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  • Review Article
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Ni-catalysed remote C(sp3)–H functionalization using chain-walking strategies

Nature Reviews Chemistry volume 8, pages 833–850 (2024)Cite this article

Subjects

Abstract

The dynamic translocation of a metal catalyst along an alkyl side chain — often coined as ‘chain-walking’ — has opened new retrosynthetic possibilities that enable functionalization at unactivated C(sp3)–H sites. The use of nickel complexes in chain-walking strategies has recently gained considerable momentum owing to their versatility for forging sp3 architectures and their redox promiscuity that facilitates both one-electron or two-electron reaction manifolds. This Review discusses the relevance and impact that these processes might have in synthetic endeavours, including mechanistic considerations when appropriate. Particular emphasis is given to the latest discoveries that leverage the potential of Ni-catalysed chain-walking scenarios for tackling transformations that would otherwise be difficult to accomplish, including the merger of chain-walking with other new approaches such as photoredox catalysis or electrochemical activation.

Key points

  • Iterative β-hydride elimination and migratory insertion (‘chain-walking’) can be an enabling vehicle for promoting functionalization at remote C(sp3)–H sites.

  • Site-selective C(sp3)–H functionalization can be performed through the exploitation of native molecular features (the binding ability of a functional group, thermodynamic stability, or kinetic availability of reaction intermediates).

  • Regiodivergent C(sp3)–H manipulation can be realized by fine-tuning of ligand structure, reaction conditions, or by the nature of an appended functional group.

  • Ni-catalysed chain-walking represents a novel, contemporary strategy to forge new C(sp3)–C(sp2) and C(sp3)–C(sp2) bonds.

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Fig. 1: Importance and challenges of C–H bond functionalization.
Fig. 2: Remote benzylic arylation.
Fig. 3: C–C and C–heteroatom bond formation at remote benzylic-allylic C(sp3)–H bonds.
Fig. 4: Remote functionalization at terminal C(sp3)–H sites.
Fig. 5: Remote functionalization adjacent to functional groups.
Fig. 6: Remote β-selective and γ-selective functionalization.
Fig. 7: Regiodivergent carboxylation and hydroalkylation.
Fig. 8: Miscellaneous regiodivergent functionalizations.
Fig. 9: Other miscellaneous regiodivergent functionalizations.

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Acknowledgements

The authors thank the Institute of Chemical Research of Catalonia (ICIQ) and FEDER (Fondo Europeo de Desarrollo Regional)/MCI (Ministerio Ciencia e Innovación) PID2021-123801NB-I00 for the financial support. The authors also sincerely thank all co-workers from the Martin laboratory at ICIQ, particularly those involved in Ni-catalysed reactions, for their invaluable intellectual and experimental contributions in the past years.

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Authors and Affiliations

  1. Department of Chemistry, University of Manchester, Manchester, UK

    Ciro Romano

  2. Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain

    Ciro Romano & Ruben Martin

  3. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

    Ruben Martin

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  1. Ciro Romano
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The authors contributed equally to all aspects of the article.

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Correspondence to Ciro Romano or Ruben Martin.

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Glossary

Metallacycle

A cyclic organometallic species containing a metal. In some cases, the specific metal may be named — as in nickelacycle.

Multivariate linear regression

(MLR). A statistical technique used to model the linear relationship between variables and predict the outcome when changing one of them.

Photoredox

A branch of photochemistry capable of converting visible light into chemical energy for enabling a series of chemical reactions under exceptionally mild conditions.

Redox-active ligands

Also frequently termed ‘redox non-innocent ligands’, these are molecules able to coordinate a transition metal and change its oxidation state by accepting (donating) one electron from (to) the metal.

Site-selectivity

Selectivity towards specific positions within the molecular structure.

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Romano, C., Martin, R. Ni-catalysed remote C(sp3)–H functionalization using chain-walking strategies. Nat Rev Chem 8, 833–850 (2024). https://doi.org/10.1038/s41570-024-00649-4

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