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:

Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

Nature Chemistry volume 11, pages 117–122 (2019)Cite this article

Subjects

Abstract

Transition-metal-catalysed cross-coupling reactions, particularly those mediated by palladium, are some of the most broadly used chemical transformations. The fundamental reaction steps of such cross-couplings typically include oxidative addition, transmetallation, carbopalladation of a π-bond and/or reductive elimination. Herein, we describe an unprecedented fundamental reaction step: a C–C σ-bond carbopalladation. Specifically, an aryl palladium(ii) complex interacts with a σ-bond of a strained bicyclo[1.1.0]butyl boronate complex to enable addition of the aryl palladium(ii) species and an organoboronic ester substituent across a C–C σ-bond. The overall process couples readily available aryl triflates and organoboronic esters across a cyclobutane unit with total diastereocontrol. The pharmaceutically relevant 1,1,3-trisubstituted cyclobutane products are decorated with an array of modular building blocks, including a boronic ester that can be readily derivatized.

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: Previous palladium-mediated cross-coupling reactions involving organoboron reagents, and our reaction design.
Fig. 2: Applications of the distal cross-coupling reaction.
Fig. 3: Proposed catalytic cycle for the distal cross-coupling.

Similar content being viewed by others

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for compounds 5, 7, 15 and 35 are available free of charge from the Cambridge Crystallographic Date Centre (www.ccdc.cam.ac.uk) under reference numbers 1835072, 1847415, 1835073 and 1847416, respectively.

References

  1. de Meijere, A., Bräse, S. & Oestreich, M. (eds) Metal-Catalyzed Cross-Coupling Reactions and More (Wiley, New York, 2013).

  2. Cooper, T. W. J., Campbell, I. B. & Macdonald, S. J. F. Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). Angew. Chem. Int. Ed. 49, 8082–8091 (2010).

    Article  CAS  Google Scholar 

  3. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  Google Scholar 

  4. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).

    Article  CAS  Google Scholar 

  5. Zhang, L. et al. Catalytic conjunctive cross-coupling enabled by metal-induced metalate rearrangement. Science 351, 70–74 (2016).

    Article  CAS  Google Scholar 

  6. Lovinger, G. J., Aparece, M. D. & Morken, J. P. Pd-catalyzed conjunctive cross-coupling between Grignard-derived boron ‘ate’ complexes and C(sp 2) halides or triflates: NaOTf as a Grignard activator and halide scavenger. J. Am. Chem. Soc. 139, 3153–3160 (2017).

    Article  CAS  Google Scholar 

  7. Edelstein, E. K., Namirembe, S. & Morken, J. P. Enantioselective conjunctive cross-coupling of bis(alkenyl)borates: a general synthesis of chiral allylboron reagents. J. Am. Chem. Soc. 139, 5027–5030 (2017).

    Article  CAS  Google Scholar 

  8. Chierchia, M., Law, C. & Morken, J. P. Ni-catalyzed enantioselective conjunctive cross-coupling of 9-BBN borates. Angew. Chem. Int. Ed. 56, 11870–11874 (2017).

    Article  CAS  Google Scholar 

  9. Lovinger, G. J. & Morken, J. P. Ni-catalyzed enantioselective conjunctive coupling with C(sp 3) electrophiles: a radical-ionic mechanistic dichotomy. J. Am. Chem. Soc. 139, 17293–17296 (2017).

    Article  CAS  Google Scholar 

  10. McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(ii)-catalyzed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011).

    Article  CAS  Google Scholar 

  11. Crabtree, R. H. Transition metal complexation of σ bonds. Angew. Chem. Int. Ed. Engl. 32, 789–805 (1993).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Murakami, M. & Chatani, N. (eds) Cleavage of Carbon–Carbon Single Bonds by Transition Metals (Wiley, New York, 2015).

  15. Murakami, M. & Ishida, N. Potential of metal-catalyzed C–C single bond cleavage for organic synthesis. J. Am. Chem. Soc. 138, 13759–13769 (2016).

    Article  CAS  Google Scholar 

  16. Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015).

    Article  CAS  Google Scholar 

  17. Aoki, S., Fujimura, T., Nakamura, E. & Kuwajima, I. Palladium-catalyzed arylation of siloxycyclopropanes with aryl triflates. Carbon chain elongation via catalytic carbon–carbon bond cleavage. J. Am. Chem. Soc. 110, 3296–3298 (1988).

    Article  CAS  Google Scholar 

  18. Chen, L. et al. Palladium-catalyzed ring-opening of 2-alkylidenecyclobutanols: stereoselective synthesis of γ,δ-unsaturated ketones by C–C bond cleavage. Adv. Synth. Catal. 360, 411–415 (2018).

    Article  CAS  Google Scholar 

  19. Wiberg, K. B. et al. Bicyclo[1.1.0]butane. Tetrahedron 21, 2749–2769 (1965).

    Article  CAS  Google Scholar 

  20. Khoury, P. R., Goddard, J. D. & Tam, W. Ring strain energies: substituted rings, norbornanes, norbornenes and norbornadienes. Tetrahedron 60, 8103–8112 (2004).

    Article  CAS  Google Scholar 

  21. Walczak, M. A. A., Krainz, T. & Wipf, P. Ring-strain-enabled reaction discovery: new heterocycles from bicyclo[1.1.0]butanes. Acc. Chem. Res. 48, 1149–1158 (2015).

    Article  CAS  Google Scholar 

  22. Walczak, M. A. A. & Wipf, P. Rhodium(i)-catalyzed cycloisomerizations of bicyclobutanes. J. Am. Chem. Soc. 130, 6924–6925 (2008).

    Article  CAS  Google Scholar 

  23. Martín-Heras, V., Parra, A. & Tortosa, M. Cyclopropyl- and cyclobutylboronates and -silanes: a stereoselective approach. Synthesis 50, 470–484 (2018).

    Article  Google Scholar 

  24. 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 

  25. Gutekunst, W. R. & Baran, P. S. Applications of C–H functionalization logic to cyclobutane synthesis. J. Org. Chem. 79, 2430–2452 (2014).

    Article  CAS  Google Scholar 

  26. Dembitsky, V. M. Naturally occurring bioactive cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes and plants. Phytomedicine 21, 1559–1581 (2014).

    Article  CAS  Google Scholar 

  27. Blakemore, D. C. et al. Synthesis and in vivo evaluation of bicyclic gababutins. Bioorg. Med. Chem. Lett. 20, 461–464 (2010).

    Article  CAS  Google Scholar 

  28. Slade, J. et al. A concise synthesis of a novel insulin-like growth factor I receptor (IGF-IR) inhibitor. Org. Process Res. Dev. 11, 825–835 (2007).

    Article  CAS  Google Scholar 

  29. Namyslo, J. C. & Kaufmann, D. E. The application of cyclobutane derivatives in organic synthesis. Chem. Rev. 103, 1485–1537 (2003).

    Article  CAS  Google Scholar 

  30. Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2011).

    Article  CAS  Google Scholar 

  31. Wrobleski, M. L. et al. Cyclobutane derivatives as potent NK1 selective antagonists. Bioorg. Med. Chem. Lett. 16, 3859–3863 (2006).

    Article  CAS  Google Scholar 

  32. Stepan, A. P. et al. Application of the bicyclo[1.1.0]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  Google Scholar 

  33. Nicolaou, K. C. et al. Synthesis and biopharmaceutical evaluation of imatinib analogues featuring unusual structural motifs. ChemMedChem 11, 31–37 (2016).

    Article  CAS  Google Scholar 

  34. Blanco-Ania, D. et al. Rapid and scalable access into strained scaffolds through continuous flow photochemistry. Org. Process Res. Dev. 20, 409–413 (2016).

    Article  CAS  Google Scholar 

  35. Casoni, G. et al. α-Sulfinyl benzoates as precursors to Li and Mg carbenoids for the stereoselective iterative homologation of boronic esters. J. Am. Chem. Soc. 139, 11877–11886 (2017).

    Article  CAS  Google Scholar 

  36. Bottoni, A., Lombardo, M., Neri, A. & Trombini, C. Migratory aptitudes of simple alkyl groups in the anionotropic rearrangement of quaternary chloromethyl borate species: a combined experimental and theoretical investigation. J. Org. Chem. 68, 3397–3405 (2003).

    Article  CAS  Google Scholar 

  37. Barreiro, E. J., Kümmerle, A. E. & Fraga, C. A. M. The methylation effect in medicinal chemistry. Chem. Rev. 111, 5215–5246 (2011).

    Article  CAS  Google Scholar 

  38. Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).

    Article  CAS  Google Scholar 

  39. Bonet, A., Odachowski, M., Leonori, D., Essafi, S. & Aggarwal, V. K. Enantiospecific sp 2–sp 3 coupling of secondary and tertiary boronic esters. Nat. Chem. 6, 584–589 (2014).

    Article  CAS  Google Scholar 

  40. Llaveria, J., Leonori, D. & Aggarwal, V. K. Stereospecific coupling of boronic esters with N-heteroaromatic compounds. J. Am. Chem. Soc. 137, 10958–10961 (2015).

    Article  CAS  Google Scholar 

  41. Armstrong, R. J., Niwetmarin, W. & Aggarwal, V. K. Synthesis of functionalized alkenes by a transition-metal-free coupling. Org. Lett. 19, 2762–2765 (2017).

    Article  CAS  Google Scholar 

  42. Wang, Y., Noble, A., Myers, E. L. & Aggarwal, V. K. Enantiospecific alkynylation of alkylboronic esters. Angew. Chem. Int. Ed. 55, 4270–4274 (2016).

    Article  CAS  Google Scholar 

  43. Bagutski, V., Ros, A. & Aggarwal, V. K. Improved method for the conversion of pinacolboronic esters into trifluoroborate salts. Facile synthesis of chiral secondary and tertiary trifluoroborates. Tetrahedron 65, 9956–9960 (2009).

    Article  CAS  Google Scholar 

  44. Molander, G. A. Organotrifluoroborates: another branch of the mighty oak. J. Org. Chem. 80, 7837–7848 (2015).

    Article  CAS  Google Scholar 

  45. Nave, S., Sonawane, R. P., Elford, T. G. & Aggarwal, V. K. Protodeboronation of tertiary boronic esters: asymmetric synthesis of tertiary alkyl stereogenic centers. J. Am. Chem. Soc. 132, 17096–17098 (2010).

    Article  CAS  Google Scholar 

  46. Fujimoto, H., Yabuki, T. & Fukui, K. A study of orbital interactions in the reactions of bicyclo[1.1.0]butane. J. Mol. Struct. 198, 267–275 (1989).

    Article  CAS  Google Scholar 

  47. Newton, M. D. & Schulman, J. M. Theoretical studies of bicyclobutane. J. Am. Chem. Soc. 94, 767–773 (1972).

    Article  CAS  Google Scholar 

  48. Leonori, D. & Aggarwal, V. K. Stereospecific couplings of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 54, 1082–1096 (2015).

    Article  CAS  Google Scholar 

  49. Labadie, J. W. & Stille, J. K. Mechanisms of the palladium-catalyzed couplings of acid chlorides with organotin reagents. J. Am. Chem. Soc. 105, 6129–6137 (1983).

    Article  CAS  Google Scholar 

  50. Sandrock, D. L., Jean-Gérard, L., Chen, C.-Y., Dreher, S. D. & Molander, G. A. Stereospecific cross-coupling of secondary alkyl b-trifluoratoamides. J. Am. Chem. Soc. 132, 17108–17110 (2010).

    Article  CAS  Google Scholar 

  51. Hatanaka, Y. & Hiyama, T. Stereochemistry of the cross-coupling reaction of chiral alkylsilanes with aryl triflates: a novel approach to optically active compounds. J. Am. Chem. Soc. 112, 7793–7794 (1990).

    Article  CAS  Google Scholar 

  52. Ohmura, T., Awano, T. & Suginome, M. Stereospecific Suzuki–Miyaura coupling of chiral α-(acylamino)benzylboronic esters with inversion of configuration. J. Am. Chem. Soc. 132, 13191–13193 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the EPSRC (EP/I038071/1), H2020 ERC (670668) and the Bayer Science and Education Foundation (Otto–Bayer Fellowship; T.B.). The authors thank E. L. Myers (NUI Galway) and A. Noble for helpful discussions, E. Denton for technical support and H. A. Sparkes for X-ray analysis.

Author information

Authors and Affiliations

  1. School of Chemistry, University of Bristol, Bristol, UK

    Alexander Fawcett, Tobias Biberger & Varinder K. Aggarwal

Authors
  1. Alexander Fawcett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tobias Biberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Varinder K. Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.K.A. and A.F. conceived the project. A.F. designed and conducted the experiments and analysed the data. T.B. first synthesized compound 5. V.K.A. and A.F. prepared the manuscript.

Corresponding author

Correspondence to Varinder K. Aggarwal.

Ethics declarations

Competing interests

The authors declare no competing interests.

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 experimental details and compound characterization data

Crystallographic data

CIF for compound 5; CDCC reference 1835072

Crystallographic data

CIF for compound 7; CDCC reference 1847415

Crystallographic data

CIF for compound 15; CDCC reference 1835073

Crystallographic data

CIF for compound 35; CDCC reference 1847416

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fawcett, A., Biberger, T. & Aggarwal, V.K. Carbopalladation of C–C σ-bonds enabled by strained boronate complexes. Nature Chem 11, 117–122 (2019). https://doi.org/10.1038/s41557-018-0181-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0181-x

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