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:

Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis

Nature Chemistry volume 6, pages 146–150 (2014)Cite this article

Subjects

Abstract

There have been numerous developments in C–H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C–H bonds, chemists have discovered reaction conditions that enable reactions of C(sp2)–H and C(sp3)–H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp3)–H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids.

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

Figure 1: Ligand-enabled C(sp3)–H activation.

Similar content being viewed by others

References

  1. Engle, K. M., Mei, T-S., Wasa, M. & Yu, J-Q. Weak coordination as a powerful means for developing broadly useful C–H functionalization reactions. Acc. Chem. Res. 45, 788–802 (2012).

    Article  CAS  Google Scholar 

  2. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    Article  CAS  Google Scholar 

  3. Daugulis, O., Do, H-Q. & Shabashov, D. Palladium- and copper-catalyzed arylation of carbon–hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009).

    Article  CAS  Google Scholar 

  4. Wencel-Delord, J., Dröge, T., Liu, F. & Glorius, F. Towards mild metal-catalyzed C–H bond activation. Chem. Soc. Rev. 40, 4740–4761 (2011).

    Article  CAS  Google Scholar 

  5. Satoh, T. & Miura, M. Oxidative coupling of aromatic substrates with alkynes and alkenes under rhodium catalysis. Chem. Eur. J. 16, 11212–11222 (2010).

    Article  CAS  Google Scholar 

  6. Kakiuchi, F. et al. Catalytic addition of aromatic carbon–hydrogen bonds to olefins with the aid of ruthenium complexes. Bull. Chem. Soc. Jpn 68, 62–83 (1995).

    Article  CAS  Google Scholar 

  7. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C–C bond formation via heteroatom-directed C–H bond activation. Chem. Rev. 110, 624–655 (2010).

    Article  CAS  Google Scholar 

  8. Guimond, N., Gorelsky, S. I. & Fagnou, K. Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: improved reactivity and mechanistic studies. J. Am. Chem. Soc. 133, 6449–6457 (2011).

    Article  CAS  Google Scholar 

  9. Park, S. H., Kim, J. Y. & Chang, S. Rhodium-catalyzed selective olefination of arene esters via C–H bond activation. Org. Lett. 13, 2372–2375 (2011).

    Article  CAS  Google Scholar 

  10. Ackermann, L. & Pospech, J. Ruthenium-catalyzed oxidative C–H bond alkenylations in water: expedient synthesis of annulated lactones. Org. Lett. 13, 4153–4155 (2011).

    Article  CAS  Google Scholar 

  11. Shi, B-F., Maugel, N., Zhang, Y-H. & Yu, J-Q. PdII-catalyzed enantioselective activation of C(sp2)–H and C(sp3)–H bonds using monoprotected amino acids as chiral ligands. Angew. Chem. Int. Ed. 47, 4882–4886 (2008).

    Article  CAS  Google Scholar 

  12. Wang, D-H., Engle, K. M., Shi, B-F. & Yu, J-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319 (2010).

    Article  CAS  Google Scholar 

  13. Engle, K. M., Wang, D-H. & Yu, J-Q. Ligand-accelerated C–H activation reactions: evidence for a switch of mechanism. J. Am. Chem. Soc. 132, 14137–14151 (2010).

    Article  CAS  Google Scholar 

  14. Wasa, M., Engle, K. M., Lin, D. W., Yoo, E. J. & Yu, J-Q. Pd(II)-catalyzed enantioselective C–H activation of cyclopropanes. J. Am. Chem. Soc. 133, 19598–19601 (2011).

    Article  CAS  Google Scholar 

  15. Engle, K. M., Thuy-Boun, P. S., Dang, M. & Yu, J-Q. Ligand-accelerated cross-coupling of C(sp2)–H bonds with arylboron reagents. J. Am. Chem. Soc. 133, 18183–18193 (2011).

    Article  CAS  Google Scholar 

  16. Baxter, R. D., Sale, D., Engle, K. M., Yu, J-Q. & Blackmond, D. G. Mechanistic rationalization of unusual kinetics in Pd-catalyzed C–H olefination, J. Am. Chem. Soc. 134, 4600–4606 (2012).

    Article  CAS  Google Scholar 

  17. Wasa, M. et al. Ligand-enabled methylene C(sp3)–H bond activation with a Pd(II) catalyst. J. Am. Chem. Soc. 134, 18570–18572 (2012).

    Article  CAS  Google Scholar 

  18. Kubota, A., Emmert, M. H. & Sanford, M. S. Pyridine ligands as promoters in PdII/0-catalyzed C–H olefination reactions. Org. Lett. 14, 1760–1763 (2012).

    Article  CAS  Google Scholar 

  19. Chen, X., Goodhue, C. E. & Yu, J-Q. Palladium-catalyzed alkylation of sp2 and sp3 C–H bonds with methylboroxine and alkylboronic acids: two distinct C–H activation pathways. J. Am. Chem. Soc. 128, 12634–12635 (2006).

    Article  CAS  Google Scholar 

  20. Baudoin, O. Transition metal-catalyzed arylation of unactivated C(sp3)–H bonds. Chem. Soc. Rev. 40, 4902–4911 (2011).

    Article  CAS  Google Scholar 

  21. Ano, Y., Tobisu, M. & Chatani, N. Palladium-catalyzed direct ethynylation of C(sp3)–H bonds in aliphatic carboxylic acid derivatives. J. Am. Chem. Soc. 133, 12984–12986 (2011).

    Article  CAS  Google Scholar 

  22. Chen, K., Hu, F., Zhang, S-Q. & Shi, B-F. Pd(II)-catalyzed alkylation of unactivated C(sp3)–H bonds: efficient synthesis of optically active unnatural α-amino acids. Chem. Sci. 4, 3906–3911 (2013).

    Article  CAS  Google Scholar 

  23. Shang, R., Ilies, L., Matsumoto, A. & Nakamura, E. β-Arylation of carboxamides via iron-catalyzed C(sp3)−H bond activation. J. Am. Chem. Soc. 135, 6030–6032 (2013).

    Article  CAS  Google Scholar 

  24. He, G. & Chen, G. A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C(sp3)–H bonds. Angew. Chem. Int. Ed. 50, 5192–5196 (2011).

    Article  CAS  Google Scholar 

  25. Novak, P., Correa, A., Gallardo-Donaire, J. & Martin, R. Synergistic palladium-catalyzed C(sp3)–H activation/C(sp3)–O bond formation: a direct, step-economical route to benzolactones. Angew. Chem. Int. Ed. 50, 12236–12239 (2011).

    Article  CAS  Google Scholar 

  26. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of sp3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155 (2005).

    Article  CAS  Google Scholar 

  27. Reddy, B. V. S., Reddy, L. R. & Corey, E. J. Novel acetoxylation and C–C coupling reactions at unactivated positions in α-amino acid derivatives. Org. Lett. 8, 3391–3394 (2006).

    Article  CAS  Google Scholar 

  28. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of azetidines, pyrrolidines, and indolines via palladium catalyzed intramolecular amination of C(sp3)–H and C(sp2)–H bonds at γ and δ positions. J. Am. Chem. Soc. 134, 3–6 (2012).

    Article  CAS  Google Scholar 

  29. Rodríguez, N., Romero-Revilla, J. A., Fernández-Ibáñez, M. Á. & Carretero, J. C. Palladium-catalyzed N-(2-pyridyl)sulfonyl-directed C(sp3)–H γ-arylation of amino acid derivatives. Chem. Sci. 4, 175–179 (2013).

    Article  Google Scholar 

  30. Chen, G. et al. Palladium-catalyzed picolinamide-directed alkylation of unactivated C(sp3)–H bonds with alkyl iodides. J. Am. Chem. Soc. 135, 2124–2127 (2013).

    Article  Google Scholar 

  31. Liu, C. C. & Schultz, P. G. Adding new chemistries to the genetic code. Annu. Rev. Biochem. 79, 413–444 (2010).

    Article  CAS  Google Scholar 

  32. Chen, X., Engle, K. M., Wang, D-H. & Yu, J-Q. Palladium(II)-catalyzed C–H activation/C–C cross-coupling reactions: versatility and practicality. Angew. Chem. Int. Ed. 48, 5094–5115 (2009).

    CAS  Google Scholar 

  33. Yamaguchi, K., Kondo, H., Yamaguchi, J. & Itami, K. Aromatic C–H coupling with hindered arylboronic acids by Pd/Fe dual catalysts. Chem. Sci. 4, 3753–3757 (2013).

    Article  CAS  Google Scholar 

  34. Giri, R. et al. Palladium-catalyzed methylation and arylation of sp2 and sp3 C–H bonds in simple carboxylic acids. J. Am. Chem. Soc. 129, 3510–3511 (2007).

    Article  CAS  Google Scholar 

  35. Wang, D-H., Wasa, M., Giri, R. & Yu, J-Q. Pd(II)-catalyzed cross-coupling of sp3 C–H bonds with sp2and sp3 boronic acids using air as the oxidant. J. Am. Chem. Soc. 130, 7190–7191 (2008).

    Article  CAS  Google Scholar 

  36. Li, J-J., Mei, T-S. & Yu, J-Q. Synthesis of indolines and tetrahydroisoquinolines from arylethylamines by PdII-catalyzed C–H activation reactions. Angew. Chem. Int. Ed. 47, 6452–6455 (2008).

    Article  CAS  Google Scholar 

  37. Mei, T-S., Wang, X. & Yu, J-Q. Pd(II)-catalyzed amination of C–H bonds using single-electron or two-electron oxidants. J. Am. Chem. Soc. 131, 10806–10807 (2009).

    Article  CAS  Google Scholar 

  38. Wang, X., Mei, T-S. & Yu, J-Q. Versatile Pd(OTf)2·2H2O-catalyzed ortho-fluorination using NMP as a promoter. J. Am. Chem. Soc. 131, 7520–7521 (2009).

    Article  CAS  Google Scholar 

  39. Chemler, S. R., Trauner, D. & Danishefsky, S. J. The B-alkyl Suzuki–Miyaura cross-coupling reaction: development, mechanistic study, and applications in natural product synthesis. Angew. Chem. Int. Ed. 40, 4544–4568 (2001).

    Article  CAS  Google Scholar 

  40. Doucet, H. Suzuki–Miyaura cross-coupling reactions of alkylboronic acid derivatives or alkyltrifluoroborates with aryl, alkenyl or alkyl halides and triflates. Eur. J. Org. Chem. 2013–2030 (2008).

    Article  Google Scholar 

  41. Molander, G. & Canturk, B. Organotrifluoroborates and monocoordinated palladium complexes as catalysts – a perfect combination for Suzuki–Miyaura coupling. Angew. Chem. Int. Ed. 48, 9240–9261 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by The Scripps Research Institute and the National Institutes of Health (NIGMS, 2R01GM084019). K.S.L.C. thanks the Agency for Science, Technology and Research (A*STAR) Singapore for a predoctoral fellowship. M.W. thanks Bristol Myers Squibb for a predoctoral fellowship. M.M. thanks Astellas Pharma Inc. for a postdoctoral fellowship. This is The Scripps Research Institute (TSRI) manuscript no. 25049.

Author information

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura & Jin-Quan Yu

Authors
  1. Kelvin S. L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayuki Wasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian N. Laforteza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masanori Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Quan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.S.L.C. conceived the study, principally performed the experiments and wrote the manuscript, M.W. helped with conceiving the study and preparing the manuscript, L.C. and B.N.L. performed experiments on coupling-partner scope, M.M. helped with identifying the deprotection strategy and J-Q.Y. provided overall supervision. All the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Jin-Quan Yu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2185 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chan, K., Wasa, M., Chu, L. et al. Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nature Chem 6, 146–150 (2014). https://doi.org/10.1038/nchem.1836

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1836

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