Flow Chemistry System Tames Weinreb Amidation Reaction

Weinreb amidation, utilizing trialkylaluminium to activate amines for condensation with esters, is a widely used method for the formation of amide bonds. This method circumvents the detour of ester hydrolysis, activation of the carboxylic acid and treatment with amine that is otherwise usually employed in amide formation.

However, the Weinreb protocol carries some inherent risks that limit its use, especially on larger scale. Trimethylaluminium and tri-isobutylaluminium, the reagent most often employed, are highly pyrophoric and difficult to handle. In addition, the intermediate aluminium-amide that is formed usually carries high energy, making thermal runaways and explosions a risk when applying this protocol.

At least, that is the case when using a batch approach.

Vapourtec have recently published an application note showing this reaction being run and optimised under full control (and then easily scaled up) using their R Series Flow Chemistry platform.

The application note shows how the reaction can be carried out with short reaction times, high purity and excellent conversion rates. In the work described, a benzoic acid derived ester and an aliphatic ester were condensed with an aniline and benzyl amine, respectively. Then, as a showcase of the method, the chemists also performed the final step in the synthesis of the anti-obesity drug Rimonabant.

This application note (and many others) can be found via the article webpage.