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Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer

Nature volume 605, pages 477–482 (2022)Cite this article

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Abstract

For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π-electrons per olefin) cyclize to form two new C–C σ-bonds. Although the development of photochemical [2+2]-cycloadditions has made enormous progress within the last century, research has been focused on such [2π+2π]-systems, in which two π-bonds are converted into two new σ-bonds1,2. Here we report an intermolecular [2+2]-photocycloaddition that uses bicyclo[1.1.0]butanes as 2σ-electron reactants3,4,5,6,7. This strain-release-driven [2π+2σ]-photocycloaddition reaction was realized by visible-light-mediated triplet energy transfer catalysis8,9. A simple, modular and diastereoselective synthesis of bicyclo[2.1.1]hexanes from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of bicyclo[2.1.1]hexanes as bioisosteres—groups that convey similar biological properties to those they replace—in pharmaceutical research and considering their limited access10,11, there remains a need for new synthetic methodologies. Applying this strategy enabled us to extend the intermolecular [2+2]-photocycloadditions to σ-bonds and provides previously inaccessible structural motifs.

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Fig. 1: Background and motivation of the present work.
Fig. 2: Substrate scope and sensitivity assessment.
Fig. 3: Extended substrate scope and product diversification.
Fig. 4: Mechanistic studies.

Data availability

Crystallographic data are available free of charge under Cambridge Crystallographic Data Centre (CCDC) reference numbers 2145108 (3j), 2150704 (3k), 2120368 (3p), 2145107 (3x), 2120712 (3y), 2120369 (3af), 2120370 (3ak) and 2120371 (3al). All other data are available in the main text or Supplementary Information.

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Acknowledgements

We thank J.-H. Ye, J. L. Schwarz, F. Schäfers, A. Heusler, F. R. Schäfer and F. Strieth-Kalthoff for helpful discussions, and K. Bergander for the NMR analysis (all at WWU). We acknowledge Fonds der Chemischen Industrie (R.K., Kekulé Scholarship no. 106151) and Deutsche Forschungsgemeinschaft (Leibniz Award, SFB 858, ChemBion) for generous financial support. H.K. thanks S. Chang (KAIST) and the Institute for Basic Science (grant no. IBS-R010-D1) in the Republic of Korea for financial support.

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Author notes

  1. These authors contributed equally: Roman Kleinmans, Tobias Pinkert

Authors and Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Roman Kleinmans, Tobias Pinkert, Subhabrata Dutta, Tiffany O. Paulisch, Hyeyun Keum, Constantin G. Daniliuc & Frank Glorius

  2. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science, Daejeon, South Korea

    Hyeyun Keum

  3. Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, South Korea

    Hyeyun Keum

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Contributions

R.K., T.P. and F.G. conceived the project. Synthetic experiments were carried out by R.K., S.D., T.P. and H.K. T.O.P. performed the DFT calculations. C.G.D. analysed the crystal structures. The research was supervised by F.G. R.K., T.P. and F.G. wrote the manuscript with contributions from all other authors.

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Correspondence to Frank Glorius.

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Nature thanks Varinder Aggarwal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Sections 1–5, including General Information, Experimental Procedures and Characterization Data, Mechanistic Analysis, Supplementary References and Spectra Data—see Contents page for details.

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Kleinmans, R., Pinkert, T., Dutta, S. et al. Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer. Nature 605, 477–482 (2022). https://doi.org/10.1038/s41586-022-04636-x

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