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Electrocatalytic reductive deuteration of arenes and heteroarenes

Nature volume 634, pages 592–599 (2024)Cite this article

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Abstract

The incorporation of deuterium in organic molecules has widespread applications in medicinal chemistry and materials science1,2. For example, the deuterated drugs austedo3, donafenib4 and sotyktu5 have been recently approved. There are various methods for the synthesis of deuterated compounds with high deuterium incorporation6. However, the reductive deuteration of aromatic hydrocarbons—ubiquitous chemical feedstocks—to saturated cyclic compounds has rarely been achieved. Here we describe a scalable and general electrocatalytic method for the reductive deuteration and deuterodefluorination of (hetero)arenes using a prepared nitrogen-doped electrode and deuterium oxide (D2O), giving perdeuterated and saturated deuterocarbon products. This protocol has been successfully applied to the synthesis of 13 highly deuterated drug molecules. Mechanistic investigations suggest that the ruthenium–deuterium species, generated by electrolysis of D2O in the presence of a nitrogen-doped ruthenium electrode, are key intermediates that directly reduce aromatic compounds. This quick and cost-effective methodology for the preparation of highly deuterium-labelled saturated (hetero)cyclic compounds could be applied in drug development and metabolism studies.

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Fig. 1: Strategy for perdeuterated cyclic compounds and saturated deuterocarbons.
Fig. 2: Reductive deuteration of arenes.
Fig. 3: Reductive deuteration of heteroarenes.
Fig. 4: Synthetic applications and gram-scale synthesis.

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All data are available in the main text or in Supplementary Information.

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Acknowledgements

We thank the Center for Electron Microscopy at Wuhan University for their support of the transmission electron microscope work. We acknowledge the support from the National Key R&D Program of China (number 2021YFA1500100, A.L.), the National Natural Science Foundation of China (22031008, A.L.; 212200007, W.L.) and the Science Foundation of Wuhan (2020010601012192, A.L.). We thank S. Chen (WHU), Z. Wei (WHU), G. Wang (WHU) and Y. Xi (NUS) for discussions; X. Zhou from the Core Research Facilities of CCMS (WHU) for assistance with ssNMR analysis; and beamline BL11B and BL14W1 of Shanghai Synchrotron Radiation Facility (SSRF) for providing the beam time.

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Author notes

  1. These authors contributed equally: Faxiang Bu, Yuqi Deng

Authors and Affiliations

  1. College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan, People’s Republic of China

    Faxiang Bu, Yuqi Deng, Jie Xu, Dali Yang, Yan Li, Wu Li & Aiwen Lei

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  1. Faxiang Bu
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Contributions

A.L., W.L., F.B. and Y.D. conceived and designed the project. F.B., Y.D. and J.X. developed and prepared the catalysts, performed all catalytic experiments and analysed the data. F.B. and Y.L. were responsible for the TEM experiments. F.B. was responsible for the X-ray diffraction experiments. F.B. and Y.L. were responsible for the X-ray photoelectron spectroscopy experiments. D.Y. was responsible for the XAFS experiments. F.B., W.L. and A.L. co-wrote the paper.

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Correspondence to Wu Li or Aiwen Lei.

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Extended data figures and tables

Extended Data Fig. 1 Possible mechanisms.

Pathway 1 supported by our experimental data and reported data, pathway 2 involving D2 as an intermediate.

Extended Data Fig. 2 Reductive deuteration of arenes.

Standard conditions: Undivided cell, Al (+), Ru-N/CF (−) (Ru 3 mol%), a 0.4 mmol, nBu4NBr 0.4 mmol, tBuOD/D2O = 2.5/2.5 mL, constant current, 10 mA, room temperature, argon atmosphere, 8 h to 48 h, isolated yield. a0.2 mmol a was added. bReaction conditions: divided cell, anode cell, CF (+), NaF 0.8 mmol, D2O 10.0 mL; cathode cell, Ru-N/CF (−), a 0.4 mmol, nBu4NBr 0.8 mmol, tBuOD/D2O/HFIP = 5.0/5.0/0.5 mL, constant current, I = 10 mA, room temperature, argon atmosphere, 8 h to 16 h. cRu-N/CF-2 (Ru 5 mol%) was used as cathode.

Extended Data Fig. 3 Reductive deuteration of D-labelled arenes.

Standard conditions: Undivided cell, Al (+), Ru-N/CF (−) (Ru 3 mol%), c 0.4 mmol, nBu4NBr 0.4 mmol, tBuOD/D2O = 2.5/2.5 mL, constant current, 10 mA, room temperature, argon atmosphere, 8 h to 20 h, isolated yield. aReaction conditions: Divided cell, anode cell, CF (+), nBu4NCl 0.8 mmol, D2O 10.0 mL; cathode cell, Ru-N/CF (−), c 0.4 mmol, nBu4NCl 0.8 mmol, tBuOD/D2O = 5.0/5.0 mL, constant current, I = 10 mA, 14 h, room temperature, argon atmosphere.

Extended Data Fig. 4 Deuterodehalogenation.

Standard conditions: Undivided cell, Al (+), Ru-N/CF (−) (Ru 3 mol%), e 0.4 mmol, nBu4NBr 0.8 mmol, tBuOD/D2O = 5.0/5.0 mL, constant current, 10 mA, room temperature, argon atmosphere, 20 h to 72 h, isolated yield. anBu4NBr 0.4 mmol, tBuOD/D2O = 2.5/2.5 mL, t = 8 h to 20 h. bThe position of halogen in the substrates with the number less than five. cRu-N/CF-2 (Ru 5 mol%) was used. dD-incorporation (and yield) was determined by product benzoylation. ePentafluorophenylacetonitrile was used as substrate.

Extended Data Fig. 5 Synthetic applications.

Synthesis of piperazine-d8-containing pharmaceuticals from piperazine-d8 hydrochloride.

Supplementary information

Supplementary Information

This file contains Supplementary Sections 1–16 including Supplementary Figs. 1–28, Data and References—see Contents for details.

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Bu, F., Deng, Y., Xu, J. et al. Electrocatalytic reductive deuteration of arenes and heteroarenes. Nature 634, 592–599 (2024). https://doi.org/10.1038/s41586-024-07989-7

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