Skip to main content

Thank you for visiting nature.com. 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:

σ-Bond insertion reactions of two strained diradicaloids

Nature volume 640, pages 683–690 (2025)Cite this article

Subjects

Abstract

The development of new synthetic methodologies is instrumental for enabling the discovery of new medicines. The methods that provide efficient access to structural alternatives for aromatic compounds (that is, saturated arene bioisosteres) have become highly coveted1,2,3,4. The incorporation of these bioisosteres typically leads to favourable drug-like properties and represents an emerging field of research. Here we report a new synthetic method that furnishes a coveted motif, the bicyclo[2.1.1]hexane scaffold5,6, using mild reaction conditions and an operationally simple protocol. The methodology proceeds through the uncommon coupling of two strained fragments: transiently generated cyclic allenes and bicyclo[1.1.0]butanes, which possess considerable strain energies of about 30 kcal mol−1 (ref. 7) and about 60 kcal mol−1 (ref. 6), respectively. The reaction is thought to proceed by a σ-bond insertion through a diradical pathway. However, rather than requiring an external stimulus to generate radical species, reactivity is thought to arise as a result of innate diradical character present in each reactant. This diradicaloid character8, an underused parameter in reaction design, arises from the severe geometric distortions of each reactant. Our studies provide a means to access functionalized bicyclo[2.1.1]hexanes of value for drug discovery, underscore how geometric distortion of reactants can be used to enable uncommon modes of reactivity and should encourage the further exploration and strategic use of diradicaloids in chemical synthesis.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Background and overview.
Fig. 2: Geometric distortions and reaction parameters.
Fig. 3: Scope of trapping reactions with carbocyclic allene 14 and BCBs 10.
Fig. 4: Reactions of substituted or heterocyclic allenes with disubstituted BCB 18.
Fig. 5: Analysis of diradical character and reactivity.

Similar content being viewed by others

Data availability

Experimental procedures, characterization data, computational methods and computational data are provided in the Supplementary Information.

References

  1. Tsien, J., Hu, C., Merchant, R. R. & Qin, T. Three-dimensional saturated C(sp3)-rich bioisosteres for benzene. Nat. Rev. Chem. 8, 605–627 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Denisenko, A. et al. 1,2-disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene. Chem. Sci. 14, 14092–14099 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Subbaiah, M. A. M. & Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 64, 14046–14128 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Lazzara, P. R. & Moore, T. W. Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds. RSC Med. Chem. 11, 18–29 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Golfmann, M. & Walker, J. C. L. Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis. Commun. Chem. 6, 9 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kelly, C. B., Milligan, J. A., Tilley, L. J. & Sodano, T. M. Bicyclobutanes: from curiosities to versatile reagents and covalent warheads. Chem. Sci. 13, 11721–11737 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Johnson, R. P. Strained cyclic cumulenes. Chem. Rev. 89, 1111–1124 (1989).

    Article  CAS  Google Scholar 

  8. Stuyver, T. et al. Do diradicals behave like radicals? Chem. Rev. 119, 11291–11351 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Buskes, M. J. & Blanco, M.-J. Impact of cross-coupling reactions in drug discovery and development. Molecules 25, 3493 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Magano, J. & Dunetz, J. R. Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem. Rev. 111, 2177–2250 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Oehlrich, D. et al. 4-Alkoxy-6-oxo-pyridazine derivatives modulating NLRP3 and their preparation. US patent WO2022184843A1 (2009).

  12. Liu, Y. et al. Pyridine-boryl radical-catalyzed [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with alkenes. ACS Catal. 13, 5096–5103 (2023).

    Article  CAS  Google Scholar 

  13. Guo, R. et al. Strain-release [2π + 2σ] cycloadditions for the synthesis of bicyclo[2.1.1]hexanes initiated by energy transfer. J. Am. Chem. Soc. 144, 7988–7994 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ni, D. et al. Intermolecular formal cycloaddition of indoles with bicyclo[1.1.0]butanes by Lewis Acid Catalysis. Angew. Chem. Int. Ed. 62, e202308606 (2023).

    Article  CAS  Google Scholar 

  15. Tang, L. et al. Silver‐catalyzed dearomative [2π+2σ] cycloadditions of indoles with bicyclobutanes: Access to Indoline fused bicyclo[2.1.1]hexanes. Angew. Chem. Int. Ed. 135, e202310066 (2023).

    Article  Google Scholar 

  16. Dutta, S. et al. Double strain-release [2π+2σ]-photocycloaddition. J. Am. Chem. Soc. 146, 5232–5241 (2024).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Kleinmans, R. et al. ortho-Selective dearomative [2π + 2σ] photocycloadditions of bicyclic aza-arenes. J. Am. Chem. Soc. 145, 12324–12332 (2023).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, H. et al. Dearomative ring expansion of thiophenes by bicyclobutane insertion. Science 381, 75–81 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Wang, J.-J. et al. Switching between the [2π+2σ] and hetero‐[4π+2σ] cycloaddition reactivity of bicyclobutanes with Lewis acid catalysts enables the synthesis of spirocycles and bridged heterocycles. Angew. Chem. Int. Ed. 63, e202405222 (2024).

    Article  CAS  Google Scholar 

  21. Yan, H., Liu, Y., Feng, X. & Shi, L. Hantzsch esters enabled [2π+2σ] cycloadditions of bicyclo [1.1.0] butanes and alkenes under photo conditions. Org. Lett. 25, 8116–8120 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Agasti, S. et al. A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres. Nat. Chem. 15, 535–541 (2023).

    Article  CAS  PubMed  Google Scholar 

  23. Meijere, A.De et al. Cycloadditions of methylenecyclopropanes and strained bicyclo[n.1.0]alkanes to radicophilic olefins. Tetrahedron 42, 1291–1297 (1986).

    Article  Google Scholar 

  24. Dutta, S. et al. Photoredox-enabled dearomative [2π + 2σ] cycloaddition of phenols. J. Am. Chem. Soc. 146, 2789–2797 (2024).

    Article  CAS  PubMed  Google Scholar 

  25. Wittig, G. & Fritze, P. On the intermediate occurrence of 1,2-cyclohexadiene. Angew. Chem. Int. Ed. 5, 846 (1966).

    Article  Google Scholar 

  26. Moser, W. R. The Reactions of gem-Dihalocyclopropanes with Organometallic Reagents. PhD dissertation, Massachusetts Institute of Technology (1964).

  27. Shi, J., Li, L. & Li, Y. o-Silylaryl triflates: a journey of Kobayashi aryne precursors. Chem. Rev. 121, 3892–4044 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Roberts, C. C. Strained allenes for heterocycle difunctionalization. Nat. Synth. 3, 286–287 (2024).

    Article  ADS  CAS  Google Scholar 

  30. Wang, B. et al. Generation and trapping of electron-deficient 1,2-cyclohexadienes. Unexpected hetero-Diels–Alder reactivity. Org. Biomol. Chem. 19, 399–405 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Lofstrand, V. A., McIntosh, K. C., Almehmadi, Y. A. & West, F. G. Strain-activated Diels–Alder trapping of 1,2-cyclohexadienes: intramolecular capture by pendent furans. Org. Lett. 21, 6231–6234 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Lofstrand, V. A. & West, F. G. Efficient trapping of 1,2‐cyclohexadienes with 1,3‐dipoles. Chem. Eur. J. 22, 10763–10767 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Kelleghan, A. V., Tena Meza, A. & Garg, N. K. Generation and reactivity of unsymmetrical strained heterocyclic allenes. Nat. Synth. 3, 329–336 (2024).

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Yamano, M. M. et al. Intercepting fleeting cyclic allenes with asymmetric nickel catalysis. Nature 586, 242–247 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. McVeigh, M. S., Sorrentino, J. P., Hands, A. T. & Garg, N. K. Access to complex scaffolds through [2 + 2] cycloadditions of strained cyclic allenes. J. Am. Chem. Soc. 146, 15420–15427 (2024).

    Article  CAS  PubMed  Google Scholar 

  36. Westphal, M. V. et al. Water-compatible cycloadditions of oligonucleotide-conjugated strained allenes for DNA-encoded library synthesis. J. Am. Chem. Soc. 142, 7776–7782 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ippoliti, F. M. et al. Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene. Science 379, 261–265 (2023).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pomerantz, M., Gruber, G. W. & Wilke, R. N. Electronic structure and reactivity of small-ring compounds. III. mechanistic studies of the bicyclobutane-benzyne reaction. J. Am. Chem. Soc. 90, 5040–5041 (1968).

    Article  CAS  Google Scholar 

  39. Pomerantz, M., Wilke, R. N., Gruber, G. W. & Roy, U. Electronic structure and reactivity of small ring compounds. V. reaction of some bicyclobutanes with various dienophiles. J. Am. Chem. Soc. 94, 2752–2758 (1972).

    Article  CAS  Google Scholar 

  40. Dasgupta, A. et al. Stereoselective Alder-ene reactions of bicyclo[1.1.0]butanes: facile synthesis of cyclopropyl- and aryl-substituted cyclobutenes. J. Am. Chem. Soc. 146, 1196–1203 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Borden, W. T. Pyramidalized alkenes. Chem. Rev. 89, 1095–1109 (1989).

    Article  CAS  Google Scholar 

  42. Vázquez, S. & Camps, P. Chemistry of pyramidalized alkenes. Tetrahedron 61, 5147–5208 (2005).

    Article  Google Scholar 

  43. Haddon, R. C. Comment on the relationship of the pyramidalization angle at a conjugated carbon atom to the σ bond angles. J. Phys. Chem. A 105, 4164–4165 (2001).

    Article  CAS  Google Scholar 

  44. Sterling, A. J., Smith, R. C., Anderson, E. A. & Duarte, F. Beyond strain release: delocalization-enabled organic reactivity. J. Org. Chem. 89, 9979–9989 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Carpino, L. A. & Sau, A. C. Convenient source of ‘naked’ fluoride: tetra-n-butylammonium chloride and potassium fluoride dihydrate. J. Chem. Soc., Chem. Commun. 1979, 514–515 (1979).

    Article  Google Scholar 

  46. Garwood, J. J. A., Chen, A. D. & Nagib, D. A. Radical polarity. J. Am. Chem. Soc. 146, 28034–28059 (2024).

    CAS  Google Scholar 

  47. McVeigh, M. S. & Garg, N. K. Interception of 1,2-cyclohexadiene with TEMPO radical. Tetrahedron Lett. 87, 153539–153543 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Braslavsky, S. E. Glossary of terms used in Photochemistry, 3rd edition (IUPAC recommendations 2006). Pure Appl. Chem. 79, 293–465 (2007).

    Article  CAS  Google Scholar 

  49. Wu, J. Diradicaloids (Jenny Stanford, 2022).

  50. Dewar, M. J. S., Ford, G. P., McKee, M. L., Rzepa, H. S. & Wade, L. E. The Cope rearrangement. MINDO/3 studies of the rearrangements of 1,5-hexadiene and bicyclo[2.2.0]hexane. J. Am. Chem. Soc. 99, 5069–5073 (1977).

    Article  CAS  Google Scholar 

  51. Salem, L. & Rowland, C. The electronic properties of diradicals. Angew. Chem. Int. Ed. 11, 92–111 (1972).

    Article  CAS  Google Scholar 

  52. Doehnert, D. & Koutecky, J. Occupation numbers of natural orbitals as a criterion for biradical character. Different kinds of biradicals. J. Am. Chem. Soc. 102, 1789–1796 (1980).

    Article  CAS  Google Scholar 

  53. Abe, M. Diradicals. Chem. Rev. 113, 7011–7088 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction‐activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

    Article  CAS  Google Scholar 

  55. Viesser, R. V., Donald, C. P., May, J. A. & Wu, J. I. Can twisted double bonds facilitate stepwise [2 + 2] cycloadditions? Org. Lett. 26, 3778–3783 (2024).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the NIH-NIGMS (R35 GM139593 to N.K.G. and F31 GM149161 to A.T.M.), the NSF (CHE–2153972 to K.N.H. and DGE-2034835 to A.V.K.), the UCLA Cota Robles Fellowship program (C.A.R.), the Foote family (A.V.K. and A.T.M.) and the Trueblood family (N.K.G.). These studies were supported by shared instrumentation grants from the NSF (CHE-1048804), the NIH NCRR (S10RR025631) and the NIH ORIP (S10OD028644). Calculations were performed on the Hoffman2 cluster and the UCLA Institute of Digital Research and Education (IDRE) at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575). We thank Z. G. Walters (UCLA) and A. Wong (UCLA) for computational assistance. We are indebted to our recently departed colleague and dear friend, F. Stoddart (1942–2024), for inspiring us, by his example, to explore the unknown with curiosity and passion, and to support and cherish the next generation of brilliant scientific minds.

Author information

Author notes

  1. These authors contributed equally: Christina A. Rivera, Huiling Shao

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA

    Arismel Tena Meza, Christina A. Rivera, Huiling Shao, Andrew V. Kelleghan, K. N. Houk & Neil K. Garg

Authors
  1. Arismel Tena Meza
    View author publications

    Search author on:PubMed Google Scholar

  2. Christina A. Rivera
    View author publications

    Search author on:PubMed Google Scholar

  3. Huiling Shao
    View author publications

    Search author on:PubMed Google Scholar

  4. Andrew V. Kelleghan
    View author publications

    Search author on:PubMed Google Scholar

  5. K. N. Houk
    View author publications

    Search author on:PubMed Google Scholar

  6. Neil K. Garg
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.T.M., C.A.R. and A.V.K. designed and performed the experiments and analysed the experimental data. H.S., A.T.M. and C.A.R. designed, performed and analysed the computational studies. K.N.H and N.K.G. directed the investigations and prepared the paper with contributions from all authors; all authors contributed to discussions.

Corresponding authors

Correspondence to K. N. Houk or Neil K. Garg.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature thanks the anonymous reviewers 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.

Extended data figures and tables

Extended Data Fig. 1 Computational study using BCB 21.

Reaction pathway and calculated transition states TS1a and TS1b for the σ-bond insertion reaction of strained cyclic allene 14 and monosubstituted BCB 21. ΔG and ΔH are calculated at ωΒ97X-D/def2TZVPP/SMD(DME)//ωΒ97X-D/def2SVP level of theory. Ph, phenyl; TS, transition state.

Extended Data Fig. 2 Computational study using BCB 18.

Reaction pathway and calculated transition states TS3a and TS3b for the σ-bond insertion reaction of strained cyclic allene 14 and disubstituted BCB 18. ΔG and ΔH are calculated at ωΒ97X-D/def2TZVPP/SMD(DME)//ωΒ97X-D/def2SVP level of theory. Me, methyl; Ph, phenyl; TS, transition state.

Supplementary information

Supplementary Information

This file contains two parts: part 1: Experimental Section and NMR Spectra; and part 2: Computational Section and References.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tena Meza, A., Rivera, C.A., Shao, H. et al. σ-Bond insertion reactions of two strained diradicaloids. Nature 640, 683–690 (2025). https://doi.org/10.1038/s41586-025-08745-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41586-025-08745-1

Search

Advanced search

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