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Hydrogenative alkene perdeuteration aided by a transient cooperative ligand

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Abstract

Deuterogenation of unsaturated organic compounds is an attractive route for installing C(sp3)−D bonds, but the existing methods typically use expensive D2 and introduce only two deuterium atoms per unsaturation. Herein we report the hydrogenative perdeuteration of alkenes using readily available H2 and D2O instead of D2, catalysed by an acridanide-based ruthenium pincer complex and resulting in the incorporation of up to 4.9 D atoms per C=C double bond in a single synthetic step. Importantly, adding a catalytic amount of thiol, which serves as a transient cooperative ligand, ensures the incorporation of deuterium rather than protium by balancing the rates of two sequential deuteration processes. The current method opens an avenue for installing perdeuteroalkyl groups at specific sites from widely available alkenes under mild conditions.

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Fig. 1: Deuterated drugs and hydrogenative perdeuteration of C=C bonds.
Fig. 2: Deuteration of H2 with D2O catalysed by Ru-1.
Fig. 3: Establishment of reaction conditions for hydrogenative perdeuteration and mechanistic studies.

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Supplementary Notes, synthetic procedures, NMR spectra, gas chromatography traces, characterization data and computational details are available within this Article and its Supplementary Information.

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Acknowledgements

J.L. thanks the Feinberg Graduate School (FGS) of the Weizmann Institute of Science for a Senior Postdoctoral Fellowship. L.L. thanks the FGS for a Dean Excellence Postdoctoral Fellowship. We thank M. Rauch for help with the computational work.

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Authors and Affiliations

  1. Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot, Israel

    Jie Luo, Lijun Lu, Michael Montag, Yaoyu Liang & David Milstein

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Contributions

D.M. and J.L. conceived and directed the project and designed the experiments. J.L. performed and analysed the majority of experiments. L.L. and Y.L. performed selected experiments. L.L. and M.M. provided insightful discussions. All authors were involved in manuscript preparation.

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Correspondence to David Milstein.

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Nature Chemistry thanks Wen-Guang Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Proposed catalytic cycles for deuteration of H2 with D2O promoted by Ru-1.

Based on our previous work (ref. 22), the catalytically active form of Ru-1 (species I) most likely exhibits a facially-coordinated pincer ligand (fac). For each of the above reactions, reactants and products are only shown for the forward direction, to enhance clarity.

Extended Data Fig. 2 Kinetic profile of H/D exchange between H2 and D2O in the presence of thiol.

Progress of the deuterium labeling reaction in the presence of varying amounts of thiol, as represented by the amount of protium incorporated into D2O.

Extended Data Fig. 3 Additional control experiments.

a,b, Deuteration attempts in the absence of H2 (see Supplementary Fig. 97); the incomplete deuteration in D-1a may be due to consumption of the ruthenium-hydride complex without regeneration. c,d, Deuterogenation with D2 in a 30 mL (c) and 220 mL (d) reactor; the improvement in the deuterium content of D-2a indicates that the reaction is affected by the amount of D2, which can be explained by the theoretical D content of the system (considering 1.5 mmol of H atoms in 1a; see Supplementary Note 3). e, Deuterogenation with D2 in a 220 mL reactor in the absence of thiol; the results indicate direct exchange between D2 and Ru-1. f, Hydrogenative perdeuteration of 1a; although only 0.6 mmol of H2 was employed, the thiol ensured fast and continuous transfer of deuterium from D2O (55 mmol) to both H2 and the alkene C − H bonds.

Extended Data Fig. 4 Screening of catalytic reactions for alkene perdeuteration.

a, Screening of different thiols. Various thiol TCLs exert different effects on the H/D exchange between D2O and H2, as well as alkene perdeuteration, due to differences in their electronic and steric properties. Consequently, different thiols lead to varying deuteration results, with cyHexSH providing the best result of all examined thiols. b, Compatibility of the catalytic system with different functional groups that are frequently found in bioactive molecules and pharmaceuticals (active protons were not taken into consideration in evaluating additive recovery). Some strongly-coordinating N-donors, that is, benzylamine, pyridine and phenylpropionitrile, showed detrimental effects, but even in these cases good product yields were obtained (71%–83%), and deuterium incorporation remained high. Among the studied additives, only benzoic acid completely halted the catalytic activity. This may be due to deactivation of the catalyst by formation of a stable ruthenium-carboxylate species, as has been previously observed (ref. 25). c, Optimization of catalytic conditions.

Supplementary information

Supplementary Information

Supplementary Figs. 1–107, Notes 1–5 and Tables 1 and 2.

Supplementary Data 1

Computational data including xyz coordinates.

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Luo, J., Lu, L., Montag, M. et al. Hydrogenative alkene perdeuteration aided by a transient cooperative ligand. Nat. Chem. 15, 1384–1390 (2023). https://doi.org/10.1038/s41557-023-01313-y

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