Periodic Reporting for period 2 - CobaltLSF (Cobalt-catalyzed late-stage functionalization of arenes through metal-ligand cooperation)
Reporting period: 2023-05-01 to 2024-04-30
The depleting reserves of precious metals within the Earth’s crust has made their replacement with more abundant first-row transition metals of signifcant importance. This project aimed to develop catalytic transformations using first-row metals such as cobalt for the functionalization of organic molecules. Such reactions, which previously have relied on precious metal catalysts, have application in the synthesis of derivatives of bioactive small molecule drugs relevant to the pharmaceutical industry.
A cobalt-catalyzed coupling between arenes, ethylene, and alkynes forming alkylated arene derivatives was developed. The cobalt-catalyzed method exhibited broad functional group tolerance enabling a wide scope of coupling partners. The optimal precatalyst was found to be air-stable, allowing for straightforward reaction set-up and benchtop storage. Mechanistic studies supported the intermediacy of a metallacycle that promotes C–H bond cleavage and subsequent C–C bond formation. Organometallic studies on an isolable cobalt metallacycle provided the first direct observation of these elementary steps leading to an improved understanding of how the catalytic rection is working and providing a basis on which to develop next-generation catalysts.
Alternative modes of activation for aromatic substrates, such as electrophilic activation by η6-arene coordination to a cationic metal center, have also been investigated during this project and will be a focus of future investigation. Another future aim of the project involves the development of an iron-catalyzed variant of the multicomponent coupling reaction, given that iron is a less toxic metal compared to cobalt and thus more desirable for applications in medicinal chemistry. Overall, the project establishes a new method to synthesize alkylated arenes and is expected to have broad impact on the development of first-row transition metal catalysts that could serve as sustainable alternatives to precious metals.