimental studies (kinetic, radical trapping and electron paramagnetic resonance experiments) were conducted to shed light on the reaction mechanism. As a result, a new use for dioxygen as an inducer of the direct amidation between amines and carboxylic acids or esters has been found. Thus, an earth-abundant first-row metal catalyst (Fe(acac)₃) at low loading combined with pivalic acid and molecular oxygen at atmospheric pressure triggers the reaction in a biodegradable greener solvent such as diethyl carbonate. More than 65 high-yielding examples prove the generality of the procedure, which also resulted to be scalable. In addition, insight into the mechanism behind this reaction taking place under oxygenated conditions is provided as well as an explanation for the results obtained in the absence of dioxygen.