CE07 - Chimie moléculaire et procédés associés pour une chimie durable

Redox modulation of rhodium-catalyzed nitrene insertions into C(sp3)-H bonds – CHamRhOx

Electrons at the service of a more eco-responsible catalysis for the synthesis of amines

We plan to design new dirhodium(II) complexes in order to develop a more efficient and subsequently enantioselective intermolecular amination of C(sp3)-H bonds in the context of sustainable chemistry. Our approach will be based on a mechanistic study from the point of view of the design of the catalysts, and the influence of the electronic properties of the ligands on their efficiency, selectivity and stability.

More eco-friendly intermolecular C(sp3)-H bond amination by designing new dirhodium(II) catalysts.

The direct transformation of C-H bonds into C-N bonds is an area of intense research because, as an atom-economical reaction, it makes the synthesis of complex nitrogen-containing molecules more efficient, with multiple applications in both life sciences and fine chemistry. In this context, rhodium-catalyzed nitrene transfer has rapidly become a method of choice to obtain amines.<br /><br />Nitrenes are nitrogen-based compounds possessing only 6 valence electrons, and therefore very reactive. As such, while catalytic intramolecular insertion of nitrenes occurs with very good levels of regio-, chemo-, and enantioselectivity, selective intermolecular C(sp3)-H amination remains a challenge, particularly for compounds with double bonds, for which C-H amination competes with a reaction on these double bonds. Furthermore, although conventional generation of metallanitrenes with a hypervalent iodine oxidant is very efficient, it can induce catalyst decomposition and is not optimal in atom economy with the production of stoichiometric amounts of PhI.<br /><br />The range of available catalysts is quite limited and the Rh2(esp)2 complex is among the few stable and efficient catalysts for intermolecular aminations by nitrene insertion. Recently, two research groups have revealed the coexistence of a PCET (proton coupled electron transfer) type mechanism in the intermolecular version, which can work without the usual hypervalent iodine oxidant. It was also shown that the value of the redox potential of the dirhodium complex is very important for the course of the reactions. However, this new mechanism contains many grey areas that need to be explored to better control the amination reaction.<br /><br />Our strategy takes advantage of the integration of redox-active ferrocenyl ligands that will enable the mechanistic study of intermolecular amination, as well as investigating the efficiency, chemoselectivity and stereoselectivity issues. We target new dirhodium complexes that can efficiently catalyse the intermolecular amination of challenging substrates and give us some valuable mechanistic information. The questions that we are trying to answer currently are:<br /><br />- Is this alternative PCET mechanism, that does not need hypervalent iodine oxidants, really effective for these challenging intermolecular C-H amination reactions? Under which conditions?<br />- What will be the most appropriate ligand/dirhodium complex to finally explore a wider range of substrates in this intermolecular reaction, for stereoselective transformations?

The project has been divided into several tasks distributed between the two partners according to their respective expertise.

The task dedicated to the synthesis and characterization by electrochemistry of ferrocenyl redox-active ligands, assigned to partner 1 at the LCC, is carried out by a PhD student. The coordination chemistry of these ferrocene ligands on dirhodium(II) is also carried out in the team of partner 1.

Catalytic studies carried out under «classical« conditions with hypervalent iodine or according to the PCET mechanism, with the different dirhodium(II) complexes, are carried out by partner 2 at ICSN. A PhD student is studying the efficiency of new chiral dirhodium(II) complexes for intermolecular amination reactions on different C(sp3)-H sites. The evaluation of the efficiency and stability of new ferrocene catalysts in these same reactions is also planned.

The studies on the PCET mechanism (and its reinterpretation) are carried out jointly by the two partners: by the electrochemical route at LCC, and by the chemical route at ICSN. Different parameters are systematically evaluated: nature of the catalyst, nature of the sulfamate as nitrogen source, solvent, type of base, redox potential applied to the system.

In the first 24 months:

The alternative mechanism of C-H amination without hypervalent iodine, described by a research group in 2011, has been questioned. Indeed, we found that the hypotheses put forward in that publication were based on partial and/or misinterpreted results. An extensive study of this PCET-like mechanism is underway, where all parameters are systematically investigated, in order to know the real viability of the mechanism.

As part of the PCET mechanism study mentioned above, we showed that intermolecular C-H amination of ethylbenzene occurred without dirhodium(II), but in the presence of a cerium(IV) salt. The yields are low but a preliminary study of reaction optimization has been started. The reaction will be studied in a more systematic way, in the framework of a Master 2 project in 2022.

The synthesis of a series of 10 heteroleptic ferrocene dirhodium(II) complexes has been performed. They have been characterized by electrochemistry and are currently evaluated in catalysis.

Selective functionalization of tertiary C(sp3)-H bonds within alkanes and functional molecules was successfully achieved by choosing a suitable dirhodium(II) catalyst.

The evaluation of new dirhodium(II) complexes with ferrocene ligands in intermolecular C-H amination catalysis will be performed. The «classical« (hypervalent iodine) and alternative (PCET, others) conditions will be tested in order to evaluate the stability of the complexes as a function of the ligand and thus of the electrophilicity of the metal centre.

The study of stereoselective C-H amination reactions without hypervalent iodine oxidant for the formation of nitrogen heterocycles is under development at ICSN by combining N-haloamine chemistry and photoredox catalysis.

The synthesis of ferrocene-based chiral ligands is envisaged if time allows.

In preparation : « Heteroleptic dirhodium(II) complexes with redox-active ferrocenyl ligands: synthesis, electrochemical properties and redox-controlled catalysis », I. Ruzhylo, A. Sournia-Saquet, A. Labande, invitation to EJIC, submission November 2021.

Illia RUZHYLO, Junio GUIMARAES, Eric MANOURY, Rinaldo POLI, Agnès LABANDE and Philippe DAUBAN, “Investigation of mechanistic regimes in dirhodium-catalyzed C-H amination”, CEHC-1 (Cutting-Edge Homogeneous Catalysis, International Workshop, Toulouse 4 May 2021). Oral Communication.

Illia RUZHYLO, Junio GUIMARAES, Eric MANOURY, Rinaldo POLI, Agnès LABANDE and Philippe DAUBAN, « Study of one-electron mechanistic regime in dirhodium-catalyzed C-H amination”, Journées de Chimie de Coordination de la SCF, Paris, 23-24 Septembre 2021. Flash poster.

The direct transformation of C-H bonds into C-N bonds via nitrene insertion is an atom-economical reaction that allows a streamlined access to highly valuable molecules for life sciences and fine chemicals. Dirhodium complexes are among the best catalysts for the C(sp3)-H insertion of nitrenes into alkanes, despite intensive research efforts toward the use of more abundant transition metals. Whereas the catalytic intramolecular nitrene insertion occurs with very good levels of regio- and chemo-control, reactivity and selectivity in the intermolecular version remain a challenge. The design of chiral catalysts able to efficiently discriminate between two enantiotopic C-H bonds under oxidizing conditions is also challenging. This proposal aims to tackle these issues through the incorporation of redox-active ferrocenyl ligands into dirhodium catalysts. The study should allow us to gain a better understanding of the intermolecular C-H amination mechanism from the angle of catalyst design and the influence of the ligands’ electronic properties on their efficiency and selectivity. It should also make it possible to carry out the reactions with softer oxidants than classical hypervalent iodine compounds via the electron-relay of ferrocene, and to give access to new chiral catalysts. The CHamRhOx project is mainly of fundamental nature, aimed at removing bottlenecks and extending the applicability of the intermolecular C(sp3)-H amination reaction. It particularly addresses problems of relevance to sustainability since it associates the use of – potentially asymmetric - catalysis with the objective of using more ecofriendly reagents. Preliminary results, recently obtained by a team of the consortium, showed that a dirhodium complex bearing a ferrocenyl ligand could perform an intermolecular C-H amination reaction, while keeping the same level of diastereoselectivity as the reference complex without ferrocene. The project will be implemented by a multifaceted approach that includes synthesis, coordination chemistry, analytical studies and thorough catalytic studies of C-H amination.

Project coordination


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.


ICSN Institut de Chimie des Substances Naturelles

Help of the ANR 360,439 euros
Beginning and duration of the scientific project: October 2019 - 48 Months

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