HSE Researchers Make Aldehydes Perform Dual Function

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Chemists from HSE University have discovered a way to carry out a reductive addition reaction without using an external reducing agent. Instead, the required 'resource' is supplied by the aldehyde itself, one of the reaction participants. This approach helps prevent unwanted side reactions, reduces toxicity, and simplifies the production and synthesis of organic molecules, including those used in the manufacture of medicines. The study has been published in Journal of Catalysis.

Aldehydes are organic molecules that people encounter in everyday life: cinnamaldehyde and vanillin in baked goods, and citronellal and cyclamen aldehyde in perfumes. Many aldehydes are produced on a scale of millions of tons per year—for example, n-butanal, which is used to manufacture raw materials for producing PVC, resins, and laminated glass. The aldehyde group is also present in biologically active molecules, such as vitamin B6 in its aldehyde form, pyridoxal.

In chemical synthesis, aldehydes are typically used as electrophilic compounds—molecules that accept electrons and participate in addition reactions. Much less often, their other property is exploited: their reducing ability, when the aldehyde group is oxidised—for example, to a carboxylic acid—while the molecule donates electrons.

Researchers from HSE University and the Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences (INEOS RAS) have proposed combining these two roles using the example of reductive alkylation of ketones—an important reaction used in industry, including in the synthesis of medicinal compounds. In the classical version, this reaction requires not only the main reagents but also an external reducing agent, such as hydrogen, borohydrides, or carbon monoxide (CO). This complicates the process, as reducing agents can be toxic or explosive, cause side reactions, and require special equipment. In the proposed approach, the role of the reducing agent is taken on by the aldehyde itself. The reaction proceeds in the presence of a ruthenium catalyst and a base, without a solvent and without the addition of an external hydrogen source.

Fedor Kliuev

'We selected the necessary reaction conditions and proposed a conceptually simpler scheme: to eliminate the additional reagent and use the aldehyde as an internal reducing agent. As a result, the reaction can be represented not as A + B + C → product, but as A + B → product, where one of the starting molecules performs a dual function,' comments Fedor Kliuev, Lecturer at the Joint Department with the RAS Nesmeyanov Institute of Organoelement Compounds of the HSE Faculty of Chemistry and co-author of the study.

The authors demonstrated that the method is versatile: it works with both aromatic and aliphatic ketones and aldehydes, while preserving sensitive molecular fragments such as double bonds and certain functional groups. It is also effective for aliphatic aldehydes, which would normally react with each other under alkaline conditions to form by-products.

Aldehyde Reactivity. Aldehydes can act as both electrophiles and reducing agents; in this work, both roles are combined in a single reaction.

© Photo courtesy of Fedor Kliuev

The authors tested the approach with other nucleophiles—amines, amides, sulfonamides, and nitriles—and showed that it can be used not only to form carbon–carbon bonds but also carbon–nitrogen bonds. In total, the article presents around two dozen examples, including the synthesis of the anti-inflammatory drug nabumetone and a derivative of the hormone pregnenolone acetate.

Denis Chusov

'We conducted dozens of reactions with ketones and also confirmed that the method works in reactions with amines. In the future, we plan to further investigate reductive amination and refine our method for this type of reaction. If we can eliminate the need for an external reducing agent in a wide range of cases, this would be particularly important for pharmaceutical synthesis, where roughly a quarter of carbon–nitrogen bonds are formed using this method,' comments Prof. Denis Chusov, Head of the Joint Department of Organoelement Chemistry with the RAS Nesmeyanov Institute of Organoelement Compounds, HSE Faculty of Chemistry.

The study was supported by a grant from the Russian Science Foundation and by the Ministry of Science and Higher Education of the Russian Federation.