New developments in ELectrosynthesis and MulticomponEnt pRocesses – ELMER

To meet the goals of cleaner and more efficient chemical synthesis, this project combines three innovative and complementary technologies: electrosynthesis, multicomponent reactions (MCRs), and asymmetric organocatalysis.

Electrosynthesis:

Central to the project, electrosynthesis uses electricity—rather than traditional reagents—to drive chemical reactions. It offers key advantages: reduced use of toxic substances, less waste, and precise control of reaction conditions. Since electricity can come from renewable sources, electrosynthesis supports a shift toward sustainable and eco-friendly chemistry.

Using modern electrochemical setups (constant-current or constant-potential cells), researchers generate reactive species (e.g., radical cations) under mild conditions. This enables new pathways and improves molecular selectivity. The project also explores indirect electrosynthesis, where electricity activates a catalyst that transforms the substrate, increasing both precision and efficiency.

Multicomponent Reactions (MCRs):

The second approach involves MCRs, which combine three or more components in one step to form complex molecules. MCRs are ideal for green chemistry: they maximize atom economy, reduce the number of steps, purification processes, solvents, and energy use.

Here, the team develops electrochemically induced MCRs, especially with isocyanides—versatile, stable compounds capable of diverse transformations. Merging MCRs with electrosynthesis opens new avenues for constructing complex, functionalized molecules from simple, readily available starting materials.

Asymmetric Organocatalysis:

A key challenge in synthesis is the enantioselective production of chiral molecules—non-superimposable mirror images crucial in pharmaceuticals. The project applies organocatalysis, which uses small organic molecules to guide reactions. Coupled with electrosynthesis, it promises a more selective and sustainable route to chiral compounds. Both anodic (oxidation) and cathodic (reduction) electro-organocatalytic strategies are explored.

Mechanistic Studies and Rational Design:

The project's success depends on a deep understanding of reaction mechanisms. It employs advanced electroanalytical tools like cyclic voltammetry and chronoamperometry to study redox behavior and optimize conditions. These insights guide rational design for efficient, reproducible, and scalable processes.

By integrating these approaches, the project aims to build a toolbox of green, selective synthetic methods with broad applications in pharmaceuticals, materials science, and industrial chemistry.

ELMER has demonstrated that ordinary electric current is a powerful, clean reagent for assembling complex molecules.

• Electro-multicomponent toolbox. We created the first alcohol-based electro-Passerini and electro-Ugi reactions. Simple methanol or ethanol is anodically oxidised in situ to the corresponding carbonyl partner, then trapped by an isocyanide and a carboxylic (Passerini) or amine/acid pair (Ugi). Using TEMPO as a mild redox mediator, these one-pot sequences give highly functionalised α-acyloxy amides and bis-amide adducts in a single step, without metals or added electrolyte.

• Selective C–H activation. we directly functionalized benzylic C–H bonds by insertion of isoncyanide, delivering an easy access α-carbamoyl derivatives with broad functional-group tolerance. Following a “convergent paired electrolysis” approach, a benzylic arylation method was also developed.

• Radical polycyclisations. With ferrocene as catalyst we triggered cascade radical cyclisations of unsaturated malonates, rapidly building diterpenoid-like cores. The platform was adapted to form γ-lactones—motifs found in many natural products—without the need for stoichiometric oxidants.

• Alternative sustainable activation. A multicomponent amidination of styrenes revealed difficult to achieve via electrosynthesis. However, switching to visible-light photoredox catalysis allowed the same transformation under green conditions, illustrating the complementary features of electrosynthesis and photoredox catalysis.

Together these results provide a scalable, metal-free reaction set that cuts waste, shortens syntheses and showcases the real-world potential of electrosynthesis.

Building on the results achieved in the ELMER project, several promising directions have emerged to further develop and expand the work already undertaken.

One of the key advances was the development of efficient electro-induced multicomponent reactions, especially new versions of the Passerini and Ugi reactions that use simple alcohols directly as starting materials. This success opens the door to applying the same strategy to other easily oxidized compounds such as ethers, thioethers, or amides, with the aim of creating even more complex and diverse molecular structures.

The electrochemical activation of benzylic C–H bonds—a challenging but highly valuable transformation—also proved effective, as did the development of convergent electrolysis techniques for selective arylation. These methods allow for the rapid construction of structural motifs commonly found in biologically active molecules. Future work may explore direct trapping of aromatic radical cations with isocyanides, which could lead to new electrochemical pathways for C–H carbamoylation—the formal insertion of amide-like groups into aromatic C-H bond.

Another area of interest is the refinement of convergent paired electrolysis, where two reactions occur simultaneously at the anode and cathode. Improving the electrochemical efficiency of these processes will be a key objective. In particular, using alternating current (AC) instead of direct current may help overcome limitations related to mass transfer within electrochemical cells. As a complementary approach, photoredox catalysis could also be used. The project has already shown that these two technologies can complement each other effectively and open new reactivity windows.

Progress was also made in radical polycyclisation and oxidative ring formation, using ferrocene as redox catalyst. These reactions allowed the team to generate complex carbon frameworks from simple building blocks. Looking ahead, these strategies will be applied in more ambitious contexts, such as the total synthesis of complex natural or bioactive molecules.

Finally, the development of enantioselective (chiral) electrochemical reactions remains a major challenge. While early attempts at combining electrochemistry with organocatalysis did not yet yield fully successful results, they provided valuable insight into the key factors that influence selectivity. Future work will focus on identifying better-suited redox mediators and designing new chiral organocatalysts that are compatible with electrochemical conditions.

All of these future directions align with a clear vision: to continue designing cleaner, more selective, and scalable synthetic methods that meet both scientific goals and industrial demands for sustainable chemistry.

The ELMER project concerns the development of new sustainable methods allowing the access to densely functionalized organic scaffolds in a limited number of steps. To this aim, the ChimieParisTech/ICMMO consortium, based on their respective field of expertise, will study original approaches in which electrosynthesis will be merged with multicomponent processes and enantioselective organocatalysis. By implementing advanced electrochemical and analytical technics, collaborative mechanistic studies will be key to the rational optimization of experimental conditions. These methodologies will grant the opportunity to further explore the complexity of the molecular space and to access molecules of biological interest.