JCJC SIMI 7 - JCJC - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique

Development of iron-based hydroamination catalysts for the cyclisation of primary and secondary aliphatic amines – DHAMFER

Iron: a «precious« metal catalyst for the clean C-N bond formation

A simple and eco-friendly access to nitrogen heterocycles

To develop iron catalysts for the environmentally friendly synthesis of nitrogen molecules

The need to develop new and more viable for the production of nitrogen molecules technologies has never been as high as these days. In this context, the direct addition of a simple amine onto a non-activated carbon-carbon double bond, the so-called hydroamination reaction, is a very promising approach for the development of a more economical and environmentally friendly methodology for the synthesis of these compounds. Despite significant advances in the field, much progress still to come for this approach to become an effective methodology with a high potential for industrial applications. Indeed, this apparently simple reaction usually requires a catalyst. Among the different metals used to catalyse this reaction, iron has the best potential to meet the industrial specifications. An ease of handling, a low toxicity, a functional tolerance, combined with a low cost and a high availability confer to iron preferential advantages towards the noble metals. However, to our knowledge, there are no examples of iron-catalysed hydroamination involving simple amines. This project aims to fill this gap by developing catalysts based on iron, which are more accessible and more efficient than those known in the prior art, for the hydroamination reaction of unprotected simple amines.

The main objective of the project is to develop an iron-based catalyst that is effective for the direct addition of a simple amine (that is to say unmodified by prior chemical methods) to an olefin intramolecularly. The success of this approach will result in a simple and efficient atom-economic catalytic method opening attractive industrial perspectives on the state of the art. The development of a metal catalyst which is compatible with simple amines (which intrinsically have very high affinity for the metal, which can lead to its degradation) is one of the major scientific obstacles to achieve this goal. The expertise of the partner in the field of organometallic catalysis has allowed to develop, after several phases of optimisation, an iron catalyst that is effective for the cyclization of unprotected amines. The study of the catalyst operative mode has also improved the ability of the latter to promote this transformation selectively.

During this project, a methodology for the intramolecular direct addition of a simple amine to an olefin promoted by a catalyst based on iron as an abundant, cheap and low toxic metal, was developed. The study of the various elementary steps of the addition reaction has elucidated the operative mode of the catalyst, which was then used to improve the overall efficiency of the methodology. The scope of the methodology was reviewed and its limitations have been highlighted.

The development of a catalytic system based on iron as a abundant, inexpensive, and low toxic metal to directly add an unprotected amine on a non-activated olefin, offers real prospects in the academic and industrial field of carbon-nitrogen bond. This methodology will provide access to nitrogen heterocycles whose economic sector of the cosmetics industry, food, agrochemical and pharmaceutical industries are particularly important.

The project results have so far led to the publication of an article in an high impact factor journal. This article has aroused some invitations to write scientific reviews in the field. A second article will also be shortly submitted in a journal of high impact factor. This work has led so far to three oral presentations and three poster presentations at national and international conferences. These results were also presented at three invited lectures.

Nitrogen-heterocycles constitute key scaffolds of a variety of natural and synthetic organic molecules with diverse applications as pharmaceuticals, fine and bulk chemicals and catalysts. The quest for the development of sustainable, more efficient and selective processes for their syntheses has never been as high as these years and will undoubtedly increase exponentially in the near future. Amongst the plethora of synthetic routes, the direct addition of an amine onto an unactivated carbon-carbon double bond, the so-called hydroamination reaction, represents a very promising research field towards the development of an economical and environmentally begnin synthetic method. Indeed, this reaction offers a waste free process with 100% atom efficiency from relatively inexpensive and ubiquitous olefins and amines. Despite major breakthroughs in the field of intramolecular hydroamination, some advances are still needed to bring this attractive alternative up to the requirements of a truly efficient and low-environmental impact methodology. This seemingly simple transformation is usually done in the presence of a catalyst which brings the opportunity to control the regio- and stereoselectivities of the transformation by the appropriate metal-chiral ligand(s) synergy. Among the variety of metals used to catalyse this reaction, iron seems to be a promising candidate to bring this methodology up to compete against traditional and stoichiometric methods for the synthesis of nitrogen-heterocycles. Iron offers indeed significant advantages compare with precious or rare-earth metals for example. It is a relatively cheap and abundant material, easy to handle with a relatively low toxicity and high functional group compatibility. This proposal has the objective to develop a metallo-catalysed methodology based on iron for intramolecular hydroamination. The long-term objective will be to develop an asymmetric version which is out of the context of this proposal. To the best of our knowledge, there is no example of iron-catalysed hydroamination reaction for the cyclisation of primary and secondary aliphatic amines. This proposal aims to address this void by taking the challenge to develop more accessible and efficient hydroamination catalysts for the cyclisation of primary and secondary aliphatic amines tethered to mono- and 1,2-dialkyl-substituted olefins. The screening of a variety of iron sources having different oxidation states (from +III to –II), chemically or electrochemically generated, will be done for the cyclisation of model substrates. The reactivity of the metal center will be modulated by ligands from different denticity and stereoelectronic effects and by the use of additives (salts, Brønsted acids). The scope of the methodology will be next expanded to other primary and secondary amines, in particular challenging amines such as amines tethered to 1,2-dialkyl-substituted or thoses without any gem-substituants faciliting the cyclisation. The synthetic potential of the methodology will be illustrated by the construction of key functionalised scaffolds and 2 alkaloïds. In the course of this proposal, a mechanistic study of the catalytic, intermolecular hydroamination reaction will be undertaken through a kinetic study and the isolation and characterisation of intermediates. As a demonstration of the iron potential in catalysis, we will investigated the use of iron complexes in multicatalysis reactions. For this purpose, the hydroamination reaction will be combined to a cross-coupling reaction in an iron-multicatalysed tandem process assisted by electrochemistry

Project coordination

Jérôme Hannedouche (UNIVERSITE DE PARIS XI [PARIS- SUD]) – Jerome.hannedouche@universite-paris-saclay.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 165,984 euros
Beginning and duration of the scientific project: October 2011 - 36 Months

Useful links

Explorez notre base de projets financés



ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter