Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.


  1. Poplata, S., Tröster, A., Zou, Y.-Q. & Bach, T. Recent advances in the synthesis of cyclobutanes by olefin [2+2] photocycloaddition reactions. Chem. Rev. 116, 9748–9815 (2016).

    Article  CAS  Google Scholar 

  2. Sarkar, D., Bera, N. & Ghosh, S. [2+2] Photochemical cycloaddition in organic synthesis. Eur. J. Org. Chem. 2020, 1310–1326 (2020).

    Article  CAS  Google Scholar 

  3. Fawcett, A., Biberger, T. & Aggarwal, V. K. Carbopalladation of C–C σ-bonds enabled by strained boronate complexes. Nat. Chem. 11, 117–122 (2019).

    Article  CAS  Google Scholar 

  4. Silvi, M. & Aggarwal, V. K. Radical addition to strained σ-bonds enables the stereocontrolled synthesis of cyclobutyl boronic esters. J. Am. Chem. Soc. 141, 9511–9515 (2019).

    Article  CAS  Google Scholar 

  5. Ociepa, M., Wierzba, A. J., Turkowska, J. & Gryko, D. Polarity-reversal strategy for the functionalization of electrophilic strained molecules via light-driven cobalt catalysis. J. Am. Chem. Soc. 142, 5355–5361 (2020).

    Article  CAS  Google Scholar 

  6. Ernouf, G., Chirkin, E., Rhyman, L., Ramasami, P. & Cintrat, J. Photochemical strain‐release‐driven cyclobutylation of C(sp3)‐centered radicals. Angew. Chem. Int. Ed. 59, 2618–2622 (2020).

    Article  CAS  Google Scholar 

  7. Bennett, S. H. et al. Difunctionalization of C–C σ-bonds enabled by the reaction of bicyclo[1.1.0]butyl boronate complexes with electrophiles: reaction development, scope, and stereochemical origins. J. Am. Chem. Soc. 142, 16766–16775 (2020).

    Article  CAS  Google Scholar 

  8. Strieth-Kalthoff, F., James, M. J., Teders, M., Pitzer, L. & Glorius, F. Energy transfer catalysis mediated by visible light: principles, applications, directions. Chem. Soc. Rev. 47, 7190–7202 (2018).

    Article  CAS  Google Scholar 

  9. Strieth-Kalthoff, F. & Glorius, F. Triplet energy transfer photocatalysis: unlocking the next level. Chem 6, 1888–1903 (2020).

    Article  CAS  Google Scholar 

  10. Denisenko, A., Garbuz, P., Shishkina, S. V., Voloshchuk, N. M. & Mykhailiuk, P. K. Saturated bioisosteres of ortho‐substituted benzenes. Angew. Chem. Int. Ed. 59, 20515–20521 (2020).

    Article  CAS  Google Scholar 

  11. Yang, Y. et al. An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates. Nat. Chem. 13, 950–955 (2021).

    Article  CAS  Google Scholar 

  12. Trost, B. M. The atom economy—a search for synthetic efficiency. Science 254, 1471–1477 (1991).

    Article  CAS  ADS  Google Scholar 

  13. Liebermann, C. Ueber polythymochinon. Ber. Dtsch. Chem. Ges. 10, 2177–2179 (1877).

    Article  Google Scholar 

  14. Ciamician, G. & Silber, P. Chemische lichtwirkungen. Ber. Dtsch. Chem. Ges. 41, 1928–1935 (1908).

    Article  CAS  Google Scholar 

  15. Schenck, G. O., Hartmann, W., Mannsfeld, S.-P., Metzner, W. & Krauch, C. H. Vierringsynthesen durch photosensibilisierte symmetrische und gemischte cyclo-additionen. Chem. Ber. 95, 1642–1647 (1962).

    Article  CAS  Google Scholar 

  16. Eaton, P. E. On the mechanism of the photodimerization of cyclopentenone. J. Am. Chem. Soc. 84, 2454–2455 (1962).

    Article  CAS  Google Scholar 

  17. Tolbert, L. M. & Ali, M. B. High optical yields in a photochemical cycloaddition. Lack of cooperativity as a clue to mechanism. J. Am. Chem. Soc. 104, 1742–1744 (1982).

    Article  CAS  Google Scholar 

  18. Bach, T. Stereoselective intermolecular [2+2]-photocycloaddition reactions and their application in synthesis. Synthesis 1998, 683–703 (1998).

  19. Blum, T. R., Miller, Z. D., Bates, D. M., Guzei, I. A. & Yoon, T. P. Enantioselective photochemistry through Lewis acid–catalyzed triplet energy transfer. Science 354, 1391–1395 (2016).

    Article  CAS  ADS  Google Scholar 

  20. Tröster, A., Alonso, R., Bauer, A. & Bach, T. Enantioselective intermolecular [2+2] photocycloaddition reactions of 2(1H)-quinolones induced by visible light irradiation. J. Am. Chem. Soc. 138, 7808–7811 (2016).

    Article  Google Scholar 

  21. Oderinde, M. S. et al. Photocatalytic dearomative intermolecular [2+2] cycloaddition of heterocycles for building molecular complexity. J. Org. Chem. 86, 1730–1747 (2021).

    Article  CAS  Google Scholar 

  22. Murray, P. R. D. et al. Intermolecular crossed [2+2] cycloaddition promoted by visible-light triplet photosensitization: expedient access to polysubstituted 2-oxaspiro[3.3]heptanes. J. Am. Chem. Soc. 143, 4055–4063 (2021).

    Article  CAS  Google Scholar 

  23. Prinzbach, H., Eberbach, W. & von Veh, G. Photochemical isomerization of the tricyclo[3,2,1,02,4]octene system – a homovinylcyclopropane system. Angew. Chem. Int. Ed. 4, 436–437 (1965).

    Article  Google Scholar 

  24. Prinzbach, H. & Klaus, M. Photochemical olefin‐oxirane cyclodimerization. Angew. Chem. Int. Ed. 8, 276–278 (1969).

    Article  CAS  Google Scholar 

  25. Klaus, M. & Prinzbach, H. Photochemical olefin-aziridine cycloaddition. Angew. Chem. Int. Ed. 10, 273–274 (1971).

    Article  CAS  Google Scholar 

  26. Turkowska, J., Durka, J. & Gryko, D. Strain release – an old tool for new transformations. Chem. Commun. 56, 5718–5734 (2020).

    Article  CAS  Google Scholar 

  27. Gianatassio, R. et al. Strain-release amination. Science 351, 241–246 (2016).

    Article  CAS  ADS  Google Scholar 

  28. Cairncross, A. & Blanchard, E. P. Bicyclo[1.1.0]butane chemistry. II. Cycloaddition reactions of 3-methylbicyclo[1.1.0]butanecarbonitriles. The formation of bicyclo[2.1.1]hexanes. J. Am. Chem. Soc. 88, 496–504 (1966).

    Article  CAS  Google Scholar 

  29. Gassman, P. G. Thermal addition of carbon-carbon multiple bonds to strained carbocyclics. Acc. Chem. Res. 4, 128–136 (1971).

    Article  CAS  Google Scholar 

  30. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  31. Mykhailiuk, P. K. Saturated bioisosteres of benzene: where to go next? Org. Biomol. Chem. 17, 2839–2849 (2019).

    Article  CAS  Google Scholar 

  32. Wolff, T. & Görner, H. Photodimerization of coumarin revisited: effects of solvent polarity on the triplet reactivity and product pattern. Phys. Chem. Chem. Phys. 6, 368–376 (2004).

    Article  CAS  Google Scholar 

  33. Nikitas, N. F., Gkizis, P. L. & Kokotos, C. G. Thioxanthone: a powerful photocatalyst for organic reactions. Org. Biomol. Chem. 19, 5237–5253 (2021).

    Article  CAS  Google Scholar 

  34. Guo, L., Noble, A. & Aggarwal, V. K. α‐Selective ring‐opening reactions of bicyclo[1.1.0]butyl boronic ester with nucleophiles. Angew. Chem. Int. Ed. 60, 212–216 (2021).

    Article  CAS  Google Scholar 

  35. Pitzer, L., Schäfers, F. & Glorius, F. Rapid Assessment of the reaction‐condition‐based sensitivity of chemical transformations. Angew. Chem. Int. Ed. 58, 8572–8576 (2019).

    Article  CAS  Google Scholar 

  36. Lefarth, J., Neudörfl, J. & Griesbeck, A. G. 9a-Phenyl-2,3,3a,3b,9a,9b-hexahydro-4H-furo[3’,2’:3,4]cyclobuta- [1,2-b]chromen-4-one: a flavone-based [2+2]-photocycloadduct. Molbank 2021, M1256 (2021).

    Article  Google Scholar 

  37. Dhake, K. et al. Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes. Angew. Chem. Int. Ed. e202204719 (2022).

  38. Levterov, V. V. et al. Photochemical in-flow synthesis of 2,4-methanopyrrolidines: pyrrolidine analogues with improved water solubility and reduced lipophilicity. J. Org. Chem. 83, 14350–14361 (2018).

    Article  CAS  Google Scholar 

  39. Becker, M. R., Wearing, E. R. & Schindler, C. S. Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions. Nat. Chem. 12, 898–905 (2020).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Frank Glorius.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kleinmans, R., Pinkert, T., Dutta, S. et al. Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer. Nature 605, 477–482 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing