Letter | Published:

Base-free nickel-catalysed decarbonylative Suzuki–Miyaura coupling of acid fluorides

Naturevolume 563pages100104 (2018) | Download Citation


The Suzuki–Miyaura cross-coupling of organoboron nucleophiles with aryl halide electrophiles is one of the most widely used carbon–carbon bond-forming reactions in organic and medicinal chemistry1,2. A key challenge associated with these transformations is that they generally require the addition of an exogenous base, the role of which is to enable transmetallation between the organoboron nucleophile and the metal catalyst3. This requirement limits the substrate scope of the reaction because the added base promotes competitive decomposition of many organoboron substrates3,4,5. As such, considerable research has focused on strategies for mitigating base-mediated side reactions6,7,8,9,10,11,12. Previous efforts have primarily focused either on designing strategically masked organoboron reagents (to slow base-mediated decomposition)6,7,8 or on developing highly active palladium precatalysts (to accelerate cross-coupling relative to base-mediated decomposition pathways)10,11,12. An attractive alternative approach involves identifying combinations of catalyst and electrophile that enable Suzuki–Miyaura-type reactions to proceed without an exogenous base12,13,14. Here we use this approach to develop a nickel-catalysed coupling of aryl boronic acids with acid fluorides15,16,17, which are formed in situ from readily available carboxylic acids18,19,20,21,22. This combination of catalyst and electrophile enables a mechanistic manifold in which a ‘transmetallation-active’ aryl nickel fluoride intermediate is generated directly in the catalytic cycle13,16. As such, this transformation does not require an exogenous base and is applicable to a wide range of base-sensitive boronic acids and biologically active carboxylic acids.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Data availability

The main data supporting the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding author upon request. Metrical parameters for the structures of complexes 2b and 3 (see Supplementary Information) are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference numbers CCDC 1837039 and CCDC 1837038, respectively.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).

  2. 2.

    Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

  3. 3.

    Lennox, A. J. J. & Lloyd-Jones, G. C. Transmetalation in the Suzuki–Miyaura coupling: the fork in the trail. Angew. Chem. Int. Ed. 52, 7362–7370 (2013).

  4. 4.

    Cox, P. A. et al. Base-catalyzed aryl-B(OH)2 protodeboronation revisited: from concerted proton transfer to liberation of a transient aryl anion. J. Am. Chem. Soc. 139, 13156–13165 (2017).

  5. 5.

    Cox, P. A., Leach, A. G., Campbell, A. D. & Lloyd-Jones, G. C. Protodeboronation of heteroaromatic, vinyl, cyclopropyl boronic acids: pH–rate profiles, autocatalysis, and disproportionation. J. Am. Chem. Soc. 138, 9145–9157 (2016).

  6. 6.

    Molander, G. A. & Biolatto, B. Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions of potassium aryl- and heteroaryltrifluoroborates. J. Org. Chem. 68, 4302–4314 (2003).

  7. 7.

    Knapp, D. M., Gillis, E. P. & Burke, M. D. A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates. J. Am. Chem. Soc. 131, 6961–6963 (2009).

  8. 8.

    Robbins, D. W. & Hartwig, J. F. A C–H borylation approach to Suzuki–Miyaura coupling of typically unstable 2-heteroaryl and polyfluorophenyl boronates. Org. Lett. 14, 4266–4269 (2012).

  9. 9.

    Bulfield, D. & Huber, S. M. Synthesis of polyfluorinated biphenyls; pushing the boundaries of Suzuki–Miyaura cross coupling with electron-poor substrates. J. Org. Chem. 82, 13188–13203 (2017).

  10. 10.

    Kinzel, T., Zhang, Y. & Buchwald, S. L. A new palladium precatalyst allows for the fast Suzuki–Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids. J. Am. Chem. Soc. 132, 14073–14075 (2010).

  11. 11.

    Chen, L., Francis, H. & Carrow, B. P. An “on-cycle” precatalyst enables room-temperature polyfluoroarylation using sensitive boronic acids. ACS Catal. 8, 2989–2994 (2018).

  12. 12.

    Chen, L., Sanchez, D. R., Zhang, B. & Carrow, B. P. “Cationic” Suzuki–Miyaura coupling with acutely base-sensitive boronic acids. J. Am. Chem. Soc. 139, 12418–12421 (2017).

  13. 13.

    Ohashi, M., Saijo, H., Shibata, M. & Ogoshi, S. Palladium-catalyzed base-free Suzuki–Miyaura coupling reactions of fluorinated alkenes and arenes via a palladium fluoride key intermediate. Eur. J. Org. Chem. 443–447 (2013).

  14. 14.

    Graham, T. J. A. & Doyle, A. G. Nickel-catalyzed cross-coupling of chromene acetals and boronic acids. Org. Lett. 14, 1616–1619 (2012).

  15. 15.

    Zhang, Y. & Rovis, T. A unique catalyst effects the rapid room-temperature cross-coupling of organozinc reagents with carboxylic acid fluorides, chlorides, anhydrides, and thioesters. J. Am. Chem. Soc. 126, 15964–15965 (2004).

  16. 16.

    Keaveney, S. T. & Schoenebeck, F. Palladium-catalyzed decarbonylative trifluoromethylation of acid fluorides. Angew. Chem. Int. Ed. 57, 4073–4077 (2018).

  17. 17.

    Ogiwara, Y., Sakurai, Y., Hattori, H. & Sakai, N. Palladium-catalyzed reductive conversion of acyl fluorides via ligand-controlled decarbonylation. Org. Lett. 20, 4204–4208 (2018).

  18. 18.

    Gooßen, L. J., Deng, G. & Levy, L. M. Synthesis of biaryls via catalytic decarboxylative coupling. Science 313, 662–664 (2006).

  19. 19.

    Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carbonyl sp3-carbons with aryl halides. Science 345, 437–440 (2014).

  20. 20.

    Wang, J. et al. Nickel-catalyzed cross-coupling of redox active esters with boronic acids. Angew. Chem. Int. Ed. 55, 9676–9679 (2016).

  21. 21.

    Edwards, J. T. et al. Decarboxylative alkenylation. Nature 545, 213–218 (2017).

  22. 22.

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

  23. 23.

    Carrow, B. P. & Hartwig, J. F. Distinguishing between pathways for transmetalation in Suzuki–Miyaura reactions. J. Am. Chem. Soc. 133, 2116–2119 (2011).

  24. 24.

    Amatore, C., Jutand, A. & Le Duc, G. The triple role of fluoride ions in palladium-catalyzed Suzuki–Miyaura reactions: unprecedented transmetalation from [ArPdFL2] complexes. Angew. Chem. Int. Ed. 51, 1379–1382 (2012).

  25. 25.

    Thomas, A. A. & Denmark, S. E. Pre-transmetalation intermediates in the Suzuki–Miyaura reaction revealed: the missing link. Science 352, 329–332 (2016).

  26. 26.

    Muto, K., Yamaguchi, J., Musaev, D. G. & Itami, K. Decarbonylative organoboron cross-coupling of esters by nickel catalysis. Nat. Commun. 6, 7508 (2015).

  27. 27.

    Shi, S., Meng, G. & Szostak, M. Synthesis of biaryls through nickel-catalyzed Suzuki–Miyaura coupling of amides by carbon–nitrogen bond cleavage. Angew. Chem. Int. Ed. 55, 6959–6963 (2016).

  28. 28.

    Guo, L. & Rueping, M. Decarbonylative cross-couplings: nickel catalyzed functional group interconversion strategies for the construction of complex organic molecules. Acc. Chem. Res. 51, 1185–1195 (2018).

  29. 29.

    Masson-Makdissi, J., Vandavasi, J. K. & Newman, S. G. Switchable selectivity in the Pd-catalyzed alkylative cross-coupling of esters. Org. Lett. 20, 4094–4098 (2018).

  30. 30.

    Ichiishi, N., Malapit, C. A., Wozniak, L. & Sanford, M. S. Palladium- and nickel-catalyzed decarbonylative C–S coupling to convert thioesters to thioethers. Org. Lett. 20, 44–47 (2018).

  31. 31.

    Schaub, T., Backes, M. & Radius, U. Catalytic C–C bond formation accomplished by selective C–F activation of perfluorinated arenes. J. Am. Chem. Soc. 128, 15964–15965 (2006).

  32. 32.

    Tobisu, M., Xu, T., Shimasaki, T. & Chatani, N. Nickel-catalyzed Suzuki–Miyaura reaction of aryl fluorides. J. Am. Chem. Soc. 133, 19505–19511 (2011).

  33. 33.

    Liu, X.-W., Echavarren, J., Zarate, C. & Martin, R. Ni-catalyzed borylation of aryl fluorides via C–F cleavage. J. Am. Chem. Soc. 137, 12470–12473 (2015).

Download references


We acknowledge financial support from National Institutes of Health NIGMS (GM073836) and the Danish National Research Foundation (Carbon Dioxide Activation Center; CADIAC). We acknowledge J. Kampf for X-ray crystallographic analyses of 2b and 3.

Author information


  1. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

    • Christian A. Malapit
    • , James R. Bour
    • , Conor E. Brigham
    •  & Melanie S. Sanford


  1. Search for Christian A. Malapit in:

  2. Search for James R. Bour in:

  3. Search for Conor E. Brigham in:

  4. Search for Melanie S. Sanford in:


C.A.M., J.R.B. and C.E.B. developed the stoichiometric reactions. C.A.M. discovered and developed the catalytic reactions. C.A.M., J.R.B. and M.S.S. conceived and designed the investigations. M.S.S. directed and supported the research. C.A.M., J.R.B. and M.S.S. wrote and revised the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Melanie S. Sanford.

Supplementary information

  1. Supplementary Information

    This file contains supplementary information for methods and characterization data; which includes supplementary figures S1-S9 and supplementary tables S1-S5.

  2. Supplementary Data

    This file contains SI Complex 2b.

  3. Supplementary Data

    This file contains SI Complex 3.

About this article

Publication history




Issue Date



Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.