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Silylation of C–H bonds in aromatic heterocycles by an Earth-abundant metal catalyst


Heteroaromatic compounds containing carbon–silicon (C–Si) bonds are of great interest in the fields of organic electronics and photonics1, drug discovery2, nuclear medicine3 and complex molecule synthesis4,5,6, because these compounds have very useful physicochemical properties. Many of the methods now used to construct heteroaromatic C–Si bonds involve stoichiometric reactions between heteroaryl organometallic species and silicon electrophiles6,7 or direct, transition-metal-catalysed intermolecular carbon–hydrogen (C–H) silylation using rhodium or iridium complexes in the presence of excess hydrogen acceptors8,9. Both approaches are useful, but their limitations include functional group incompatibility, narrow scope of application, high cost and low availability of the catalysts, and unproven scalability. For this reason, a new and general catalytic approach to heteroaromatic C–Si bond construction that avoids such limitations is highly desirable. Here we report an example of cross-dehydrogenative heteroaromatic C–H functionalization catalysed by an Earth-abundant alkali metal species. We found that readily available and inexpensive potassium tert-butoxide catalyses the direct silylation of aromatic heterocycles with hydrosilanes, furnishing heteroarylsilanes in a single step. The silylation proceeds under mild conditions, in the absence of hydrogen acceptors, ligands or additives, and is scalable to greater than 100 grams under optionally solvent-free conditions. Substrate classes that are difficult to activate with precious metal catalysts are silylated in good yield and with excellent regioselectivity. The derived heteroarylsilane products readily engage in versatile transformations enabling new synthetic strategies for heteroaromatic elaboration, and are useful in their own right in pharmaceutical and materials science applications.

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Figure 1: Approaches to the silylation of heteroarenes.
Figure 2: Scope of the KOt-Bu-catalysed silylation of indoles.
Figure 3: KOt-Bu-catalysed silylation of N-, O- and S-containing heteroarenes.
Figure 4: Synthetic applications of the KOt-Bu-catalysed C–H silylation.


  1. Zhang, F., Wu, D., Xu, Y. & Feng, X. Thiophene-based conjugated oligomers for organic solar cells. J. Mater. Chem. 21, 17590–17600 (2011)

    CAS  Article  Google Scholar 

  2. Showell, G. A. & Mills, J. S. Chemistry challenges in lead optimization: silicon isosteres in drug discovery. Drug Discov. Today 8, 551–556 (2003)

    CAS  Article  Google Scholar 

  3. Franz, A. K. & Wilson, S. O. Organosilicon molecules with medicinal applications. J. Med. Chem. 56, 388–405 (2013)

    CAS  Article  Google Scholar 

  4. Ball, L. T., Lloyd-Jones, G. C. & Russell, C. A. Gold-catalyzed direct arylation. Science 337, 1644–1648 (2012)

    CAS  Article  ADS  Google Scholar 

  5. Denmark, S. E. & Baird, J. D. Palladium-catalyzed cross-coupling reactions of silanolates: a paradigm shift in silicon-based cross-coupling reactions. Chem. Eur. J. 12, 4954–4963 (2006)

    CAS  Article  Google Scholar 

  6. Langkopf, E. & Schinzer, D. Uses of silicon-containing compounds in the synthesis of natural products. Chem. Rev. 95, 1375–1408 (1995)

    CAS  Article  Google Scholar 

  7. Whisler, M. C., MacNeil, S., Snieckus, V. & Beak, P. Beyond thermodynamic acidity: A perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions. Angew. Chem. Int. Ed. 43, 2206–2225 (2004)

    CAS  Article  Google Scholar 

  8. Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 343, 853–857 (2014)

    CAS  Article  ADS  Google Scholar 

  9. Lu, B. & Falck, J. R. Efficient iridium-catalyzed C–H functionalization/silylation of heteroarenes. Angew. Chem. Int. Ed. 47, 7508–7510 (2008)

    CAS  Article  Google Scholar 

  10. Tamao, K., Uchida, M., Izumizawa, T., Furukawa, K. & Yamaguchi, S. Silole derivatives as efficient electron transporting materials. J. Am. Chem. Soc. 118, 11974–11975 (1996)

    CAS  Article  Google Scholar 

  11. Ting, R., Adam, M. J., Ruth, T. J. & Perrin, D. M. Arylfluoroborates and alkylfluorosilicates as potential PET imaging agents: high-yielding aqueous biomolecular 18F-labeling. J. Am. Chem. Soc. 127, 13094–13095 (2005)

    CAS  Article  Google Scholar 

  12. Du, W., Kaskar, B., Blumbergs, P., Subramanian, P. -K. & Curran, D. P. Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals. Bioorg. Med. Chem. 11, 451–458 (2003)

    CAS  Article  Google Scholar 

  13. Furukawa, S., Kobayashi, J. & Kawashima, T. Development of a sila-Friedel–Crafts reaction and its application to the synthesis of dibenzosilole derivatives. J. Am. Chem. Soc. 131, 14192–14193 (2009)

    CAS  Article  Google Scholar 

  14. Curless, L. D., Clark, E. R., Dunsford, J. J. & Ingleson, M. J. E–H (E = R3Si or H) bond activation by B(C6F5)3 and heteroarenes; competitive dehydrosilylation, hydrosilylation and hydrogenation. Chem. Commun. 50, 5270–5272 (2014)

    CAS  Article  Google Scholar 

  15. Klare, H. F. T. et al. Cooperative catalytic activation of Si–H bonds by a polar Ru–S bond: regioselective low-temperature C–H silylation of indoles under neutral conditions by a Friedel-Crafts mechanism. J. Am. Chem. Soc. 133, 3312–3315 (2011)

    CAS  Article  Google Scholar 

  16. Seregin, I. V. & Gevorgyan, V. Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 36, 1173–1193 (2007)

    CAS  Article  Google Scholar 

  17. Fedorov, A., Toutov, A. A., Swisher, N. A. & Grubbs, R. H. Lewis-base silane activation: from reductive cleavage of aryl ethers to selective ortho-silylation. Chem. Sci. 4, 1640–1645 (2013)

    CAS  Article  Google Scholar 

  18. Weickgenannt, A. & Oestreich, M. Potassium tert-butoxide-catalyzed dehydrogenative Si–O coupling: reactivity pattern and mechanism of an underappreciated alcohol protection. Chem. Asian J. 4, 406–410 (2009)

    CAS  Article  Google Scholar 

  19. Song, J. J. et al. Organometallic methods for the synthesis and functionalization of azaindoles. Chem. Soc. Rev. 36, 1120–1132 (2007)

    CAS  Article  Google Scholar 

  20. Li, C.-J. & Trost, B. M. Green chemistry for chemical synthesis. Proc. Natl Acad. Sci. USA 105, 13197–13202 (2008)

    CAS  Article  ADS  Google Scholar 

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

    CAS  Article  ADS  Google Scholar 

  22. Seiple, I. B. et al. Direct C−H arylation of electron-deficient heterocycles with arylboronic acids. J. Am. Chem. Soc. 132, 13194–13196 (2010)

    CAS  Article  Google Scholar 

  23. Zhao, Z. & Snieckus, V. Directed ortho metalation-based methodology. Halo-, nitroso-, and boro-induced ipso-desilylation. Link to an in situ Suzuki reaction. Org. Lett. 7, 2523–2526 (2005)

    CAS  Article  Google Scholar 

  24. Lee, M., Ko, S. & Chang, S. Highly selective and practical hydrolytic oxidation of organosilanes to silanols catalyzed by a ruthenium complex. J. Am. Chem. Soc. 122, 12011–12012 (2000)

    CAS  Article  Google Scholar 

  25. Hansen, M. M. et al. Lithiated benzothiophenes and benzofurans require 2-silyl protection to avoid anion migration. Synlett 8, 1351–1354 (2004)

    Article  Google Scholar 

  26. Wang, Y. & Watson, M. D. Transition-metal-free synthesis of alternating thiophene-perfluoroarene copolymers. J. Am. Chem. Soc. 128, 2536–2537 (2006)

    CAS  Article  Google Scholar 

  27. Kuznetsov, A., Onishi, Y., Inamoto, Y. & Gevorgyan, Y. Fused heteroaromatic dihydrosiloles: synthesis and double-fold modification. Org. Lett. 15, 2498–2501 (2013)

    CAS  Article  Google Scholar 

  28. Oyamada, J., Nishiura, M. & Hou, Z. Scandium-catalyzed silylation of aromatic C–H bonds. Angew. Chem. Int. Ed. 50, 10720–10723 (2011)

    CAS  Article  Google Scholar 

  29. Kakiuchi, F., Tsuchiya, K., Matsumoto, M., Mizushima, E. & Chatani, N. Ru3(CO)12-catalyzed silylation of benzylic C–H bonds in arylpyridines and arylpyrazoles with hydrosilanes via C-H bond cleavage. J. Am. Chem. Soc. 126, 12792–12793 (2004)

    CAS  Article  Google Scholar 

  30. Sakakura, T., Tokunaga, Y., Sodeyama, T. & Tanaka, M. Catalytic C–H activation. Silylation of arenes with hydrosilane or disilane by RhCl(CO)(PMe3)2 under irradiation. Chem. Lett. 16, 2375–2378 (1987)

    Article  Google Scholar 

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This work was supported by the NSF under the CCI Center for Selective C–H Functionalization (CHE-1205646) and under CHE-1212767, and by BP under the XC2 initiative. We thank the Novartis Institutes for Biomedical Research Incorporated for the donation of samples to the CCHF. D. Morton is thanked for a donation of thenalidine. A.A.T. is grateful to the Resnick Sustainability Institute at Caltech and to Dow Chemical for a predoctoral fellowship, and to NSERC for a PGS D fellowship. The Shanghai Institute of Organic Chemistry (SIOC) and S.-L. You are thanked for a postdoctoral fellowship to W.-B.L. We thank S. Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment. D. Vandervelde is acknowledged for assistance with NMR interpretation. N. Dalleska is thanked for assistance with ICP-MS trace metal analysis. M. Shahgoli and N. Torian are acknowledged for assistance with high-resolution mass spectrometry.

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A.A.T., W.-B.L. and K.N.B. developed the reactions, performed the experiments and analysed data. A.F. analysed data. A.A.T and R.H.G. had the idea for and directed the investigations with W.-B.L. and B.M.S. A.A.T. and W.-B.L. prepared the manuscript with contributions from all authors. All authors contributed to discussions.

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Correspondence to Brian M. Stoltz or Robert H. Grubbs.

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The authors declare no competing financial interests.

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Toutov, A., Liu, WB., Betz, K. et al. Silylation of C–H bonds in aromatic heterocycles by an Earth-abundant metal catalyst. Nature 518, 80–84 (2015).

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