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Overcoming limitations in dual photoredox/nickel-catalysed C–N cross-couplings due to catalyst deactivation

Abstract

Dual photoredox/nickel-catalysed C–N cross-couplings suffer from low yields for electron-rich aryl halides. The formation of catalytically inactive nickel-black is responsible for this limitation and causes severe reproducibility issues. Here, we demonstrate that catalyst deactivation can be avoided by using a carbon nitride photocatalyst. The broad absorption of the heterogeneous photocatalyst enables wavelength-dependent control of the rate of reductive elimination to prevent nickel-black formation during the coupling of cyclic, secondary amines and aryl halides. A second approach, which is applicable to a broader set of electron-rich aryl halides, is to run the reactions at high concentrations to increase the rate of oxidative addition. Less nucleophilic, primary amines can be coupled with electron-rich aryl halides by stabilizing low-valent nickel intermediates with a suitable additive. The developed protocols enable reproducible, selective C–N cross-couplings of electron-rich aryl bromides and can also be applied for electron-poor aryl chlorides.

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Fig. 1: Nickel-catalysed C–N cross-coupling reactions.
Fig. 2: Catalyst deactivation during the reaction of 4-bromofluorobenzene with pyrrolidine.
Fig. 3: Evaluation of different coupling protocols.
Fig. 4: Reduction of catalyst deactivation using longer wavelengths.

Data availability

Experimental procedures and relevant material and compound characterization data are available in the Supplementary Information. Any other data are available from the authors on reasonable request.

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Acknowledgements

We acknowledge the Max Planck Society for generous financial support. S.G. and B.P. thank the International Max Planck Research School on Multiscale Bio-Systems for funding. B.P. and S.R. acknowledge financial support from a Liebig Fellowship of the German Chemical Industry Fund (Fonds der Chemischen Industrie, FCI). B.P. thanks the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC 2008 – 390540038 – UniSysCat) for financial support. We thank our colleagues P.H. Seeberger, J. Malik, K. Gilmore, T. Heil, D. Cruz, H. Runge, R. Pitschke, J. Brandt and K. ten Brummelhuis (all MPIKG) for scientific, technical and analytical support.

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B.P. conceived and directed the research study. B.P., S.G. and S.R. designed all experiments. S.G. performed all synthetic experiments. S.G. and S.R. carried out characterizations of materials and studies on nickel-black formation. S.G. and B.P. wrote the manuscript with contributions from S.R.

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Correspondence to Bartholomäus Pieber.

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The authors declare no competing interests.

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Supplementary Information

Supplementary Methods, Notes 1–9, Figs. 1–41, Tables 1–34 and references.

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Gisbertz, S., Reischauer, S. & Pieber, B. Overcoming limitations in dual photoredox/nickel-catalysed C–N cross-couplings due to catalyst deactivation. Nat Catal 3, 611–620 (2020). https://doi.org/10.1038/s41929-020-0473-6

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