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Cobaltaelectro-catalyzed C–H activation for resource-economical molecular syntheses

Nature Protocols volume 15, pages 1760–1774 (2020)Cite this article

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Abstract

The direct cleavage of otherwise inert C–H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C–H/N–H alkyne annulations and C–H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C–H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10–20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C–H activation protocols for the direct C–H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.

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Fig. 1
Fig. 2: Cobaltaelectrocatalysis.
Fig. 3: Design and dimensions of the reaction vessel cap.
Fig. 4: Preparation and assembly of the electrodes.
Fig. 5: Overview of the setup for cobaltaelectrocatalysis.
Fig. 6

Data availability

The authors declare that all data supporting the findings of this study are available within the article and previously published reports (https://doi.org/10.1021/jacs.7b11025 and https://doi.org/10.1002/anie.201712647). Additional data are available from the corresponding author on request.

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Acknowledgements

Generous support by the DFG (Gottfried-Wilhelm-Leibniz award) to L.A., the CSC (scholarship to C.T.) and the DAAD (fellowship to U.D.) is gratefully acknowledged.

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Author notes

  1. These authors contributed equally: Cong Tian, Tjark H. Meyer.

Authors and Affiliations

  1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany

    Cong Tian, Tjark H. Meyer, Maximilian Stangier, Uttam Dhawa, Karsten Rauch, Lars H. Finger & Lutz Ackermann

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  1. Cong Tian
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Contributions

C.T., T.H.M. and L.A. designed the experiments. C.T., M.S., T.H.M., U.D. and K.R. performed the experiments. C.T., T.H.M., M.S. and L.H.F. designed the device. C.T., M.S., T.H.M., U.D. and L.A. wrote the manuscript.

Corresponding author

Correspondence to Lutz Ackermann.

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The authors declare no competing interests.

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Peer review information Nature Protocols thanks Fengzhi Zhang and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Mei, R. et al. J. Am. Chem. Soc. 140, 7913–7921 (2018): https://doi.org/10.1021/jacs.8b03521

Meyer, T. H. et al. ACS Catal. 8, 9140–9147 (2018): https://doi.org/10.1021/acscatal.8b03066

Tian, C. et al. Angew. Chem. Int. Ed. 57, 2383–2387 (2018): https://doi.org/10.1002/anie.201712647

Sauermann, N. et al. J. Am. Chem. Soc. 139, 18452–18455 (2017): https://doi.org/10.1021/jacs.7b11025

Key data used in this protocol

Tian, C. et al. Angew. Chem. Int. Ed. 57, 2383–2387 (2018): https://doi.org/10.1002/anie.201712647

Sauermann, N. et al. J. Am. Chem. Soc. 139, 18452–18455 (2017): https://doi.org/10.1021/jacs.7b11025

Integrated supplementary information

Supplementary Fig. 1 Cyclic voltammograms at 100 mVs–1.

n-Bu4NPF6 (0.1 M in MeOH), concentration of substrates 1 mM (NaOPiv 4 mM). (black) blank; (red) substrate 1a; (blue) Co(OAc)2∙4H2O and NaOPiv; (green) Co(OAc)2∙4H2O, NaOPiv and 1a.

Supplementary Fig. 2 Cyclic voltammograms at 100 mVs–1.

n-Bu4NPF6 (0.1 M in MeCN), concentration of substrates 1 mM (NaOPiv 4 mM). (black) blank; (red) substrate 1a; (blue) Co(OAc)2∙4H2O and NaOPiv; (green) Co(OAc)2∙4H2O, NaOPiv and 1a; (purple) Co(OAc)2∙4H2O, NaOPiv, 1a and EtOH (1 mM); (orange) Co(OAc)2∙4H2O, NaOPiv and 1a and EtOH (2 mM); (magenta) Co(OAc)2∙4H2O, NaOPiv and 1a and EtOH (4 mM).

Supplementary Fig. 3

Proposed catalytic cycle for cobaltaelectro-catalyzed oxygenation.

Supplementary Fig. 4

Proposed catalytic cycle for cobaltaelectro-catalyzed annulation.

Supplementary Fig. 5

Technical drawing of the thermal reservoir.

Supplementary Fig. 6

Schlenk-type glass cell.

Supplementary Fig. 7 Parameter settings of the galvanostat.

a) Set the maximum output voltage with “V-Set” to 5.000 V; b) Set the output current with “I-Set” to 0.0040 A; c) Press the “output” button to start the electrolysis.

Supplementary Fig. 8

Cleaning of the platinum electrode.

Supplementary Fig. 9

Gram-scale cobaltaelectrocatalysis setup.

Supplementary Fig. 10

Cobaltaelectrocatalysis in ElectraSyn 2.0.

Supplementary information

Supplementary Information

Supplementary Figs. 1–10 and Supplementary Methods.

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Tian, C., Meyer, T.H., Stangier, M. et al. Cobaltaelectro-catalyzed C–H activation for resource-economical molecular syntheses. Nat Protoc 15, 1760–1774 (2020). https://doi.org/10.1038/s41596-020-0306-8

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