Cobalt-catalysed C–H methylation for late-stage drug diversification


The magic methyl effect is well acknowledged in medicinal chemistry, but despite its significance, accessing such analogues via derivatization at a late stage remains a pivotal challenge. In an effort to mitigate this major limitation, we here present a strategy for the cobalt-catalysed late-stage C–H methylation of structurally complex drug molecules. Enabling broad applicability, the transformation relies on a boron-based methyl source and takes advantage of inherently present functional groups to guide the C–H activation. The relative reactivity observed for distinct classes of functionalities were determined and the sensitivity of the transformation towards a panel of common functional motifs was tested under various reaction conditions. Without the need for prefunctionalization or postdeprotection, a diverse array of marketed drug molecules and natural products could be methylated in a predictable manner. Subsequent physicochemical and biological testing confirmed the magnitude with which this seemingly minor structural change can affect important drug properties.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Realizing a C–H activation–methylation protocol for LSF.
Fig. 2: Competition experiment that ranked different common functional groups as directing groups for the cobalt-catalysed C–H methylation with trimethylboroxine.
Fig. 3: Effect exerted by additives on the C–H methylation reaction under various conditions.
Fig. 4: Application of cobalt-mediated C–H methylation for LSF of biologically active substrates.
Fig. 5: Modulation of pharmaceutically relevant properties on C–H methylation.

Data availability

Data, which include experimental procedures, references that support Fig. 1b, physicochemical, DMPK and pharmacological activity data for selected compounds, de novo synthesis strategies and NMR spectra, are available in the Supplementary Information.


  1. 1.

    Bergman, R. G. Organometallic chemistry: CH activation. Nature 446, 391–393 (2007).

    CAS  Article  Google Scholar 

  2. 2.

    Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, R. & 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 

  3. 3.

    Wencel-Delord, J. & Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 5, 369–375 (2013).

    CAS  Article  Google Scholar 

  4. 4.

    Larsen, M. A. & Hartwig, J. F. Iridium-catalyzed C–H borylation of heteroarenes: scope, regioselectivity, application to late-stage functionalization, and mechanism. J. Am. Chem. Soc. 136, 4287–4299 (2014).

    CAS  Article  Google Scholar 

  5. 5.

    Berger, F. et al. Site-selective and versatile aromatic C–H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    CAS  Article  Google Scholar 

  6. 6.

    Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp 3)–H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).

    Article  Google Scholar 

  7. 7.

    Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016).

    CAS  Article  Google Scholar 

  8. 8.

    Liao, K. et al. Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C–H bonds. Nat. Chem. 10, 1048–1055 (2018).

    CAS  Article  Google Scholar 

  9. 9.

    Willcox, D. et al. A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams. Science 354, 851–857 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Hong, S. Y. et al. Selective formation of γ-lactams via C–H amidation enabled by tailored iridium catalysts. Science 359, 1016–1021 (2018).

    CAS  Article  Google Scholar 

  11. 11.

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

    CAS  Article  Google Scholar 

  12. 12.

    Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Ed. 52, 12256–12267 (2013).

    Article  Google Scholar 

  13. 13.

    Li, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp 3 C–H alkylation via polarity-match-based cross-coupling. Nature 547, 79–83 (2017).

  14. 14.

    He, Z.-T., Li, H., Haydl, A. M., Whiteker, G. T. & Hartwig, J. F. Trimethylphosphate as a methylating agent for cross coupling: a slow-release mechanism for the methylation of arylboronic esters. J. Am. Chem. Soc. 140, 17197–17202 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    Daugulis, O., Roane, J. & Tran, L. D. Bidentate, monoanionic auxiliary-directed functionalization of carbon–hydrogen bonds. Acc. Chem. Res. 48, 1053–1064 (2015).

    CAS  Article  Google Scholar 

  16. 16.

    Rouquet, G. & Chatani, N. Catalytic functionalization of C(sp 2)–H and C(sp 3)–H bonds by using bidentate directing groups. Angew. Chem. Int. Ed. 52, 11726–11743 (2013).

    CAS  Article  Google Scholar 

  17. 17.

    Gandeepan, P. et al. 3d transition metals for C–H activation. Chem. Rev. 119, 2192–2452 (2019).

    CAS  Article  Google Scholar 

  18. 18.

    Evano, G. & Theunissen, C. Beyond Friedel and Crafts: directed alkylation of C–H bonds in arenes. Angew. Chem. Int. Ed. 58, 2–37 (2019).

    Article  Google Scholar 

  19. 19.

    Chen, Z. et al. Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups. Org. Chem. Front. 2, 1107–1295 (2015).

    CAS  Article  Google Scholar 

  20. 20.

    Graczyk, K., Haven, T. & Ackermann, L. Iron-catalyzed C(sp 2)–H and C(sp 3)–H methylations of amides and anilides. Chem. Eur. J. 21, 8812–8815 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Shang, R., Ilies, L. & Nakamura, E. Iron-catalyzed ortho C–H methylation of aromatics bearing a simple carbonyl group with methylaluminum and tridentate phosphine ligand. J. Am. Chem. Soc. 138, 10132–10135 (2016).

    CAS  Article  Google Scholar 

  22. 22.

    Thuy-Boun, P. S. et al. Ligand-accelerated ortho-C–H alkylation of arylcarboxylic acids using alkyl boron reagents. J. Am. Chem. Soc. 135, 17508–17513 (2013).

    CAS  Article  Google Scholar 

  23. 23.

    Neufeldt, S. R., Seigerman, C. K. & Sanford, M. S. Mild palladium-catalyzed C–H alkylation using potassium alkyltrifluoroborates in combination with MnF3. Org. Lett. 15, 2302–2305 (2013).

    CAS  Article  Google Scholar 

  24. 24.

    Rosen, B. R. et al. C–H functionalization logic enables synthesis of (+)-hongoquercin A and related compounds. Angew. Chem. Int. Ed. 52, 7317–7320 (2013).

    CAS  Article  Google Scholar 

  25. 25.

    Yoshino, T. & Matsunaga, S. (Pentamethylcyclopentadienyl)cobalt(iii)-catalyzed C–H bond functionalization: from discovery to unique reactivity and selectivity. Adv. Synth. Catal. 359, 1245–1262 (2017).

    CAS  Article  Google Scholar 

  26. 26.

    Moselage, M., Li, J. & Ackermann, L. Cobalt-catalyzed C–H activation. ACS Catal. 6, 498–525 (2016).

    CAS  Article  Google Scholar 

  27. 27.

    Weissman, S. A. & Anderson, N. G. Design of experiments (DoE) and process optimization. A review of recent publications. Org. Process Res. Dev. 19, 1605–1633 (2015).

    CAS  Article  Google Scholar 

  28. 28.

    Santanilla, A. B. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).

    Article  Google Scholar 

  29. 29.

    Tu, N. P. et al. High-throughput reaction screening with nanomoles of solid reagents coated on glass beads. Angew. Chem. Int. Ed. 58, 7987–7991 (2019).

    CAS  Article  Google Scholar 

  30. 30.

    Gesmundo, N. J. et al. Nanoscale synthesis and affinity ranking. Nature 557, 228–332 (2018).

    CAS  Article  Google Scholar 

  31. 31.

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

    CAS  Article  Google Scholar 

  32. 32.

    Tomberg, A. et al. Relative strength of common directing groups in palladium-catalyzed aromatic C–H activation. iScience 20, 373–391 (2019).

    CAS  Article  Google Scholar 

  33. 33.

    Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).

    CAS  Article  Google Scholar 

  34. 34.

    Kutchukian, P. S. et al. Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods. Chem. Sci. 7, 2604–2613 (2016).

    CAS  Article  Google Scholar 

  35. 35.

    Smith, J. M., Dixon, J. A., deGruyter, J. N. & Baran, P. S. Alkyl sulfinates: radical precursors enabling drug discovery. J. Med. Chem. 62, 2256–2264 (2019).

    CAS  Article  Google Scholar 

  36. 36.

    Uehling, M. R., King, R. P., Krska, S. W., Cernak, T. & Buchwald, S. L. Pharmaceutical diversification via palladium oxidative addition complexes. Science 363, 405–408 (2019).

    CAS  Article  Google Scholar 

  37. 37.

    Dai, H.-X., Stepan, A. F., Plummer, M. S., Zhang, Y.-H. & Yu, J.-Q. Divergent C–H functionalizations directed by sulfonamide pharmacophores: late-stage diversification as a tool for drug discovery. J. Am. Chem. Soc. 133, 7222–7228 (2011).

    CAS  Article  Google Scholar 

  38. 38.

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

  39. 39.

    Bäurle, S. et al. Identification of a benzimidazolecarboxylic acid derivative (BAY 1316957) as a potent and selective human prostaglandin E2 receptor subtype 4 (hEP4-R) antagonist for the treatment of endometriosis. J. Med. Chem. 62, 2541–2563 (2019).

    Article  Google Scholar 

Download references


The authors thank R. Sheppard and M. A. Hayes for valuable insight on biological testing, M. Härslätt and A. Ristinmaa for purification support, and M. A. Hayes and M. Lemurell for advice on the preparation of this manuscript. S.D.F. and M.J.J. acknowledge AstraZeneca and the AstraZeneca PostDoc program for their financial support. L.A. acknowledges the Georg-August-Universität Göttingen.

Author information




S.D.F., M.J.J. and L.A. conceived the project and designed the experiments. M.J.J. and L.A. directed the project. S.D.F performed and analysed the experiments. S.D.F., M.J.J. and L.A. prepared the manuscript.

Corresponding authors

Correspondence to Magnus J. Johansson or Lutz Ackermann.

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

Experimental protocols and characterization for compounds mentioned in this work, references supporting Fig. 1b, overview of reaction optimization, description of competition experiments and compatibility screening, de novo synthesis strategies, PhysChem-, DMPK- and pharmacological activity data for selected compound and NMR spectra..

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Friis, S.D., Johansson, M.J. & Ackermann, L. Cobalt-catalysed C–H methylation for late-stage drug diversification. Nat. Chem. 12, 511–519 (2020).

Download citation

Further reading