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

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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


  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.


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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


  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


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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The authors declare no competing financial interests.

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