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Congested C(sp3)-rich architectures enabled by iron-catalysed conjunctive alkylation

Nature Catalysis volume 7, pages 321–329 (2024)Cite this article

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Abstract

Catalytic cross-coupling by transition metals has revolutionized the formation of carbon–carbon bonds in organic synthesis. However, the challenge of forming multiple alkyl–alkyl bonds in crowded environments remains largely unresolved. Here we report the regioselective functionalization of olefins with sp3-hybridized organohalides and organozinc reagents using a simple (terpyridine)iron catalyst. Aliphatic groups of various sizes are successfully installed on either olefinic carbon, furnishing a diverse array of products with congested cores featuring carbon- or heteroatom-substituted stereocentres. The method enables access to valuable but synthetically challenging C(sp3)-rich molecules, including alicyclic compounds bearing multiple contiguous stereocentres, through annulation cascades. Mechanistic and theoretical studies suggest a stepwise iron-mediated radical carbometallation pathway followed by outer-sphere carbon–carbon bond formation, which potentially opens the door to a broader scope of transformations and new chemical space.

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Fig. 1: Development of an iron-catalysed strategy for conjunctive alkylation.
Fig. 2: Evaluation of reaction conditions (selected).
Fig. 3: Preliminary mechanistic investigations.
Fig. 4: Scope of olefins.
Fig. 5: Scope of dialkylation and synthetic utility.

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Data availability

DFT-optimized structures, relevant intrinsic reaction coordinate (IRC) and transition state movies and Mulliken spin population analysis files have been uploaded to zenodo.org (https://zenodo.org/records/8174459). All other data are available in the main text or the Supplementary Information, or from the authors upon reasonable request.

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Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 2 (A-8000034-00-00 (M.J.K.)), the Foundation of Wenzhou Science & Technology Bureau (ZY2020027 (T.-D.T. and P.-C.Q.)), the Institute of High Performance Computing and the Deputy Chief Executive Research Office (DCERO) A*STAR Career Development Fund (C210812008 (X.Z.)), the Manufacturing, Trade and Connectivity (MTC) Young Individual Research Grants (M22K3c0091 (X.Z.)) and the National Institutes of Health (GM129081 (P.L.H.)). X.Z. acknowledges the A*STAR Computational Resource Centre (A*CRC) of Singapore for the partial use of its high-performance computing facilities.

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Author notes

  1. These authors jointly supervised this work: Patrick L. Holland, Xinglong Zhang, Ming Joo Koh.

Authors and Affiliations

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

    Tong-De Tan, Xiaohua Luo & Ming Joo Koh

  2. Institute of New Materials & Industry Technology, College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, China

    Tong-De Tan & Peng-Cheng Qian

  3. Department of Chemistry, Yale University, New Haven, CT, USA

    Juan M. I. Serviano & Patrick L. Holland

  4. Institute of High-Performance Computing, Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore

    Xinglong Zhang

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Contributions

M.J.K. and T.-D.T. conceived the project. T.-D.T., X.L. and P.-C.Q. developed the catalytic method. J.M.I.S. and P.L.H. designed and performed the Mössbauer studies. X.Z. designed and performed the DFT studies. All authors contributed to the writing of the manuscript.

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Correspondence to Patrick L. Holland, Xinglong Zhang or Ming Joo Koh.

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Supplementary Tables 1–9, Figs. 1–43, Methods and References.

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Tan, TD., Serviano, J.M.I., Luo, X. et al. Congested C(sp3)-rich architectures enabled by iron-catalysed conjunctive alkylation. Nat Catal 7, 321–329 (2024). https://doi.org/10.1038/s41929-024-01113-8

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