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Catalytic C–H bond silylation of aromatic heterocycles


This protocol describes a method for the direct silylation of the carbon–hydrogen (C–H) bond of aromatic heterocycles using inexpensive and abundant potassium tert-butoxide (KOt-Bu) as the catalyst. This catalytic cross-dehydrogenative coupling of simple hydrosilanes and various electron-rich aromatic heterocycles enables the synthesis of valuable silylated heteroarenes. The products thus obtained can be used as versatile intermediates, which facilitate the divergent synthesis of pharmaceutically relevant compound libraries from a single Si-containing building block. Moreover, a variety of complex Si-containing motifs, such as those produced by this protocol, are being actively investigated as next-generation therapeutic agents, because they can have improved pharmacokinetic properties compared with the original all-carbon drug molecules. Current competing methods for C–H bond silylation tend to be incompatible with functionalities, such as Lewis-basic heterocycles, that are often found in pharmaceutical substances; this leaves de novo synthesis as the principal strategy for preparation of the target sila-drug analog. Moreover, competing methods tend to be limited in the scope of hydrosilane that can be used, which restricts the breadth of silicon-containing small molecules that can be accessed. The approach outlined in this protocol enables the chemoselective and regioselective late-stage silylation of small heterocycles, including drugs and drug derivatives, with a broad array of hydrosilanes in the absence of precious metal catalysts, stoichiometric reagents, sacrificial hydrogen acceptors or high temperatures. Moreover, H2 is the only by-product generated. The procedure normally requires 48–75 h to be completed.

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Figure 1: Synthetic utility of arylsilanes and heteroarylsilanes.
Figure 2: Current approaches to the silylation of heteroaroenes.
Figure 3: Catalytic C–H silylation: one-step access to sila-drug libraries.
Figure 4: Scope of the KOt-Bu–catalyzed C–H silylation of heteroarenes.
Figure 5: Late-stage C–H silylation of pharmaceutical substances and derivatives.
Figure 6
Figure 7: Appearance of the reaction mixture after heating for 72 h.


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

    Article  CAS  Google Scholar 

  2. Godula, K. & Sames, D. C–H bond functionalization in complex organic synthesis. Science 312, 67–72 (2006).

    Article  CAS  Google Scholar 

  3. Labinger, J.A. & Bercaw, J.E. Understanding and exploiting C–H bond activation. Nature 417, 507–514 (2002).

    Article  CAS  Google Scholar 

  4. Cheng, C. & Hartwig, J.F. Catalytic silylation of unactivated C–H bonds. Chem. Rev. 115, 8946–8975 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. 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. Engl. 43, 2206–2225 (2004).

    Article  CAS  Google Scholar 

  12. Cheng, C. & Hartwig, J.F. Iridium-catalyzed silylation of aryl C–H bonds. J. Am. Chem. Soc. 137, 592–595 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Toutov, A.A. et al. Silylation of C–H bonds in aromatic heterocycles by an Earth-abundant metal catalyst. Nature 518, 80–85 (2015).

    Article  CAS  Google Scholar 

  16. Järup, L. Hazards of heavy metal contamination. Br. Med. Bull. 68, 167–182 (2003).

    Article  Google Scholar 

  17. Collins, K.D., Rühling, A. & Glorius, F. Application of a robustness screen for the evaluation of synthetic organic methodology. Nat. Protoc. 9, 1348–1353 (2014).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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This work was supported by the US National Science Foundation (NSF) under the Centers for Chemical Innovation (CCI) Center for Selective C–H Functionalization (CCHF) (grant no. CHE-1205646) and under grant no. CHE-1212767. We thank the Novartis Institutes for Biomedical Research Incorporated for the donation of samples to the CCHF. A.A.T. is grateful to the Resnick Sustainability Institute at Caltech and to Dow Chemical for a predoctoral fellowship, and to the National Sciences and Engineering Research Council of Canada (NSERC) for a Postgraduate Scholarship-Doctoral Program (PGS D) fellowship. We thank the Shanghai Institute of Organic Chemistry (SIOC) and S.-L. You (SIOC) 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.

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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., W.-B.L. and K.N.B. developed the reactions, performed the experiments and analyzed the data. A.A.T. and W.-B.L. prepared the manuscript with contributions from all authors.

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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. Catalytic C–H bond silylation of aromatic heterocycles. Nat Protoc 10, 1897–1903 (2015).

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