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Directing-group-free catalytic dicarbofunctionalization of unactivated alkenes

Nature Chemistry volume 14, pages 188–195 (2022)Cite this article

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An Author Correction to this article was published on 13 January 2022

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Abstract

In the absence of directing auxiliaries, the catalytic addition of carbogenic groups to unactivated alkenes with control of regioselectivity remains an ongoing challenge in organic chemistry. Here we describe a directing-group-free, nickel-catalysed strategy that couples a broad array of unactivated and activated olefins with aryl-substituted triflates and organometallic nucleophiles to afford diarylation adducts in either regioisomeric form, in up to 93% yield and >98% site selectivity. By switching the reagents involved, the present strategy may be extended to other classes of dicarbofunctionalization reactions. Mechanistic and computational investigations offer insights into the origin of the observed regiochemical outcome and the utility of the method is highlighted through the concise syntheses of biologically active molecules. The catalyst control principles reported are expected to advance efforts towards the development of general site-selective alkene functionalizations, removing the requirement for neighbouring activating groups.

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Fig. 1: The significance and challenges of designing a catalyst-controlled blueprint for olefin dicarbofunctionalization.
Fig. 2: Mechanistic rationale and reaction optimization.
Fig. 3: Mechanistic validation and application to complex molecule synthesis.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for compound 4i have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2069191. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This research was supported by the National University of Singapore Academic Research Fund Tier 1: R-143-000-B57-114 (M.J.K.) and by the National Institutes of Health R35GM137797 (O.G.). O.G. is grateful to the MARCC/BlueCrab HPC clusters and XSEDE (CHE160082 and CHE160053) for computational resources. We thank G. K. Tan for X-ray crystallographic analysis.

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Author notes

  1. These authors jointly supervised this work: Osvaldo Gutierrez, Ming Joo Koh.

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Hongyu Wang, Chen-Fei Liu & Ming Joo Koh

  2. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA

    Robert T. Martin & Osvaldo Gutierrez

  3. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Osvaldo Gutierrez

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  1. Hongyu Wang
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Contributions

H.W. and C.-F.L. synthesized the Ni-based complexes and developed the catalytic method. R.T.M. carried out the DFT calculations. O.G. directed the DFT studies. M.J.K. directed the investigations and wrote the manuscript with revisions provided by the other authors.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Ming Joo Koh.

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Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–8, Figs. 1–5, experimental data, synthesis and characterization data, NMR spectra, X-ray crystallographic data, DFT calculation data and references.

Supplementary Data 1

Crystallographic data for compound 4i; CCDC reference 2069191.

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Wang, H., Liu, CF., Martin, R.T. et al. Directing-group-free catalytic dicarbofunctionalization of unactivated alkenes. Nat. Chem. 14, 188–195 (2022). https://doi.org/10.1038/s41557-021-00836-6

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