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:

Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes

Nature Chemistry volume 11, pages 948–956 (2019)Cite this article

Subjects

Abstract

Difluorocarbene has important applications in pharmaceuticals, agrochemicals and materials, but all these applications proceed using just a few types of reaction by taking advantage of its intrinsic electrophilicity. Here, we report a palladium-catalysed strategy that confers the formed palladium difluorocarbene (Pd=CF2) species with both nucleophilicity and electrophilicity by switching the valence state of the palladium centre (Pd(0) and Pd(ii), respectively). Controllable catalytic difluorocarbene transfer occurs between readily available arylboronic acids and the difluorocarbene precursor diethyl bromodifluoromethylphosphonate (BrCF2PO(OEt)2). From just this simple fluorine source, difluorocarbene transfer enables access to four types of product: difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones. The transfer can also be applied to the modification of pharmaceuticals and agrochemicals as well as the one-pot diversified synthesis of fluorinated compounds. Mechanistic and computational studies consistently reveal that competition between nucleophilic and electrophilic palladium difluorocarbene ([Pd]=CF2) is the key factor controlling the catalytic difluorocarbene transfer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Previous and present approaches to difluorocarbene transfer.
Fig. 2: Diversified synthesis of fluoroalkylated arenes.
Fig. 3: Mechanistic studies.
Fig. 4: Calculated energy profile of the palladium-catalysed difluorocarbene transfer reactions.
Fig. 5: Outline of a possible pathway for controllable palladium-catalysed difluorocarbene transfer.

Similar content being viewed by others

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Center under deposition numbers CCDC 1902891 (B1-1), 1916606 (B1-2), 1916607 (A1-2), 1902894 (C1-1a), 1902898 (C2), 1902901 (E1) and 1902900 (cis-G1). Copies of the data can be obtained free of charge from https://www.ccdc.cam.ac.uk/strucutres/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

References

  1. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications 2nd edn (Wiley-VCH, 2013).

  2. Brahms, D. L. S. & Dailey, W. P. Fluorinated carbenes. Chem. Rev. 96, 1585–1632 (1996).

    Article  CAS  Google Scholar 

  3. Ni, C. & Hu, J. Recent advances in the synthetic application of difluorocarbene. Synthesis 46, 842–863 (2014).

    Article  Google Scholar 

  4. Hudlicky, M. & Pavlath, A. E. Chemistry of Organic Fluorine Compounds II (American Chemical Society, 1995).

  5. Miller, T. G. & Thanassi, J. W. The preparation of aryl difluoromethyl ethers. J. Org. Chem. 25, 2009–2012 (1960).

    Article  CAS  Google Scholar 

  6. Hohlfeld, J. M. et al. Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial. Pulm. Pharmacol. Ther. 21, 616–623 (2008).

    Article  CAS  Google Scholar 

  7. Dolbier, W. R. Jr. & Battiste, M. A. Structure, synthesis and chemical reactions of fluorinated cyclopropanes and cyclopropenes. Chem. Rev. 103, 1071–1098 (2003).

    Article  CAS  Google Scholar 

  8. Burch, J. D. et al. Tetrahydroindazoles as interleukin-2 inducible T-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity and pharmacodynamic modulation in vivo. J. Med. Chem. 58, 3806–3816 (2015).

    Article  CAS  Google Scholar 

  9. Fuqua, S. A., Duncan, W. G. & Silverstein, R. M. A one-step synthesis of 1,1-difluoroolefins from aldehydes by a modified Wittig synthesis. Tetrahedron Lett. 5, 1461–1463 (1964).

    Article  Google Scholar 

  10. MacNeil, J. G.Jr & Burton, D. J. Generation of trifluoromethylcopper from chlorodifluoroacetate. J. Fluor. Chem. 55, 225–227 (1991).

    Article  CAS  Google Scholar 

  11. Duan, J.-X., Su, D.-B. & Chen, Q.-Y. Trifluoromethylation of organic halides with methyl halodifluoroacetates—a process via difluorocarbene and trifluoromethide intermediates. J. Fluor. Chem. 61, 279–284 (1993).

    Article  CAS  Google Scholar 

  12. Huiban, M. et al. A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nat. Chem. 5, 941–944 (2013).

    Article  CAS  Google Scholar 

  13. Levin, M. D. et al. A catalytic fluoride-rebound mechanism for C(sp 3)–CF3 bond formation. Science 356, 1272–1276 (2017).

    Article  CAS  Google Scholar 

  14. Dilman, A. D. & Levin, V. V. Difluorocarbene as a building block for consecutive bond-forming reactions. Acc. Chem. Res. 51, 1272–1280 (2018).

    Article  CAS  Google Scholar 

  15. Reger, D. L. & Dukes, M. D. Molybdenum perfluorocarbene complexes. J. Organomet. Chem. 153, 67–72 (1978).

    Article  CAS  Google Scholar 

  16. Brothers, P. J. & Roper, W. R. Transition-metal dihalocarbene complexes. Chem. Rev. 88, 1293–1326 (1988).

    Article  CAS  Google Scholar 

  17. Harrison, D. J., Gorelsky, S. I., Lee, G. M., Korobkov, I. & Baker, R. T. Cobalt fluorocarbene complexes. Organometallics 32, 12–15 (2013).

    Article  CAS  Google Scholar 

  18. Harrison, D. J., Daniels, A. L., Korobkov, I. & Baker, R. T. d 10 nickel difluorocarbenes and their cycloaddition reactions with tetrafluoroethylene. Organometallics 34, 5683–5686 (2015).

    Article  CAS  Google Scholar 

  19. Trnka, T. M., Day, M. W. & Grubbs, R. H. Olefin metathesis with 1,1-difluoroethylene. Angew. Chem. Int. Ed. 40, 3441–3444 (2001).

    Article  CAS  Google Scholar 

  20. Takahira, Y. & Morizawa, Y. Ruthenium-catalyzed olefin cross-metathesis with tetrafluoroethylene and analogous fluoroolefins. J. Am. Chem. Soc. 137, 7031–7034 (2015).

    Article  CAS  Google Scholar 

  21. Feng, Z., Min, Q.-Q. & Zhang, X. Access to difluoromethylated arenes by Pd-catalyzed reaction of arylboronic acids with bromodifluoroacetate. Org. Lett. 18, 44–47 (2016).

    Article  CAS  Google Scholar 

  22. Feng, Z., Min, Q.-Q., Fu, X.-P., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem. 9, 918–923 (2017).

    Article  CAS  Google Scholar 

  23. Deng, X.-Y., Lin, J.-H. & Xiao, J.-C. Pd-catalyzed transfer of difluorocarbene. Org. Lett. 18, 4384–4387 (2016).

    Article  CAS  Google Scholar 

  24. Clark, G. R., Hoskins, S. V., Jones, T. C. & Roper, W. R. Oxidation state control of the reactivity of a transition metal–carbon double bond. Synthesis, X-ray crystal structure, and reactions of the zerovalent difluorocarbene complex [Ru(=CF2)(CO)2(PPh3)2]. J. Chem. Soc. Chem. Commun. 719–721 (1983).

  25. Brothers, P. J., Burrell, A. K., Clark, G. R., Rickard, C. E. F. & Roper, W. R. Trifluoromethyl, difluorocarbene and tetrafluoroethylene complexes of iridium and the crystal structures of IrI(CH3)(CF3)(CO)(PPh3)2, Ir(CF3)(C2F4)(CO)(PPh3)2 and Ir(CF3)(CF2)(CO)(PPh3)2. J. Organomet. Chem. 394, 615–642 (1990).

    Article  CAS  Google Scholar 

  26. Hughes, R. P. et al. A simple route to difluorocarbene and perfluoroalkylidene complexes of iridium. J. Am. Chem. Soc. 127, 15020–15021 (2005).

    Article  CAS  Google Scholar 

  27. Negishi, E. & de Meijere, A. Handbook of Organopalladium Chemistry for Organic Synthesis 2nd edn (Wiley, 2002).

  28. Yang, Z.-Y., Wiemers, D. M. & Burton, D. J. Trifluoromethylcopper: a useful difluoromethylene transfer reagent: a novel double insertion of difluoromethylene into pentafluorophenylcopper. J. Am. Chem. Soc. 114, 4402–4403 (1992).

    Article  CAS  Google Scholar 

  29. Zafrani, Y., Sod-Moriah, G. & Segall, Y. Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluorocarbene precursor. Tetrahedron 65, 5278–5283 (2009).

    Article  CAS  Google Scholar 

  30. Cordaro, J. G. & Bergman, R. G. Dissociation of carbanions from acyl iridium compounds: an experimental and computational investigation. J. Am. Chem. Soc. 126, 16912–16929 (2004).

    Article  CAS  Google Scholar 

  31. Fujiwara, Y. et al. A new reagent for direct difluoromethylation. J. Am. Chem. Soc. 134, 1494–1497 (2012).

    Article  CAS  Google Scholar 

  32. Fier, P. S. & Hartwig, J. F. Copper-mediated difluoromethylation of aryl and vinyl iodides. J. Am. Chem. Soc. 134, 5524–5527 (2012).

    Article  CAS  Google Scholar 

  33. Gu, Y., Leng, X. & Shen, Q. Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides. Nat. Commun. 5, 5405 (2014).

    Article  CAS  Google Scholar 

  34. Xu, L. & Vicic, D. A. Direct difluoromethylation of aryl halides via base metal catalysis at room temperature. J. Am. Chem. Soc. 138, 2536–2539 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Erickson, J. A. & McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 60, 1626–1631 (1995).

    Article  CAS  Google Scholar 

  37. Vaclavik, J., Klimankova, I., Budinska, A. & Beier, P. Advances in the synthesis and application of tetrafluoroethylene- and 1,1,2,2-tetrafluoroethyl-containing compounds. Eur. J. Org. Chem. 2018, 3554–3593 (2018).

    Article  CAS  Google Scholar 

  38. 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  Google Scholar 

  39. Jean, Y. Molecular Orbitals of Transition Metal Complexes (Oxford Univ. Press, 2005).

  40. Li, L., Wang, F., Ni, C. & Hu, J. Synthesis of gem-difluorocyclopropa(e)nes and O-, S-, N- and P-difluoromethylated compounds with TMSCF2Br. Angew. Chem. Int. Ed. 52, 12390–12394 (2013).

    Article  CAS  Google Scholar 

  41. Pu, M. I., Sanhueza, A., Senol, E. & Schoenebeck, F. Divergent reactivity of stannane and silane in the trifluoromethylation of PdII: cyclic transition state versus difluorocarbene release. Angew. Chem. Int. Ed. 57, 15081–15085 (2018).

    Article  CAS  Google Scholar 

  42. Frisch, M. J. et al. Gaussian 09, revision D.01 (Gaussian, 2009).

  43. Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B. 37, 785–789 (1988).

    Article  CAS  Google Scholar 

  44. Becke, A. D. Density functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    Article  CAS  Google Scholar 

  45. Becke, A. D. A new mixing of Hartree–Fock and local density-functional theories. J. Chem. Phys. 98, 1372–1377 (1993).

    Article  CAS  Google Scholar 

  46. Hay, P. J. & Wadt, W. R. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys. 82, 299–310 (1985).

    Article  CAS  Google Scholar 

  47. Hehre, W. J., Ditchfield, R. & Pople, J. A. Self-consistent molecular orbital methods. XII. Further extensions of Gaussian-type basis sets for use in molecular orbital studies of organic molecules. J. Chem. Phys. 56, 2257–2261 (1972).

    Article  CAS  Google Scholar 

  48. Marenich, A. V., Cramer, C. J. & Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 113, 6378–6396 (2009).

    Article  CAS  Google Scholar 

  49. Zhao, Y. & Truhlar, D. G. Density functionals with broad applicability in chemistry. Acc. Chem. Res. 41, 157–167 (2008).

    Article  CAS  Google Scholar 

  50. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008).

    Article  CAS  Google Scholar 

  51. Andrae, D., Haussermann, U., Dolg, M., Stoll, H. & Preuss, H. Energy-adjusted ab initio pseudo potentials for the second and third row transition elements. Theor. Chim. Acta 77, 123–141 (1990).

    Article  CAS  Google Scholar 

  52. Dolg, M., Wedig, U., Stoll, H. & Preuss, H. Energy-adjusted ab initio pseudo potentials for the first row transition elements. J. Chem. Phys. 86, 866–872 (1987).

    Article  CAS  Google Scholar 

  53. Legault, C. Y. CYLview, 1.0b (Université de Sherbrooke, 2009); http://www.cylview.org.

Download references

Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (21425208, 21672238, 21790362 and 21421002), the National Basic Research Program of China (973 Program) (No. 2015CB931900), the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB20000000). We thank H.-L. Qin for MS analysis of 18O-labelled compound 7 and G.-Y. Li for 13C NMR analysis of the palladium complexes. K.N.H. acknowledges the National Science Foundation (NSF) for support (CHE-1764320). Computations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575).

Author information

Author notes

  1. These authors contributed equally: Xia-Ping Fu, Xiao-Song Xue.

Authors and Affiliations

  1. Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Xia-Ping Fu, Xue-Ying Zhang, Yu-Lan Xiao, Yin-Long Guo, Xuebing Leng & Xingang Zhang

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Xiao-Song Xue & Kendall N. Houk

  3. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Xiao-Song Xue

  4. School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Shu Zhang

Authors
  1. Xia-Ping Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Song Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue-Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Lan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yin-Long Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xuebing Leng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kendall N. Houk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xingang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.Z. and X.-P.F. conceived and designed the experiments. X.Z. directed the project. X.-P.F. performed the experiments and mechanism studies. X.-S.X. conducted the DFT calculations and contributed parts of the mechanism analysis. K.N.H. directed the DFT calculations. X.-Y.Z. conducted parts of the mechanistic studies. Y.-L.G. conducted MS analysis of the palladium complexes. X.L. analysed the X-ray crystal structure of the palladium difluorocarbene complex. X.-P.F., Y.-L.X. and X.Z. analysed the data. X.Z., X.-S.X., S.Z. and K.N.H. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Kendall N. Houk or Xingang Zhang.

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 procedures, experimental data, optimization data, compound characterization data and computational methods.

A1-2.cif

Crystallographic information file for compound A1-2, CCDC 1916607.

B1-1.cif

Crystallographic information file for compound B1-1, CCDC 1902891.

B1-2.cif

Crystallographic information file for compound B1-2, CCDC 1916606.

C1-1a.cif

Crystallographic information file for compound C1-1a, CCDC 1902894.

C2.cif

Crystallographic information file for compound C2, CCDC 1902898.

cis-G1.cif

Crystallographic information file for compound cis-G1, CCDC 1902900.

E1.cif

Crystallographic information file for compound E1, CCDC 1902901.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, XP., Xue, XS., Zhang, XY. et al. Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes. Nat. Chem. 11, 948–956 (2019). https://doi.org/10.1038/s41557-019-0331-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0331-9

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