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Energy-transfer-induced [3+2] cycloadditions of N–N pyridinium ylides

Nature Chemistry volume 15, pages 1091–1099 (2023)Cite this article

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Abstract

Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N–N pyridinium ylides in the presence of a photosensitizer. The corresponding triplet diradical intermediates allow the stepwise radical [3+2] cycloaddition with a broad range of activated and unactivated alkenes under mild conditions. This method exhibits excellent efficiency, diastereoselectivity and functional group tolerance, providing a useful synthon for ortho-pyridyl γ- and δ-lactam scaffolds with syn-configuration in a single step. Combined experimental and computational studies reveal that the energy transfer process leads to a triplet-state diradical of N–N pyridinium ylides, which promotes the stepwise cycloaddition.

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Fig. 1: Design plan for EnT-driven [3+2] cycloadditions of N–N pyridinium ylides.
Fig. 2: Development of [3+2] cycloadditions of N–N pyridinium ylides via EnT-induced pathway.
Fig. 3: Mechanistic investigations.
Fig. 4: The proposed reaction mechanism and calculated energy diagram.

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Data availability

Experimental procedure and characterization data of new compounds are available within Supplementary Information. Computational details, optimized Cartesian coordinates of all structures, vibrational frequencies and energy components are also available within Supplementary Information. Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2214977 (2a), 2214980 (2y) and 2214981 (4n). 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 financially by the Institute for Basic Science (IBS-R010-A2). We thank D. Kim (IBS) for X-ray diffraction analysis.

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Authors and Affiliations

  1. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    Wooseok Lee, Yejin Koo, Hoimin Jung, Sukbok Chang & Sungwoo Hong

  2. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, Korea

    Wooseok Lee, Yejin Koo, Hoimin Jung, Sukbok Chang & Sungwoo Hong

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Contributions

Experiment, W.L., Y.K. and S.H.; computation, W.L. and H.J.; paper, W.L., Y.K., H.J., S.C. and S.H.

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Correspondence to Sungwoo Hong.

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Nature Chemistry thanks Bozhen Chen, Jia-Rong Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Fig. 1, Discussion and Tables 1–4.

Supplementary Data 1

Crystallographic data for compound 2a; CCDC 2214977.

Supplementary Data 2

Crystallographic data for compound 2y; CCDC 2214980.

Supplementary Data 3

Crystallographic data for compound 4n; CCDC 2214981.

Supplementary Data 4

Computational data for DFT calculations.

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Lee, W., Koo, Y., Jung, H. et al. Energy-transfer-induced [3+2] cycloadditions of N–N pyridinium ylides. Nat. Chem. 15, 1091–1099 (2023). https://doi.org/10.1038/s41557-023-01258-2

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