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:

Exploiting the sp2 character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane

Nature Chemistry volume 14, pages 1068–1077 (2022)Cite this article

Subjects

Abstract

Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.1]pentane (BCP) as a para-disubstituted benzene replacement has made it a highly valuable pharmacophore. However, various challenges, including limited and lengthy access to useful BCP building blocks, are hampering early discovery research. Here we report a single-step transition-metal-free multi-component approach to synthetically versatile BCP boronates. Radicals derived from commonly available carboxylic acids and organohalides perform additions onto [1.1.1]propellane to afford BCP radicals, which then engage in polarity-matched borylation. A wide array of alkyl-, aryl- and alkenyl-functionalized BCP boronates were easily prepared. Late-stage functionalization performed on natural products and approved drugs proceeded with good efficiency to generate the corresponding BCP conjugates. Various photoredox transformations forging C–C and C–N bonds were demonstrated by taking advantage of BCP trifluoroborate salts derived from the BCP boronates.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: One-step multi-component access to diverse BCP boronates.
Fig. 2: Strain-induced increase in s character in alkyl radicals leads to favourable borylations in competition experiments.
Fig. 3: One-pot synthesis of BCP-BF3K 6 and its diversification by photoredox-mediated processes.
Fig. 4: Mechanistic investigations into the radical intermediacy and origin of chemoselectivity.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available in this Article and its Supplementary Information. Crystallographic data for the structure 4ar reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under the deposition number CCDC 2105768. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. van de Waterbeemd, H. & Gifford, E. ADMET in silico modelling: towards prediction paradise? Nat. Rev. Drug Discov. 2, 192–204 (2003).

    Article  PubMed  Google Scholar 

  2. Honorio, K. M., Moda, T. L. & Andricopulo, A. D. Pharmacokinetic properties and in silico ADME modeling in drug discovery. Med. Chem. 9, 163–176 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Ishikawa, M. & Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem. 54, 1539–1554 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529–2591 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Lovering, F. Escape from flatland 2: complexity and promiscuity. Med. Chem. Commun. 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  7. Walker, M. A. Novel tactics for designing water-soluble molecules in drug discovery. Expert Opin. Drug Discov. 9, 1421–1433 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Ritchie, T. J. & Macdonald, S. J. F. The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design? Drug Discov. Today 14, 1011–1020 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Auberson, Y. P. et al. Improving nonspecific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres. ChemMedChem 12, 590–598 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Stepan, A. F. et al. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J. Med. Chem. 55, 3414–3424 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Wiberg, K. B. & Walker, F. H. [1.1.1]Propellane. J. Am. Chem. Soc. 104, 5239–5240 (1982).

    Article  CAS  Google Scholar 

  13. Wiberg, K. B. Small ring propellanes. Chem. Rev. 89, 975–983 (1989).

    Article  CAS  Google Scholar 

  14. Kanazawa, J. & Uchiyama, M. Recent advances in the synthetic chemistry of bicyclo[1.1.1]pentane. Synlett 30, 1–11 (2019).

    Article  CAS  Google Scholar 

  15. Pramanik, M. M. D., Qian, H., Xiao, W.-J. & Chen, J.-R. Photoinduced strategies towards strained molecules. Org. Chem. Front. 7, 2531–2537 (2020).

    Article  CAS  Google Scholar 

  16. Makarov, I. S., Brocklehurst, C. E., Karaghiosoff, K., Koch, G. & Knochel, P. Synthesis of bicyclo[1.1.1]pentane bioisosteres of internal alkynes and para-disubstituted benzenes from [1.1.1]propellane. Angew. Chem. Int. Ed. 56, 12774–12777 (2017).

    Article  CAS  Google Scholar 

  17. Schwärzer, K., Zipse, H., Karaghiosoff, K. & Knochel, P. Highly regioselective addition of allylic zinc halides and various zinc enolates to [1.1.1]propellane. Angew. Chem. Int. Ed. 59, 20235–20241 (2020).

    Article  CAS  Google Scholar 

  18. Kanazawa, J., Maeda, K. & Uchiyama, M. Radical multicomponent carboamination of [1.1.1]propellane. J. Am. Chem. Soc. 139, 17791–17794 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Kondo, M. et al. Silaboration of [1.1.1]propellane: a storable feedstock for bicyclo[1.1.1]pentane derivatives. Angew. Chem. Int. Ed. 59, 1970–1974 (2020).

    Article  CAS  Google Scholar 

  20. Caputo, D. F. J. et al. Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes. Chem. Sci. 9, 5295–5300 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nugent, J. et al. A general route to bicyclo[1.1.1]pentanes through photoredox catalysis. ACS Catal. 9, 9568–9574 (2019).

    Article  CAS  Google Scholar 

  22. Yu, S., Jing, C., Noble, A. & Aggarwal, V. K. 1,3-Difunctionalizations of [1.1.1]propellane via 1,2-metallate rearrangements of boronate complexes. Angew. Chem. Int. Ed. 59, 3917–3921 (2020).

    Article  CAS  Google Scholar 

  23. Kim, J. H., Ruffoni, A., Al-Faiyz, Y. S. S., Sheikh, N. S. & Leonori, D. Divergent strain-release amino-functionalization of [1.1.1]propellane with electrophilic nitrogen-radicals. Angew. Chem. Int. Ed. 59, 8225–8231 (2020).

    Article  CAS  Google Scholar 

  24. Zhang, X. et al. Copper-mediated synthesis of drug-like bicyclopentanes. Nature 580, 220–226 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shelp, R. A. et al. Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates. Chem. Sci. 12, 7066–7072 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shin, S., Lee, S., Choi, W., Kim, N. & Hong, S. Visible-light-induced 1,3-aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts. Angew. Chem. Int. Ed. 60, 7873–7879 (2021).

    Article  CAS  Google Scholar 

  27. Wu, Z., Xu, Y., Zhang, H., Wu, X. & Zhu, C. Radical-mediated sulfonyl alkynylation, allylation, and cyanation of propellane. Chem. Commun. 57, 6066–6069 (2021).

    Article  CAS  Google Scholar 

  28. VanHeyst, M. D. et al. Continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts and their utilization in metallaphotoredox cross-couplings. Org. Lett. 22, 1648–1654 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Merchant, R. R. & Lopez, J. A. A general C(sp3)–C(sp3) cross-coupling of benzyl sulfonylhydrazones with alkyl boronic acids. Org. Lett. 22, 2271–2275 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Zarate, C. et al. Development of scalable routes to 1-bicyclo[1.1.1]pentylpyrazoles. Org. Process Res. Dev. 25, 642–647 (2021).

    Article  CAS  Google Scholar 

  31. Yang, Y. et al. Practical and modular construction of C(sp3)-rich alkyl boron compounds. J. Am. Chem. Soc. 143, 471–480 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Ripenko, V., Vysochyn, D., Klymov, I., Zhersh, S. & Mykhailiuk, P. K. Large-scale synthesis and modifications of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (BCP). J. Org. Chem. 86, 14061–14068 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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  PubMed  PubMed Central  Google Scholar 

  34. Fawcett, A. et al. Photoinduced decarboxylative borylation of carboxylic acids. Science 357, 283–286 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Friese, F. W. & Studer, A. New avenues for C–B bond formation via radical intermediates. Chem. Sci. 10, 8503–8518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Levin, M. D., Kaszynski, P. & Michl, J. Bicyclo[1.1.1]pentanes, [n]staffanes, [1.1.1]propellanes, and tricyclo[2.1.0.02,5]pentanes. Chem. Rev. 100, 169–234 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Jin, S. et al. Visible light-induced borylation of C–O, C–N, and C–X bonds. J. Am. Chem. Soc. 142, 1603–1613 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu, Q. et al. Transition-metal-free borylation of alkyl iodides via a radical mechanism. Org. Lett. 21, 6597–6602 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Cheng, Y., Mück-Lichtenfeld, C. & Studer, A. Transition metal-free 1,2-carboboration of unactivated alkenes. J. Am. Chem. Soc. 140, 6221–6225 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Toriyama, F. et al. Redox-active esters in Fe-catalyzed C–C coupling. J. Am. Chem. Soc. 138, 11132–11135 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qin, T. et al. A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352, 801–805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fawcett, A. New Developments in Organoboron Incorporation, Homologation and Functionalization. PhD thesis, Bristol Univ. (2018).

  43. Hu, D., Wang, L. & Li, P. Decarboxylative borylation of aliphatic esters under visible-light photoredox conditions. Org. Lett. 19, 2770–2773 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Polites, V. C., Badir, S. O., Keess, S., Jolit, A. & Molander, G. A. Nickel-catalyzed decarboxylative cross-coupling of bicyclo[1.1.1]pentyl radicals enabled by electron donor–acceptor complex photoactivation. Org. Lett. 23, 4828–4833 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Primer, D. N. & Molander, G. A. Enabling the cross-coupling of tertiary organoboron nucleophiles through radical-mediated alkyl transfer. J. Am. Chem. Soc. 139, 9847–9850 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Suzuki, J., Tanigawa, M., Inagi, S. & Fuchigami, T. Electrochemical oxidation of organotrifluoroborate compounds. ChemElectroChem 3, 2078–2083 (2016).

    Article  CAS  Google Scholar 

  47. Pickford, H. D. et al. Twofold radical-based synthesis of N,C-difunctionalized bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 143, 9729–9736 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Matsui, J. K., Primer, D. N. & Molander, G. A. Metal-free C–H alkylation of heteroarenes with alkyltrifluoroborates: a general protocol for 1°, 2° and 3° alkylation. Chem. Sci. 8, 3512–3522 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. West, M. J., Fyfe, J. W. B., Vantourout, J. C. & Watson, A. J. B. Mechanistic development and recent applications of the Chan–Lam amination. Chem. Rev. 119, 12491–12523 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Lam, P. Y. S. in Synthetic Methods in Drug Discovery Vol. 1 (eds Blakemore, D., Doyle, P. & Fobian, Y.) 242–273 (The Royal Society of Chemistry, 2016).

  51. Rossi, S. A., Shimkin, K. W., Xu, Q., Mori-Quiroz, L. M. & Watson, D. A. Selective formation of secondary amides via the copper-catalyzed cross-coupling of alkylboronic acids with primary amides. Org. Lett. 15, 2314–2317 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lavagnino, M. N., Liang, T. & MacMillan, D. W. C. HARC as an open-shell strategy to bypass oxidative addition in Ullmann–Goldberg couplings. Proc. Natl Acad. Sci. USA 117, 21058–21064 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Campbell, M. W., Compton, J. S., Kelly, C. B. & Molander, G. A. Three-component olefin dicarbofunctionalization enabled by nickel/photoredox dual catalysis. J. Am. Chem. Soc. 141, 20069–20078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yoon, U. C. & Mariano, P. S. The synthetic potential of phthalimide SET photochemistry. Acc. Chem. Res. 34, 523–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Cheng, Y., Mück-Lichtenfeld, C. & Studer, A. Metal-free radical borylation of alkyl and aryl iodides. Angew. Chem. Int. Ed. 57, 16832–16836 (2018).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for financial support provided by NIGMS (R35 GM 131680 to G.A.M.). Financial support for this research was provided in part by AbbVie. AbbVie participated in the interpretation of data, review and approval of the publication. The NSF Major Research Instrumentation Program (award NSF CHE-1827457), the NIH supplements awards 3R01GM118510-03S1 and 3R01GM087605-06S1, as well as the Vagelos Institute for Energy Science and Technology supported the purchase of the NMR instruments used in this study. We thank C. W. Ross III (UPenn) for mass spectral data and M. R. Gau (UPenn) for X-ray crystallography data. We thank Frontier for donations of B2pin2, BASF for donations of B2(OH)4, Kessil for donations of LED lamps and Merck for donations of informer sets.

Author information

Author notes

  1. These authors contributed equally: Weizhe Dong, Expédite Yen-Pon, Longbo Li.

Authors and Affiliations

  1. Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA

    Weizhe Dong, Expédite Yen-Pon, Longbo Li, Ayan Bhattacharjee & Gary A. Molander

  2. Medicinal Chemistry Department, Neuroscience Discovery Research, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany

    Anais Jolit

Authors
  1. Weizhe Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Expédite Yen-Pon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Longbo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayan Bhattacharjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anais Jolit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gary A. Molander
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.D., E.Y.-P., L.L. and A.B. performed the laboratory experiments. W.D. and G.A.M. conceived the project. W.D., A.J. and G.A.M. directed the investigations. W.D., E.Y.-P., L.L. and G.A.M. analysed the experimental data and prepared the manuscript.

Corresponding author

Correspondence to Gary A. Molander.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Edward Anderson 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

General information, experimental procedures, extended optimizations, synthesis and characterization data, mechanistic studies, discussion, X-ray crystallographic data, references, NMR spectra, Supplementary Scheme 1, Figs. 1–16 and Tables 1–13.

Supplementary Data 1

Crystallographic data for compound 4ar; CCDC reference 2105768.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, W., Yen-Pon, E., Li, L. et al. Exploiting the sp2 character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane. Nat. Chem. 14, 1068–1077 (2022). https://doi.org/10.1038/s41557-022-00979-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-022-00979-0

This article is cited by

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