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Metal-free organocatalytic S-formylation of thiols using CO2

Nature Catalysis volume 7, pages 375–385 (2024)Cite this article

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Abstract

S-formylation of thiols is achieved via an enzymatic process catalysed by formate dehydrogenase enzyme that fixes CO2 onto substrates, which plays a crucial role in regulating important biological pathways in living organisms. The achievement of this reactivity through a chemical approach could also be advantageous, which would allow the fixation of CO2 on a diverse range of thiols. Here we demonstrate a chemical process to prepare S-formyl thiols from CO2 using a mesoionic N-heterocyclic olefin under metal-free conditions. This catalytic reaction is used to diversify a variety of biologically active thiols obtained from natural terpenoids, fatty alcohols, antioxidants, and commercially accessible analgesic and anti-inflammatory medication molecules, as well as preparation of 13C-labelled formyl coenzyme A. Furthermore, we establish a one-pot S-formylation-olefination process for the synthesis of vinyl sulfides under completely metal-free conditions in the presence of CO2. Overall, this study provides a platform to transform thiols and CO2 into value-added products.

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Fig. 1: S-formylation of thiols.
Fig. 2: Interaction of mNHO with CO2.
Fig. 3: Catalytic S-formylation of thiols using CO2.
Fig. 4: Scope of S-formylation.
Fig. 5: Mechanistic investigations.
Fig. 6: Application.
Fig. 7: One-pot metal-free synthesis of vinyl sulfides from CO2/13CO2.

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Data availability

All the data generated in this study are available within the main text and Supplementary Information. Data are also available from the corresponding author upon request. Crystallographic data for structure 2 reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2244147. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

S.K.M. thanks the SERB (DST), India (grant no. CRG/2022/000471). S.M. thanks the CSIR, India for a research fellowship (09/921(0233)/2019-EMR-I). A.D. thanks the IISER Kolkata for a research fellowship.

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Authors and Affiliations

  1. Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India

    Subir Maji, Arpan Das, Madhur Mahesh Bhatt & Swadhin K. Mandal

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Contributions

S.K.M. and S.M. conceived the idea of this work. S.M. carried out all synthetic and catalytic experiments. A.D. contributed to crystallization and X-ray structure determination. M.M.B. carried out the experiments for thiol synthesis. S.K.M. supervised the overall work. The manuscript was written through the contributions of all authors. All authors have given approval for the final version of the manuscript.

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Correspondence to Swadhin K. Mandal.

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Nature Catalysis thanks Vania Andre and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary methods, Figs. 1–206 and references.

Supplementary Data 1

CIF file of the crystal structure of compound 2.

Supplementary Data 2

Check CIF file of the crystal structure of compound 2.

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Maji, S., Das, A., Bhatt, M.M. et al. Metal-free organocatalytic S-formylation of thiols using CO2. Nat Catal 7, 375–385 (2024). https://doi.org/10.1038/s41929-024-01114-7

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