Skip to main content

Thank you for visiting 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.

Dual-catalytic transition metal systems for functionalization of unreactive sites of molecules

A Publisher Correction to this article was published on 29 January 2019

This article has been updated


Catalytic reactions occur readily at the sites of starting materials that are both innately reactive and sterically accessible, or that are predisposed by a functional group amenable to direct a catalyst. However, selective reactions at unbiased sites of substrates remain challenging and typically require additional preactivation steps or the use of highly reactive reagents. Here we report dual-catalytic transition metal systems that merge a reversible activation cycle with a functionalization cycle, which together enable the functionalization of substrates at their inherently unreactive sites. By engaging the Ru- or Fe-catalysed equilibrium between an alcohol and an aldehyde, methods for Pd-catalysed β-arylation of aliphatic alcohols and Rh-catalysed γ-hydroarylation of allylic alcohols were developed. The mild conditions, functional group tolerance and broad scope (81 examples) demonstrate the synthetic applicability of the dual-catalytic systems. This work highlights the potential of the multicatalytic approach to address challenging transformations to circumvent multistep procedures and the use of highly reactive reagents in organic synthesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: TM-catalysed functionalization of starting materials.
Fig. 2: Reaction design and development.
Fig. 3: Mechanistic studies.
Fig. 4: Pd-/Ru-catalysed arylation of the β-C–H bond of alcohols.
Fig. 5: γ-selective hydroarylation of allylic alcohols.

Data availability

The crystallographic data for compound 7a have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 1821986 and can be obtained free of charge from the CCDC via All the other data are available from the authors upon reasonable request.

Change history

  • 29 January 2019

    In the version of this Article originally published, some compounds in Fig. 4 had incorrect footnote notation: for 5b 47%*,b should be 47%ab; for 6w 65%‡§¶ should be 65%cdf; for 6x 50%‡§¶,” should be 50%cdf and for 6y 59%‡§¶ should be 59%cdf. Furthermore, in Fig. 2b, for the arylation reaction the text read “H–Base+ X–” but should be H-Base+X; in Fig. 3d, the reaction arrow was labelled “Doxane-d8” but should be Dioxane-d8; and in Fig. 1c there was an extraneous horizontal line at top right. All these errors have now been amended.


  1. 1.

    Hartwig, J. F. Organotransition Metal Chemistry: from Bonding to Catalysis (University Science Books, Sausalito, 2010).

  2. 2.

    Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292 (2016).

    CAS  Article  Google Scholar 

  3. 3.

    Sambiagio, C. et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 47, 6603–6743 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    CAS  Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

    Gandeepan, P. & Ackermann, L. Transient directing groups for transformative C–H activation by synergistic metal catalysis. Chem 4, 199–222 (2018).

    CAS  Article  Google Scholar 

  7. 7.

    Zhang, F.-L., Hong, K., Li, T.-J., Park, H. & Yu, J.-Q. Functionalization of C(sp 3)–H bonds using a transient directing group. Science 351, 252–256 (2016).

    CAS  Article  Google Scholar 

  8. 8.

    Park, H., Verma, P., Hong, K. & Yu, J.-Q. Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp 3)−H fluorination. Nat. Chem. 10, 755–762 (2018).

    CAS  Article  Google Scholar 

  9. 9.

    Corma, A., Navas, J. & Sabater, M. J. Advances in one-pot synthesis through borrowing hydrogen catalysis. Chem. Rev. 118, 1410–1459 (2018).

    CAS  Article  Google Scholar 

  10. 10.

    Watson, A. J. A. & Williams, J. M. J. The give and take of alcohol activation. Science 329, 635–636 (2010).

    CAS  Article  Google Scholar 

  11. 11.

    Wang, D. & Astruc, D. The golden age of transfer hydrogenation. Chem. Rev. 115, 6621–6686 (2015).

    CAS  Article  Google Scholar 

  12. 12.

    Hill, C. K. & Hartwig, J. F. Site-selective oxidation, amination and epimerization reactions of complex polyols enabled by transfer hydrogenation. Nat. Chem. 9, 1213–1221 (2017).

    CAS  Article  Google Scholar 

  13. 13.

    Guillena, G., Ramón, D. J. & Yus, M. Hydrogen autotransfer in the N-alkylation of amines and related compounds using alcohols and amines as electrophiles. Chem. Rev. 110, 1611–1641 (2010).

    CAS  Article  Google Scholar 

  14. 14.

    Bähn, S. et al. The catalytic amination of alcohols. ChemCatChem 3, 1853–1864 (2011).

    Article  Google Scholar 

  15. 15.

    Yang, Q., Wang, Q. & Yu, Z. Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation. Chem. Soc. Rev. 44, 2305–2329 (2015).

    CAS  Article  Google Scholar 

  16. 16.

    Obora, Y. Recent advances in α-alkylation reactions using alcohols with hydrogen borrowing methodologies. ACS Catal. 4, 3972–3981 (2014).

    CAS  Article  Google Scholar 

  17. 17.

    Gunanathan, C. & Milstein, D. Applications of acceptorless dehydrogenation and related transformations in chemical synthesis. Science 341, 1229712 (2013).

    Article  Google Scholar 

  18. 18.

    Bender, M., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C–C bonds: entry to type II polyketides. Science 357, 779–781 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Nguyen, K. D. et al. Metal-catalyzed reductive coupling of olefin-derived nucleophiles: reinventing carbonyl addition. Science 354, aah5133 (2016).

    Article  Google Scholar 

  20. 20.

    Black, P. J., Harris, W. & Williams, J. M. J. Catalytic electronic activation: indirect addition of nucleophiles to an allylic alcohol. Angew. Chem. Int. Ed. 40, 4475 (2001).

    CAS  Article  Google Scholar 

  21. 21.

    Quintard, A., Constantieux, T. & Rodriguez, J. An iron/amine-catalyzed cascade process for the enantioselective functionalization of allylic alcohols. Angew. Chem. Int. Ed. 52, 12883–12887 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Roudier, M., Constantieux, T., Quintard, A. & Rodriguez, J. Triple iron/copper/iminium activation for the efficient redox neutral catalytic enantioselective functionalization of allylic alcohols. ACS Catal. 6, 5236–5244 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Goldman, A. S., Roy, A. H., Huang, Z., Schinski, W. & Brookhart, M. Catalytic alkane metathesis by tandem alkane dehydrogenation–olefin metathesis. Science 312, 257–261 (2006).

    CAS  Article  Google Scholar 

  24. 24.

    Haibach, M. C., Kundu, S., Brookhart, M. & Goldman, A. S. Alkane metathesis by tandem alkane-dehydrogenation–olefin-metathesis catalysis and related chemistry. Acc. Chem. Res. 45, 947–958 (2012).

    CAS  Article  Google Scholar 

  25. 25.

    Mo, F., Tabor, J. R. & Dong, G. Alcohols or masked alcohols as directing groups for C–H bond functionalization. Chem. Lett. 43, 264–271 (2014).

    CAS  Article  Google Scholar 

  26. 26.

    Bellina, F. & Rossi, R. Transition metal-catalyzed direct arylation of substrates with activated sp 3-hybridized C−H bonds and some of their synthetic equivalents with aryl halides and pseudohalides. Chem. Rev. 110, 1082–1146 (2010).

    CAS  Article  Google Scholar 

  27. 27.

    Smith, A. M. R. & Hii, K. K. Transition metal catalyzed enantioselective α-heterofunctionalization of carbonyl compounds. Chem. Rev. 111, 1637–1656 (2011).

    CAS  Article  Google Scholar 

  28. 28.

    Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox activation for the direct β-arylation of ketones and aldehydes. Science 339, 1593–1596 (2013).

    CAS  Article  Google Scholar 

  29. 29.

    Terrett, J. A., Clift, M. D. & MacMillan, D. W. C. Direct β-alkylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 136, 6858–6861 (2014).

    CAS  Article  Google Scholar 

  30. 30.

    Zhang, X. & MacMillan, D. W. C. Direct aldehyde C–H arylation and alkylation via the combination of nickel, hydrogen atom transfer, and photoredox catalysis. J. Am. Chem. Soc. 139, 11353–11356 (2017).

    CAS  Article  Google Scholar 

  31. 31.

    Hazari, N., Melvin, P. R. & Beromi, M. M. Well-defined nickel and palladium precatalysts for cross-coupling. Nat. Rev. Chem. 1, 0025 (2017).

    CAS  Article  Google Scholar 

  32. 32.

    Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    CAS  Article  Google Scholar 

  33. 33.

    Samec, J. S. M., Bäckvall, J.-E., Andersson, P. G. & Brandt, P. Mechanistic aspects of transition metal-catalyzed hydrogen transfer reactions. Chem. Soc. Rev. 35, 237 (2006).

    CAS  Article  Google Scholar 

  34. 34.

    Alcazar-Roman, L. M. & Hartwig, J. F. Mechanistic studies on oxidative addition of aryl halides and triflates to Pd(BINAP)2 and structural characterization of the product from aryl triflate addition in the presence of amine. Organometallics. 21, 491–502 (2002).

    CAS  Article  Google Scholar 

  35. 35.

    Hartwig, J. F. Electronic effects on reductive elimination to form carbon–carbon and carbon–heteroatom bonds from palladium(ii) complexes. Inorg. Chem. 46, 1936–1947 (2007).

    CAS  Article  Google Scholar 

  36. 36.

    Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012).

    CAS  Article  Google Scholar 

  37. 37.

    Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).

    CAS  Article  Google Scholar 

  38. 38.

    Tian, P., Dong, H.-Q. & Lin, G.-Q. Rhodium-catalyzed asymmetric arylation. ACS Catal. 2, 95–119 (2012).

    CAS  Article  Google Scholar 

  39. 39.

    Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003).

    CAS  Article  Google Scholar 

  40. 40.

    Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).

    CAS  Article  Google Scholar 

  41. 41.

    Bullock, R. M. An iron catalyst for ketone hydrogenations under mild conditions. Angew. Chem. Int. Ed. 46, 7360–7363 (2007).

    CAS  Article  Google Scholar 

  42. 42.

    Knölker, H.-J., Baum, E., Goesmann, H. & Klauss, R. Demetalation of tricarbonyl(cyclopentadienone)iron complexes initiated by a ligand exchange reaction with NaOH—X-ray analysis of a complex with nearly square-planar coordinated sodium. Angew. Chem. Int. Ed. 38, 2064–2066 (1999).

    Article  Google Scholar 

Download references


This work was financially supported by the University of Strasbourg, the French National Research Agency (‘Investments for the future’ programme of the IdEx Unistra framework), FRC & LabEx Chemistry of Complex Systems, the Polish National Science Centre (Etiuda fellowship no. 2016/20/T/ST5/00494 to D.L.), the European Union (Marie Curie Actions, PCOFUND-GA-2013-609102) through the Campus France (Prestige fellowship no. PRESTIGE-2017-4-0022 to D.L.), the Polish Ministry of Science and Higher Education (Mobilnosc Plus fellowship no. 1672/l/MOB/V/l 7/2018/0 to K.H.) and the Foundation for Polish Science (Start fellowship no. START-036.2018 to K.H.). We thank L. Karmazin for the crystallographic measurements, E. Richmond for help with the initial high-performance liquid chromatography analysis and W. Dzik for helpful discussions.

Author information




D.L. and P.D. conceived, designed and performed the initial experiments. D.L., Y.Z. and P.D. designed and performed subsequent experiments. D.L., Y.Z. and K.H. performed the experiments during the revision. P.D. conceived the concept and prepared the manuscript with feedback from D.L.

Corresponding author

Correspondence to Paweł Dydio.

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 Methods, Supplementary Figures 1–19, Supplementary Tables 1–4, Supplementary References

Compound 7a

Crystallographic data for compound 7a

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lichosyt, D., Zhang, Y., Hurej, K. et al. Dual-catalytic transition metal systems for functionalization of unreactive sites of molecules. Nat Catal 2, 114–122 (2019).

Download citation


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