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

Journal name:
Nature
Volume:
518,
Pages:
80–84
Date published:
DOI:
doi:10.1038/nature14126
Received
Accepted
Published online

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.

At a glance

Figures

  1. Approaches  to the silylation of heteroarenes.
    Figure 1: Approaches to the silylation of heteroarenes.

    a, Route A, classical synthesis of heteroaryl silanes by reaction of organometallic species with silicon electrophiles. The organometallic species is typically prepared by deprotonation of heteroarenes or by lithium–halogen exchange of heteroaryl halides. X′ = Cl or Br; Hal, halogen; LG, leaving group. Route B, recently emerging direct, transition-metal-catalysed C–H activation/silylation. Excess amounts of hydrogen acceptors are required. b, A departure from the transition metal catalysis paradigm: KOt-Bu-catalysed, acceptorless, cross-dehydrogenative heteroaromatic C–H silylation with hydrosilanes. TON, turnover number.

  2. Scope of the KOt-Bu-catalysed silylation of indoles.
    Figure 2: Scope of the KOt-Bu-catalysed silylation of indoles.

    For the reactions of 2g and 2i, silylation on the benzylic methyl group was observed with tetrahydrofuran (THF) as solvent; solvent-free conditions often led to improved regioselectivity and yield. For the reaction of 2k, silylation at C6 was observed as a by-product in THF. The reactions of 1,3-dimethyl indole with Et3SiH and PhMe2SiH were sluggish, probably owing to steric congestion at C2. For the reaction of 2o, bisindolyldiethylsilane was isolated as a by-product. See Supplementary Information for details. [Si]–H = Et3SiH, Et2SiH2, EtMe2SiH, PhMe2SiH or n-Bu3SiH. MOM, methoxylmethyl; SEM, 2-[(trimethylsilyl)ethoxy]methyl.

  3. KOt-Bu-catalysed silylation of N-, O- and S-containing heteroarenes.
    Figure 3: KOt-Bu-catalysed silylation of N-, O- and S-containing heteroarenes.

    Multigram-scale syntheses were presented for 4h and 4n. Catalyst loadings can be reduced to 1 mol% with a TON of 92 (4m). For 4j, with 3.5 mol% KOt-Bu, TON = 23 (82% yield); for 4n, with 1.5 mol% KOt-Bu, TON = 61 (91% yield). Bisfuranyldiethylsilane was isolated as a by-product in the reaction of 4o. Unsubstituted thiophene and furan favoured 2,5-bis-silyation (4q and 4r). See Supplementary Information for details. [Si]–H = Et3SiH, Et2SiH2, EtMe2SiH, PhMe2SiH or n-Bu3SiH.

  4. Synthetic applications of the KOt-Bu-catalysed C-H silylation.
    Figure 4: Synthetic applications of the KOt-Bu-catalysed C–H silylation.

    a, Preparation of 142 g of C2-silylated indole building block 2a. b, Application of heteroarylsilanes in cross-coupling and a formal C–H borylation at C7 of benzothiophene. c, Synthesis of precursors to advanced materials and polymers. d, Late-stage chemo- and regioselective modification of active pharmaceutical ingredients. e, KOt-Bu-catalysed functionalization of arenes by oxygen-directed sp2, and innate benzylic sp3 C–H silylation. See Supplementary Information for details. [Si] = Et3Si; i-Pr, isopropyl; dba, dibenzylideneacetone; Bpin, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane; TMEDA, tetramethylethylenediamine; EDOT, 3,4-ethylenedioxythiophene.

References

  1. Zhang, F., Wu, D., Xu, Y. & Feng, X. Thiophene-based conjugated oligomers for organic solar cells. J. Mater. Chem. 21, 1759017600 (2011)
  2. Showell, G. A. & Mills, J. S. Chemistry challenges in lead optimization: silicon isosteres in drug discovery. Drug Discov. Today 8, 551556 (2003)
  3. Franz, A. K. & Wilson, S. O. Organosilicon molecules with medicinal applications. J. Med. Chem. 56, 388405 (2013)
  4. Ball, L. T., Lloyd-Jones, G. C. & Russell, C. A. Gold-catalyzed direct arylation. Science 337, 16441648 (2012)
  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, 49544963 (2006)
  6. Langkopf, E. & Schinzer, D. Uses of silicon-containing compounds in the synthesis of natural products. Chem. Rev. 95, 13751408 (1995)
  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, 22062225 (2004)
  8. Cheng, C. & Hartwig, J. F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol. Science 343, 853857 (2014)
  9. Lu, B. & Falck, J. R. Efficient iridium-catalyzed C–H functionalization/silylation of heteroarenes. Angew. Chem. Int. Ed. 47, 75087510 (2008)
  10. Tamao, K., Uchida, M., Izumizawa, T., Furukawa, K. & Yamaguchi, S. Silole derivatives as efficient electron transporting materials. J. Am. Chem. Soc. 118, 1197411975 (1996)
  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, 1309413095 (2005)
  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, 451458 (2003)
  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, 1419214193 (2009)
  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, 52705272 (2014)
  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, 33123315 (2011)
  16. Seregin, I. V. & Gevorgyan, V. Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 36, 11731193 (2007)
  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, 16401645 (2013)
  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, 406410 (2009)
  19. Song, J. J. et al. Organometallic methods for the synthesis and functionalization of azaindoles. Chem. Soc. Rev. 36, 11201132 (2007)
  20. Li, C.-J. & Trost, B. M. Green chemistry for chemical synthesis. Proc. Natl Acad. Sci. USA 105, 1319713202 (2008)
  21. Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nature Chem. 5, 597601 (2013)
  22. Seiple, I. B. et al. Direct C−H arylation of electron-deficient heterocycles with arylboronic acids. J. Am. Chem. Soc. 132, 1319413196 (2010)
  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, 25232526 (2005)
  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, 1201112012 (2000)
  25. Hansen, M. M. et al. Lithiated benzothiophenes and benzofurans require 2-silyl protection to avoid anion migration. Synlett 8, 13511354 (2004)
  26. Wang, Y. & Watson, M. D. Transition-metal-free synthesis of alternating thiophene-perfluoroarene copolymers. J. Am. Chem. Soc. 128, 25362537 (2006)
  27. Kuznetsov, A., Onishi, Y., Inamoto, Y. & Gevorgyan, Y. Fused heteroaromatic dihydrosiloles: synthesis and double-fold modification. Org. Lett. 15, 24982501 (2013)
  28. Oyamada, J., Nishiura, M. & Hou, Z. Scandium-catalyzed silylation of aromatic C–H bonds. Angew. Chem. Int. Ed. 50, 1072010723 (2011)
  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, 1279212793 (2004)
  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, 23752378 (1987)

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Author information

  1. These authors contributed equally to this work.

    • Anton A. Toutov &
    • Wen-Bo Liu
  2. Present address: Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir Prelog Weg 2, CH-8093 Zürich, Switzerland.

    • Alexey Fedorov

Affiliations

  1. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA

    • Anton A. Toutov,
    • Wen-Bo Liu,
    • Kerry N. Betz,
    • Alexey Fedorov,
    • Brian M. Stoltz &
    • Robert H. Grubbs

Contributions

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.

Competing financial interests

The authors declare no competing financial interests.

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