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Cobalt-catalyzed late-stage functionalization of arenes through metal-ligand cooperation

Project description

A more sustainable catalyst for certain demanding late-stage functionalisations

Pincer complexes are well-established catalysts consisting of a metallic centre and a so-called pincer-type ligand. They have significantly advanced the field of organic synthesis thanks to their stability and versatility. Pincer-ligated cobalt complexes are promising alternatives to catalysts using the precious metal iridium, but they have not been able to accomplish more demanding late-stage functionalisations until now. With the support of the Marie Skłodowska-Curie Actions programme, the CobaltLSF project is paving the way for the use of cobalt to catalyse one such functionalisation, that of a type of cyclic hydrocarbon (arenes), with the help of a novel pincer ligand.

Objective

The depleting reserves of precious metals within the Earth’s crust has made their replacement with more abundant first-row transition metals of paramount importance. Pincer-ligated cobalt complexes have shown a unique ability to recapitulate the reactivity of commonly employed iridium catalysts for arene C–H borylation but, notably, with complementary ortho-to-fluorine site selectivity. However, the lower activity and functional group tolerance of cobalt catalysts has precluded their use in more demanding late-stage applications, depriving chemists of the possibility to selectively functionalize fluoroarenes within complex molecules. “CobaltLSF” aims to unlock the full potential of Co-catalyzed arene C–H functionalization with the use of a novel carbene-containing NCN-pincer ligand that is designed to promote metal-ligand cooperation to address three main challenges: (1) chemoselectivity, by facilitating key steps such as C–H bond cleavage and bond-forming reductive elimination, improving the efficiency of desired catalytic processes over competing side-reactions; (2) site selectivity, through ligand-assisted C–H activation which is predicted to result in a rapidly reversible process that would reinforce ortho-to-fluorine selectivity; (3) direct C–H alkylation using olefin coupling partners, with the aim of expanding the bond-forming capabilities of cobalt catalysis beyond C–H borylation in the context of a green, waste-free method for installing alkyl chains. Alongside the development of (NCN)Co catalysts, their application to the late-stage functionalization (LSF) of fluoroarene-containing drugs will be examined and their chemo- and site selectivity benchmarked against known LSF methods, providing useful comparative data for end-users, such as medicinal chemists. Overall, the successful realization of the proposal is expected to have far-reaching implications for the use of carbene-containing pincer ligands in C–H functionalization with earth-abundant metals.

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Coordinator

MAX PLANCK INSTITUT FUER KOHLENFORSCHUNG
Net EU contribution
€ 246 669,12
Address
Kaiser wilhelm platz 1
45470 Muelheim an der ruhr
Germany

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Region
Nordrhein-Westfalen Düsseldorf Mülheim an der Ruhr
Activity type
Research Organisations
Links
Other funding
€ 0,00

Partners (1)