Despite significant progress in the development of site-selective aliphatic C–H oxidations over the past decade, the ability to oxidize strong methylene C–H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic and biaryl moieties. Late-stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition nos. CCDC 1869257 for (S,S)-5, CCDC 1869258 for 73, CCDC 1869259 for 74 and CCDC 1869260 for (R,R)-S2. Copies of the data can be obtained free of charge from www.ccdc.cam.ac.uk/structures/. 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.

Additional information

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


  1. 1.

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

  2. 2.

    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).

  3. 3.

    McMurray, L., O’Hara, F. & Gaunt, M. J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation. Chem. Soc. Rev. 40, 1885–1898 (2011).

  4. 4.

    Ford, M. C. & Ho, P. S. Computational tools to model halogen bonds in medicinal chemistry. J. Med. Chem. 59, 1655–1670 (2016).

  5. 5.

    Ortiz de Montellano, P. R. (ed.) Cytochrome P450: Structure, Mechanism, and Biochemistry (Springer, Berlin, 2015).

  6. 6.

    Mack, J. B. C., Gipson, J. D., Du Bois, J. & Sigman, M. S. Ruthenium-catalyzed C–H hydroxylation in aqueous acid enables selective functionalization of amine derivatives. J. Am. Chem. Soc. 139, 9503–9506 (2017).

  7. 7.

    Ottenbacher, R. V., Samsonenko, D. G., Talsi, E. P. & Bryliakov, K. P. Highly efficient, regioselective, and stereospecific oxidation of aliphatic C–H groups with H2O2, catalyzed by aminopyridine manganese complexes. Org. Lett. 14, 4310–4313 (2012).

  8. 8.

    Adams, A. M., Du Bois, J. & Malik, H. A. Comparative study of the limitations and challenges in atom-transfer C–H oxidations. Org. Lett. 17, 6066–6069 (2015).

  9. 9.

    Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

  10. 10.

    Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

  11. 11.

    Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135, 14052–14055 (2013).

  12. 12.

    White, M. C. Adding aliphatic C–H bond oxidations to synthesis. Science 335, 807–809 (2012).

  13. 13.

    White, M. C. & Zhao, J. Aliphatic C–H oxidations for late-stage functionalization. J. Am. Chem. Soc. 140, 13988–14009 (2018).

  14. 14.

    Paradine, S. M. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3) –H amination. Nat. Chem. 7, 987–994 (2015).

  15. 15.

    Padwa, A. et al. Ligand effects on dirhodium(ii) carbene reactivities. Highly effective switching between competitive carbenoid transformations. J. Am. Chem. Soc. 115, 8669–8680 (1993).

  16. 16.

    Quinn, R. K. et al. Site-selective aliphatic C–H chlorination using N-chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc. 138, 696–702 (2016).

  17. 17.

    Asensio, G., Castellano, G., Mello, R. & González Núñez, M. E. Oxyfunctionalization of aliphatic esters by methyl(trifluoromethyl)dioxirane. J. Org. Chem. 61, 5564–5566 (1996).

  18. 18.

    Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).

  19. 19.

    Yosca, T. H. et al. Iron(iv)hydroxide pK a and the role of thiolate ligation in C–H bond activation by cytochrome P450. Science 342, 825–829 (2013).

  20. 20.

    Guroff, G. et al. Hydroxylation-induced migration. The NIH shift: recent experiments reveal an unexpected and general result of enzymatic hydroxylation of aromatic compounds. Science 157, 1524–1530 (1967).

  21. 21.

    Jeon, S. & Bruice, T. C. Redox chemistry of water-soluble iron, manganese, and chromium metalloporphyrins and acid–base behavior of their lyate axial ligands in aqueous solution: influence of electronic effects. Inorg. Chem. 31, 4843–4848 (1992).

  22. 22.

    Chen, J. et al. Tuning the reactivity of mononuclear nonheme manganese(iv)-oxo complexes by triflic acid. Chem. Sci. 6, 3624–3632 (2015).

  23. 23.

    White, M. C., Doyle, A. G. & Jacobsen, E. N. A synthetically useful, self-assembling MMO mimic system for catalytic alkene epoxidation with aqueous H2O2. J. Am. Chem. Soc. 123, 7194–7195 (2001).

  24. 24.

    Bigi, M. A., Reed, S. A. & White, M. C. Directed metal (oxo) aliphatic C–H hydroxylations: overriding substrate bias. J. Am. Chem. Soc. 134, 9721–9726 (2012).

  25. 25.

    Miao, C. et al. Proton-promoted and anion-enhanced epoxidation of olefins by hydrogen peroxide in the presence of nonheme manganese catalysts. J. Am. Chem. Soc. 138, 936–943 (2016).

  26. 26.

    Mas-Ballesté, R. & Que, L.Jr. Iron-catalyzed olefin epoxidation in the presence of acetic acid: insights into the nature of the metal-based oxidant. J. Am. Chem. Soc. 129, 15964–15972 (2007).

  27. 27.

    Marson, C. M. New and unusual scaffolds in medicinal chemistry. Chem. Soc. Rev. 40, 5514–5533 (2011).

  28. 28.

    Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

  29. 29.

    Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

  30. 30.

    Rennhack, A. et al. Synthesis of a potent photoreactive acidic gamma-secretase modulator for target identification in cells. Bioorg. Med. Chem. 20, 6523–6532 (2012).

  31. 31.

    Obach, R. S. Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacol. Rev. 65, 578–640 (2013).

  32. 32.

    Sarabu, R. et al. Discovery of piragliatin—first glucokinase activator studied in type 2 diabetic patients. J. Med. Chem. 55, 7021–7036 (2012).

  33. 33.

    Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).

  34. 34.

    D’Accolti, L., Fusco, C., Lampignano, G., Capitelli, F. & Curci, R. Oxidation of natural targets by dioxiranes. Part 6: On the direct regio- and site-selective oxyfunctionalization of estrone and of 5α-androstane steroid derivatives. Tetrahedron Lett. 49, 5614–5617 (2008).

  35. 35.

    Breslow, R., Zhang, X. & Huang, Y. Selective catalytic hydroxylation of a steroid by an artificial cytochrome P-450 enzyme. J. Am. Chem. Soc. 119, 4535–4536 (1997).

  36. 36.

    See, Y. Y., Herrmann, A. T., Aihara, Y. & Baran, P. S. Scalable C–H oxidation with copper: synthesis of polyoxypregnanes. J. Am. Chem. Soc. 137, 13776–13779 (2015).

  37. 37.

    Font, D. et al. Readily accessible bulky iron catalysts exhibiting site selectivity in the oxidation of steroidal substrates. Angew. Chem. Int. Ed. 55, 5776–5779 (2016).

  38. 38.

    Nanjo, T., de Lucca, E. C. Jr & White, M. C. Remote, late-stage oxidation of aliphatic C–H bonds in amide-containing molecules. J. Am. Chem. Soc. 139, 14586–14591 (2017).

Download references


Financial support for this work was provided by the NIH NIGMS Maximizing Investigators’ Research Award MIRA (R35 GM122525). The authors acknowledge The Uehara Memorial Foundation for a fellowship to T.N. and Conselho Nacional de Desenvolvimento Científico e Tecnológico for a fellowship to E.C.L. (proc. no. 234643/2014-5). The authors thank L. Zhu for assistance with NMR spectroscopy, D. Gray and T. Woods for X-ray crystallographic studies, and C. Delaney for preliminary studies on basic nitrogen-containing compounds. The authors also thank C. Wendell, K. Feng and W. Liu for checking the procedures. The data reported in this paper are tabulated in the Supplementary Information.

Author information


  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL, USA

    • Jinpeng Zhao
    •  & M. Christina White
  2. Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, Japan

    • Takeshi Nanjo
  3. Institute of Chemistry, University of Campinas, Campinas/SP, Brazil

    • Emilio C. de Lucca Jr


  1. Search for Jinpeng Zhao in:

  2. Search for Takeshi Nanjo in:

  3. Search for Emilio C. de Lucca Jr in:

  4. Search for M. Christina White in:


M.C.W. and J.Z. conceived and designed the project and wrote the manuscript. J.Z., T.N. and E.C.L. conducted the experiments and analysed the data. All authors provided comments on the experiments and manuscript during its preparation.

Competing interests

The University of Illinois has filed a patent application on the Mn(CF3–PDP) catalyst for methylene oxidation in aromatic molecules.

Corresponding author

Correspondence to M. Christina White.

Supplementary information

  1. Supplementary Information

    Supplementary experimental data, synthetic procedures, chemical compound characterization data and Supplementary Figs 1–4

  2. Crystallographic data

    CIF for compound S2. CCDC reference 1869260

  3. Crystallographic data

    CIF for compound 5. CCDC reference 1869257

  4. Crystallographic data

    CIF for compound 73. CCDC reference 1869258

  5. Crystallographic data

    CIF for compound 74. CCDC reference 1869259

About this article

Publication history