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Aryl halide cross-coupling via formate-mediated transfer hydrogenation

Nature Chemistry volume 17, pages 710–718 (2025)Cite this article

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Abstract

Transfer hydrogenation is widely practised across all segments of chemical industry, yet its application to aryl halide reductive cross-coupling is undeveloped because of competing hydrogenolysis. Here, exploiting the distinct reactivity of PdI species, an efficient catalytic system for the reductive cross-coupling of activated aryl bromides with aryl iodides via formate-mediated hydrogen transfer is described. These processes display orthogonality with respect to Suzuki and Buchwald–Hartwig couplings, as pinacol boronates and anilines are tolerated and, owing to the intervention of chelated intermediates, are effective for challenging 2-pyridyl systems. Experimental and computational studies corroborate a unique catalytic cycle for reductive cross-coupling where the PdI precatalyst, [Pd(I)(PtBu3)]2, is converted to the dianionic species, [Pd2I4][NBu4]2, from which aryl halide oxidative addition is more facile. Rapid, reversible Pd-to-Pd transmetallation delivers mixtures of iodide-bridged homo- and hetero-diarylpalladium dimers. The hetero-diarylpalladium dimers are more stable and have lower barriers to reductive elimination, promoting high levels of cross-selectivity.

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Fig. 1: Overview of reductive cross-couplings of aryl halides and optimization of the formate-mediated process.
Fig. 2: Experiments corroborating [Pd2I4][NBu4]2 as the active catalyst.
Fig. 3: Computational and experimental studies of oxidative addition and intermolecular transmetallation.
Fig. 4: Computed reaction energy profiles of intramolecular transmetallation and reductive elimination.
Fig. 5: General mechanism of formate-mediated cross-electrophile reductive coupling catalysed by [Pd2I4][NBu4]2.

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Data availability

All data relating to materials and methods, experimental procedures, mechanistic studies, characterization data for all new compounds (1H NMR, 13C NMR, 19F NMR, 31P NMR, IR and HRMS), computational details and additional computational results are available in the Supplementary Information. Crystallographic data for [Pd2I6][NBu4]2 have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number 2380764. Copies of data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

The Robert A. Welch Foundation (F-0038) and the National Institutes of Health (NIH)-National Institute of General Medical Sciences (NIGMS) (RO1-GM069445 and R35 GM128779) are acknowledged for partial support of this research. Genentech is acknowledged for summer predoctoral internship support (Y.C.). N.S.T. is supported in part by the NIH-NIGMS (R35GM-133566). Instrumentation for the University of Minnesota (UMN) Chemistry NMR facility was supported from a grant through the NIH (S10OD011952) and the UMN Department of Chemistry Mass Spectrometry Laboratory is supported by the Office of the Vice President for Research, College of Science and Engineering and the Department of Chemistry at UMN, as well as the National Science Foundation (NSF) (CHE-1336940). X-ray diffraction experiments were performed by A. Lovstedt and G. Murphy with a diffractometer purchased through a grant from NSF/MRI (1229400) and the UMN. DFT calculations were carried out at the University of Pittsburgh Center for Research Computing and the Advanced Cyberinfrastructure Co-ordination Ecosystem: Services and Support (ACCESS) programme, supported by NSF award numbers OAC-2117681, OAC-1928147 and OAC-1928224. We thank M. Huestis, M. Ashley and C. Stivala for helpful scientific discussions.

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  1. These authors contributed equally: Yoon Cho, Yu-Hsiang Chang, Kevin P. Quirion, Zachary H. Strong.

Authors and Affiliations

  1. Department of Chemistry, University of Texas at Austin, Austin, TX, USA

    Yoon Cho, Yu-Hsiang Chang, Zachary H. Strong, Zachary J. Dubey, Seoyoung Lee & Michael J. Krische

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Kevin P. Quirion & Peng Liu

  3. Department of Synthetic Molecule Process Chemistry, Genentech, South San Francisco, CA, USA

    Nam Nguyen & Nicholas A. White

  4. Department of Chemistry, University of Minnesota-Twin Cities, Minneapolis, MN, USA

    Natalie S. Taylor & Jessica M. Hoover

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Contributions

Y.C., Y.-H.C., Z.J.D. and S.L. designed the project under the guidance of N.A.W. and M.J.K. Y.C., Y.-H.C., Z.H.S., Z.J.D. and S.L. carried out experimental work and mechanistic studies notwithstanding Supplementary Information section XI. K.P.Q. performed calculations under the guidance of P.L. N.S.T. carried out mechanistic studies described in Supplementary Information section XI under the guidance of J.M.H. N.N. performed the HTE experiments. P.L. and M.J.K. composed the manuscript with input from all authors.

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Correspondence to Jessica M. Hoover, Nicholas A. White, Peng Liu or Michael J. Krische.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–11, detailed experimental procedures, optimization, characterization and computational data.

Supplementary Data 1

Crystallographic data for compound [Pd2I6][NBu4]2; CCDC reference 2380764.

Supplementary Data 2

Cartesian coordinates raw file for all computations.

Supplementary Data 3

Checkcif file for [Pd2I6][NBu4]2.

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Cho, Y., Chang, YH., Quirion, K.P. et al. Aryl halide cross-coupling via formate-mediated transfer hydrogenation. Nat. Chem. 17, 710–718 (2025). https://doi.org/10.1038/s41557-024-01729-0

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