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Transition metal-catalysed directed C–H functionalization with nucleophiles

Nature Synthesis volume 1, pages 841–853 (2022)Cite this article

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Abstract

The quest for sustainable ways to introduce diverse functional groups onto complex scaffolds has made directed transition metal-catalysed C–H functionalization reactions a main thrust within synthetic organic chemistry. These methodologies offer appealing opportunities to construct carbon–carbon and carbon–heteroatom bonds by using a wide array of coupling partners. Strikingly, organometallic and X-based (X = N, O and S) nucleophiles, which are key reagents in cross-coupling reactions, remain underexploited in these transformations. However, as a result of fine-tuning the reaction conditions and a better understanding of the underlying mechanisms, these reagents were recently incorporated into the synthetic toolkit of C–H functionalizations. This Review outlines a selection of recent advances in nucleophilic C–C and C–heteroatom bond-forming reactions via directed C–H activation. We focus on catalytic approaches that involve organometallic nucleophiles and X-based (X = N, O and S) coupling partners and describe how the field has evolved towards innovative strategies that enhance the applicability and versatility of these transformations. In addition, we highlight synthetic challenges that remain unsolved and that could open exciting venues within this area.

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Fig. 1: Evolution of site-selective TM catalysis: from cross-coupling to nucleophilic directed C–H functionalization.
Fig. 2: Pd-catalysed C–H functionalization with boronic acid derivatives.
Fig. 3: Pd-catalysed enantioselective C–H functionalization reactions with alkyl and arylboron reagents using chiral ligands.
Fig. 4: Alternative approaches for TM-catalysed C–H activation and/or C–C couplings.
Fig. 5: Intramolecular oxidative CDC.
Fig. 6: Intermolecular C–H activation and C–N bond-forming reactions.
Fig. 7: TM-catalysed nucleophilic C–H activation and C–O and C–S bond-forming reactions.

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Acknowledgements

This work was supported by ICIQ, CERCA Programme/Generalitat de Catalunya and the Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MICINN/AEI/Severo Ochoa Excellence Accreditation 2023—CEX2019-000925-S; grant no. PID2020-112733GB-I00). S.B. thanks the Ministerio de Universidades for the FPU predoctoral contract (FPU20/00610). J.Z. thanks the China Scholarship Council for the predoctoral fellowship. S.L.-R. thanks the Generalitat de Catalunya for the FI–Agaur predoctoral contract. A.C. is grateful for the MSCA-COFUND postdoctoral fellowship granted by I2-ICIQ Impulsion Programme (GA 801474).

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Authors and Affiliations

  1. Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona, Spain

    Sergio Barranco, Jiayu Zhang, Sara López-Resano, Alessandra Casnati & Mónica H. Pérez-Temprano

  2. Departament de Química Analítica i Química Orgánica. Universitat Rovira i Virgili, Tarragona, Spain

    Sergio Barranco, Jiayu Zhang & Sara López-Resano

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  1. Sergio Barranco
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Contributions

S.B., J.Z., S.L.-R. and A.C. contributed to the literature search, the writing of the article and the preparation of the figures. M.H.P.-T. contributed to the literature search and editing of the manuscript, coordinated the project and supervised the writing.

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Correspondence to Mónica H. Pérez-Temprano.

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Nature Synthesis thanks Debabrata Maiti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Stoddart, in collaboration with the Nature Synthesis team.

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Barranco, S., Zhang, J., López-Resano, S. et al. Transition metal-catalysed directed C–H functionalization with nucleophiles. Nat. Synth 1, 841–853 (2022). https://doi.org/10.1038/s44160-022-00180-8

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