Sustainable Synthesis of Amides

Project Information

SUSAMIDE

Grant agreement ID: 657883

DOI

10.3030/657883

Project closed

EC signature date 17 March 2015

Start date 1 April 2015

End date 31 March 2017

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 172 800,00

EU contribution

€ 172 800,00

Coordinated by

UNIVERSITEIT ANTWERPEN
Belgium

Periodic Reporting for period 1 - SUSAMIDE (Sustainable Synthesis of Amides)

Reporting period: 2015-04-01 to 2017-03-31

Summary of the context and overall objectives of the project

This project aims to develop an unprecedented methodology for amide synthesis, allowing one to access “challenging” representatives. The synthesis of an amide group is paramount to organic chemistry. The amide function is present in many polymers, pharmaceuticals and agrochemicals. The classical, seemingly simple route for its synthesis is based on either acyl chlorides or the in situ activation of a carboxylic acid followed by reaction with amine. However, these methods are not always straightforward, and even simple amides cannot always be accessed efficiently by these means. The focus of this project is on the development of an unprecedented, broadly compatible synthetic method for challenging amides using hindered carboxylic acids and electron deficient amines which can also be sterically hindered. The power of newly developed synthetic methodology can best be demonstrated by its application to challenging targets of industrial importance. To this end, synthesis of the two Active Ingredients involving amide formation is demonstrated.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

A novel method for N-(hetero)arylamide synthesis based on rarely explored amine activation, rather than classical acid activation, is developed. The key component of the new method is activation of the amine by conversion into the corresponding isothiourea using a three-component reaction with an isocyanide and an S-phenyl benzenethiosulfonate, followed by reaction with a carboxylic acid under base metal catalysis. The scope of the method is studied using variety of acids and amines as starting materials for the amide synthesis. In particular, it is shown that the challenging sterically hindered amides can efficiently be prepared by the newly developed method. The mechanism of the new method was studied. As a demonstration of the power of synthetic methodology towards the relevant targets, a fungicide boscalid and an anti-arrhythmic drug Tocainide was accomplished. Finally, in order to improve the sustainability of the new method, the recycling of the side product was demonstrated.
As a major dissemination result, 3 scientific publications have been produced (2 are published, one accepted for publication at the moment of submittign the project report) . In order to communicate about the project to the public, a project blog on a social media was maintained (see the link below). A video was published on You Tube: https://youtu.be/uQ4xvkRN00s. Both these actions target broad public and university students. A poster presentation at one of the Kekule cycle evenings organized at the University of Antwerp within the Flemish Government Initiative “Action Plan on Science Information and Innovation” targeted chemistry professionals in the broad sense, including University alumni active in industry and public sector.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The major point of progress beyond the state of the art: the new method provides the high-yield synthesis of amides which can only be produced in a modest yield, or even could not be prepared at all, via the classical methods. We have demonstrated this for a challenging amide by comparing a number of the known synthesis protocols with our newly developed methodology starting from a sterically hindered amine and a sterically hindered carboxylic acid. In addition, we demonstrated that the method can be applied to optically pure amino acids and short peptides, without causing racemization. This is an important finding with an impact for the synthesis of biopharmaceuticals. Also the possibility of recycling the side products and re-using them in the synthesis of reactants is an important achievement, not present in the state of the art methods.

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