From hydrocarbons to original chiral building blocks: new solutions for sustainable & asymmetric CH functionalization of alkanes

Project Information

AlCHIMIE

Grant agreement ID: 949804

DOI

10.3030/949804

EC signature date 7 September 2020

Start date 1 June 2021

End date 30 September 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 800,00

EU contribution

€ 1 499 800,00

Coordinated by

JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Germany

Periodic Reporting for period 3 - AlCHIMIE (From hydrocarbons to original chiral building blocks: new solutions for sustainable & asymmetric CH functionalization of alkanes)

Reporting period: 2023-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

Over the last decade, major environmental concerns, a growing worldwide population, and an increased energy demand, combined with the depletion of natural resources, have become crucial issues. Sustainable chemistry ably to supply society with key chemical products in an eco-compatible manner-has therefore rapidly become an urgent challenge. The AlCHiMIE aims at providing new solutions towards this important defy by developing a set of complementary approaches to convert hydrocarbons, the simplest feedstock, into high value-added chiral alkanes-essential building blocks for medicinal chemistry. Two approaches are thus proposed. First, undirected, metal-free functionalization of hydrocarbons will be achieved by means of regio- and stereo-selective hypervalent bromine-enabled C-H functionalization. This unique reactivity will be attained by discovering a largely uncharted, yet extremely appealing field of λ3-bromanes.
The second approach concerns earth-abundant metal-catalyzed C(sp3)-H activation. To obviate the inherent difficulties of this field, namely the low reactivity of alkanes and arduous stereoinduction while using 3d metals, bifunctional ligands for Co- and Ni-catalyzed C-H activation will be designed and synthesized. Finally, the combination of both strategies will allow unprecedented hydrocarbon valorization by means of undirected, λ3-bromanes-enabled first functionalization followed by exploiting the newly installed coordinating motif to promote directed, asymmetric Co- and Ni-catalyzed C-H activations. 

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

Over the first reporting period (18 months) significant efforts have been focused on the development of hypervalent bromine and chlorine chemistry. We have managed to establish an efficient, operationally simple, and safe protocol furnishing diversity of cyclic λ3-diarylbromanes and cyclic λ3-diarylchloranes in good yields. These compounds turned out to be stable and feature unique reactivity, complementary to the well-known chemistry of hypervalent iodines. Indeed cyclic λ3-diarylbromanes  and 3-diarylchloranes undergo various meta-selective formal C-H functionalizations under metal-free and eco-compatible conditions, furnishing a diversity of functionalized biaryls.
The next step will consist of the synthesis of various other hypervalent bromines and their applications in metal-free C-H functionalizations of alkanes.

In parallel, experimental efforts were focused on the design of new chiral polyfunctionalized ligands for 3d-metal catalyzed C-H activation. For the moment the concept has been validated on aromatic substrates and promising results were obtained for the direct functionalization of C'(sp2)-H bonds.

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)

During the first period of the project, we managed to synthesize efficiently and safely a large panel of cyclic λ3-diarylbromanes and cyclic λ3-diarylchloranes (> 50 examples) and their unknown reactivity under metal-free conditions could be explored. Straightforward transformation of these compounds into aryne intermediates under surprisingly mild reaction conditions clearly expands the state-of-the-art of the fields of hypervalent compounds but also aryne chemistry.
Until the end of the project, we expect to achieve further key developments in the chemistry of hypervalent compounds, including the synthesis of alternative families of hypervalent bromines and chlorines and their use as catalysts/mediators in metal-free functionalizations.
In parallel, we expect to design an alternative approach based on 3d-catalyzed metal C(sp3)-H activation. The use of 3d metal for such challenging transformations is extremely appealing and poorly known, in particular, while aiming for simultaneous chirality induction.

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