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.

Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes

Abstract

Catalytic borylations of sp3 C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C–H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C–H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C–H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C–B bond.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: State of the borylation of alkyl C–H bonds, applications of BCPs and routes for their synthesis relevant to this study.
Fig. 2: Conversion of the boryl group of 3-boryl-bicyclo-[1.1.1]-pentanes and 3-boryl-bicyclo-[2.1.1]-hexanes into various functional groups.
Fig. 3: Competition experiments and measurement of 1JC–H coupling constants.
Fig. 4: Mechanistic experiments.
Fig. 5: DFT studies.

Data availability

Complete experimental procedures, computational details and compound characterization data are available in the Supplementary Information. Atomic coordinates of optimized structures are available as Supplementary Data 1.

References

  1. Liskey, C. W. & Hartwig, J. F. Iridium-catalyzed borylation of secondary C–H Bonds in cyclic ethers. J. Am. Chem. Soc. 134, 12422–12425 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Liskey, C. W. & Hartwig, J. F. Iridium-catalyzed C–H borylation of cyclopropanes. J. Am. Chem. Soc. 135, 3375–3378 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Li, Q., Liskey, C. W. & Hartwig, J. F. Regioselective borylation of the C–H bonds in alkylamines and alkyl ethers. Observation and origin of high reactivity of primary C–H bonds beta to nitrogen and oxygen. J. Am. Chem. Soc. 136, 8755–8765 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Jones, M. R., Fast, C. D. & Schley, N. D. Iridium-catalyzed sp3 C–H borylation in hydrocarbon solvent enabled by 2,2′-dipyridylarylmethane ligands. J. Am. Chem. Soc. 142, 6488–6492 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Oeschger, R. et al. Diverse functionalization of strong alkyl C–H bonds by undirected borylation. Science 368, 736 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Kawazu, R., Torigoe, T. & Kuninobu, Y. Iridium-catalyzed C(sp3)−H borylation using silyl-bipyridine pincer ligands. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202202327

  7. Shu, C., Noble, A. & Aggarwal, V. K. Metal-free photoinduced C(sp3)–H borylation of alkanes. Nature 586, 714–719 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. 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 

  10. Measom, N. D. et al. Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor. ACS Med. Chem. Lett. 8, 43–48 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Pu, Q. et al. Discovery of potent and orally available bicyclo[1.1.1]pentane-derived indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors. ACS Med. Chem. Lett. 11, 1548–1554 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. 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 

  14. Barbachyn, M. R. et al. U-87947E, a protein quinolone antibacterial agent incorporating a bicyclo[1.1.1]pent-1-yl (BCP) subunit. Bioorg. Med. Chem. Lett. 3, 671–676 (1993).

    Article  CAS  Google Scholar 

  15. Westphal, M. V., Wolfstädter, B. T., Plancher, J.-M., Gatfield, J. & Carreira, E. M. Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. ChemMedChem 10, 461–469 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Levterov, V. V., Panasyuk, Y., Pivnytska, V. O. & Mykhailiuk, P. K. Water-soluble non-classical benzene mimetics. Angew. Chem. Int. Ed. 59, 7161–7167 (2020).

    Article  CAS  Google Scholar 

  18. 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  PubMed  Google Scholar 

  19. Homon, A. A. et al. 4-(Di-/Trifluoromethyl)-2-heterabicyclo[2.1.1]hexanes: advanced fluorinated phenyl isosteres and proline analogues. Eur. J. Org. Chem. 2021, 6580–6590 (2021).

    Article  CAS  Google Scholar 

  20. Wiberg, K. B., Waddell, S. T. & Laidig, K. [1.1.1]Propellane: Reaction with free radicals. Tetrahedron Lett. 27, 1553–1556 (1986).

    Article  CAS  Google Scholar 

  21. Kaszynski, P. & Michl, J. A practical photochemical synthesis of bicyclo [1.1.1] pentane-1, 3-dicarboxylic acid. J. Org. Chem. 53, 4593–4594 (1988).

    Article  CAS  Google Scholar 

  22. Wiberg, K. B. & Waddell, S. T. Reactions of [1.1.1] propellane. J. Am. Chem. Soc. 112, 2194–2216 (1990).

    Article  CAS  Google Scholar 

  23. Bunker, K. D., Sach, N. W., Huang, Q. & Richardson, P. F. Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction. Org. Lett. 13, 4746–4748 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. 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 Central  PubMed  Google Scholar 

  26. Bär, R. M., Kirschner, S., Nieger, M. & Bräse, S. Alkyl and aryl thiol addition to [1.1.1]propellane: scope and limitations of a fast conjugation reaction. Chem. Eur. J. 24, 1373–1382 (2018).

    Article  PubMed  Google Scholar 

  27. 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 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. 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 

  30. 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 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Lopchuk, J. M. et al. Strain-release heteroatom functionalization: development, scope, and stereospecificity. J. Am. Chem. Soc. 139, 3209–3226 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Shelp, R. A. & Walsh, P. J. Synthesis of BCP benzylamines from 2-azaallyl anions and [1.1.1]propellane. Angew. Chem. Int. Ed. 57, 15857–15861 (2018).

    Article  CAS  Google Scholar 

  34. Hughes, J. M. E., Scarlata, D. A., Chen, A. C. Y., Burch, J. D. & Gleason, J. L. Aminoalkylation of [1.1.1]propellane enables direct access to high-value 3-alkylbicyclo[1.1.1]pentan-1-amines. Org. Lett. 21, 6800–6804 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Trongsiriwat, N. et al. Reactions of 2-aryl-1,3-dithianes and [1.1.1]propellane. Angew. Chem. Int. Ed. 58, 13416–13420 (2019).

    Article  CAS  Google Scholar 

  36. 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 

  37. 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  Google Scholar 

  38. Garlets, Z. J. et al. Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes. Nat. Catal. 3, 351–357 (2020).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. 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 

  42. 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 Central  PubMed  Google Scholar 

  43. 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 Central  PubMed  Google Scholar 

  44. Yu, S. et al. Palladium-catalyzed stagewise strain-release-driven C–C activation of bicyclo[1.1.1]pentanyl alcohols. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202200052

  45. Hoque, M. E., Hassan, M. M. M. & Chattopadhyay, B. Remarkably efficient iridium catalysts for directed C(sp2)–H and C(sp3)–H borylation of diverse classes of substrates. J. Am. Chem. Soc. 143, 5022–5037 (2021).

    Article  CAS  PubMed  Google Scholar 

  46. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover numbers, room temperature reactions, and isolation of a potential intermediate. J. Am. Chem. Soc. 124, 390–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Hinkes, S. P. A. & Klein, C. D. P. Virtues of volatility: a facile transesterification approach to boronic acids. Org. Lett. 21, 3048–3052 (2019).

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Matteson, D. S. & Kim, G. Y. Asymmetric alkyldifluoroboranes and their use in secondary amine synthesis. Org. Lett. 4, 2153–2155 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Tian, Z. & Kass, S. R. Carbanions in the gas phase. Chem. Rev. 113, 6986–7010 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Boller, T. M. et al. Mechanism of the mild functionalization of arenes by diboron reagents catalyzed by iridium complexes. Intermediacy and chemistry of bipyridine-ligated iridium trisboryl complexes. J. Am. Chem. Soc. 127, 14263–14278 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Zhong, R.-L. & Sakaki, S. sp3 C–H borylation catalyzed by iridium(III) triboryl complex: comprehensive theoretical study of reactivity, regioselectivity, and prediction of excellent ligand. J. Am. Chem. Soc. 141, 9854–9866 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Larsen, M. A., Wilson, C. V. & Hartwig, J. F. Iridium-catalyzed borylation of primary benzylic C–H bonds without a directing group: scope, mechanism, and origins of selectivity. J. Am. Chem. Soc. 137, 8633–8643 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Huang, G., Kalek, M., Liao, R.-Z. & Himo, F. Mechanism, reactivity, and selectivity of the iridium-catalyzed C(sp3)-H borylation of chlorosilanes. Chem. Sci. 6, 1735–1746 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIGMS of the NIH under R35GM130387. I.F.Y. and J.L.M. gratefully acknowledge the National Science Foundation Graduate Research Fellowship Program and the UC Berkeley Graduate Research Fellowship Program for support under DGE 1752814 and DGE 2146752. We thank H. Celik and A. Lund and UC Berkeley’s NMR facility in the College of Chemistry (CoC-NMR) for spectroscopic assistance, in particular for assistance and advice in acquiring J-resolved spectra. Instruments in the CoC-NMR are supported in part by NIH S10OD024998. We thank K. Durkin and D. Small and UC Berkeley’s Molecular Graphics and Computation Facility (MGCF) for assistance and resources for the computations. The MGCF is supported in part by NIH S10OD023532. We thank the QB3/Chemistry Mass Spectrometry Facility for assistance in obtaining high-resolution mass spectrometry data. We wish to thank T. W. Butcher and E. D. Kalkman for helpful discussions.

Author information

Authors and Affiliations

Authors

Contributions

J.F.H., A.M. and D.M.V. conceived and created an initial design of the research. I.F.Y., J.L.M., A.M. and A.D-v. performed the synthetic experiments. I.F.Y. conducted the computational and kinetic studies. J.L.M. conducted the competition studies. I.F.Y., A.M., A.E.P., P.K.M., S.V.R. and D.M.V. selected and prepared the bicyclic reagents used in this study. I.F.Y., J.L.M., A.M., D.M.V. and J.F.H. designed and analysed the experiments and prepared the initial paper. All authors contributed to or approved the final version of the paper.

Corresponding authors

Correspondence to Antonio Misale, Dmitriy M. Volochnyuk or John F. Hartwig.

Ethics declarations

Competing interests

A.E.P., P.K.M., S.V.R. and D.M.V. are employees of Enamine, which is a chemical supplier of reagents used in the studies in this paper. All other authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Patrick Walsh 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 Figs. 1–20, Tables 1–3 and Discussion.

Supplementary Data 1

Atomic coordinates of optimized structures from DFT calculations.

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

Yu, I.F., Manske, J.L., Diéguez-Vázquez, A. et al. Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes. Nat. Chem. 15, 685–693 (2023). https://doi.org/10.1038/s41557-023-01159-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-023-01159-4

This article is cited by

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