Lewis acid promoted copper catalysis to functionalise and dearomatise arenes

Project Information

LACOPAROM

Grant agreement ID: 773264

DOI

10.3030/773264

Project closed

EC signature date 19 January 2018

Start date 1 September 2018

End date 30 November 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 398,00

EU contribution

€ 1 999 398,00

Coordinated by

RIJKSUNIVERSITEIT GRONINGEN
Netherlands

Periodic Reporting for period 4 - LACOPAROM (Lewis acid promoted copper catalysis to functionalise and dearomatise arenes)

Reporting period: 2023-03-01 to 2024-11-30

Summary of the context and overall objectives of the project

This ERC-funded project set out to address key challenges in dearomatisation, a chemical process that converts flat, stable aromatic molecules into more complex, three-dimensional structures. These transformations are particularly valuable in the synthesis of pharmaceuticals and natural products, where chiral, saturated (alicyclic) frameworks are often essential. Aromatic compounds are abundant, inexpensive, and commonly used as starting materials in organic synthesis. However, their high stability makes them difficult to chemically modify. In particular, breaking the aromatic ring requires overcoming significant thermodynamic and mechanistic barriers. Despite its potential, no general and efficient catalytic strategies for this transformation existed at the start of this project. The overarching aim of the project was to develop broadly applicable, stereoselective dearomatisation methods that could be used across different classes of aromatic compounds. To do this, we employed a strategy based on activating aromatic substrates with Lewis acids, followed by copper-catalysed transformations. Our goal was to establish a unified catalytic platform that is not only selective and efficient, but also cost-effective and environmentally friendly.
An important advantage of this approach is that multiple reaction steps can often be performed in a single operation, greatly simplifying the synthesis of complex molecules. This streamlining leads to more sustainable chemical processes—saving time, reducing waste, and lowering costs. The developed methods have the potential to become powerful tools for accessing a wide variety of chiral carbocyclic structures, which are highly relevant for drug development and other advanced applications in synthetic chemistry.
To achieve this vision, the project focused on four main areas, each targeting a different class of aromatic compounds: 1. Dearomatisation of electron-deficient aromatic systems . 2. Dearomatisation of heteroaromatic systems . 3. Dearomatisation of electron-rich aromatic systems . 4. Dearomatisation of benzylic aromatic systems
Each of these sub-projects contributed to building a versatile and general approach to dearomatisation, laying the foundation for future advances in catalysis and complex molecule synthesis.

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

The main objective was to develop new catalytic strategies that enable these transformations to occur efficiently, selectively, and in a broadly applicable way. We focused on copper-based catalysts in combination with specially designed chiral ligands to achieve precise control over the outcome of these reactions. Initial studies targeted activated aromatic compounds to better understand how to weaken aromatic stability using Lewis acids. This work laid the foundation for advancing to more challenging aromatic targets, such as quinolines and pyridines, where we successfully developed the first catalytic system capable of selective and enantioselective transformations at specific positions on the molecule—something that was not possible with previous methods.
In parallel, we explored reactions with more electron-rich aromatics like phenols and anilines, using a unique mechanism involving reactive intermediates called tautomers. These were stabilised and further functionalised under catalytic conditions, opening up new chemical pathways.
To improve the practicality and sustainability of our methods, we also developed cost-effective routes to a range of chiral ligands using earth-abundant metals like manganese. These new ligands expand the toolbox for asymmetric catalysis and reduce reliance on expensive or rare materials.
Finally, a conceptual innovation emerged from the project: oscillating catalysis—a new approach in which catalyst levels change rhythmically over time. This offers a novel way to introduce time-dependent control into chemical reactions, with potential applications across different areas of catalysis.
In summary, the project delivered new methodologies, mechanistic insights, and practical tools that advance the field of dearomatisation and contribute to more efficient and sustainable molecule construction in synthetic chemistry.

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)

Dearomatisation reactions are chemical processes that convert flat, stable aromatic molecules into more reactive, three-dimensional structures. These reactions have been studied for over a century, but most existing methods work only with a narrow set of molecules or require specially designed compounds. Developing general, sustainable, and selective approaches remains a key challenge, especially for building complex molecules needed in drug development and natural product synthesis.
This ERC-funded project made important progress in this area. We developed several new methods for dearomatising heteroaromatic compounds (those containing atoms like nitrogen or oxygen in the ring). Key results include:
Dearomatisation of naphthol derivatives/ The creation of chiral, nitrogen-containing building blocks useful for making piperidine and tetrahydroquinoline structures—common in many bioactive molecules/ A general method for adding carbon groups to nitrogen-containing rings using simple reagents and copper catalysts under mild conditions (room temperature), with high efficiency and precision
We also made a major breakthrough by directly dearomatising quinoline compounds. Previously this was only possible using modified forms called quinolinium salts, which give limited results. Our new method enables selective modification at a different position on the molecule (C4), using a copper-based catalyst, and achieves high selectivity and efficiency. Notably, we also developed the first-ever catalytic dearomatisation of pyridines without the need for prior chemical activation. This approach opens up access to valuable chiral molecules called dihydropyridines, which are useful in many areas of chemistry and drug design.
To support the sustainability of these methods, we also worked on making the process more cost-effective. Many of these reactions require expensive chiral ligands, so we developed simpler and cheaper ways to make them using abundant metals like manganese. These ligands can now be made in just a few steps and offer new options for catalyst design.
Finally, the project introduced a brand-new idea called oscillating catalysis—where catalyst levels change automatically over time in a rhythmic pattern. This new concept has been tested in early experiments and is now being explored for its potential in dearomatisation chemistry as well.
In summary, this project achieved its main goals and also opened up exciting new directions in catalysis and synthetic chemistry, with wide potential for application in science and industry.

Access chiral tetrahydro-quinolones, dihydropyridones, and piperidones