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

Nature volume 518, pages 80–84 (2015)Cite this article

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Abstract

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.

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Acknowledgements

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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Author notes

  1. Alexey Fedorov

    Present address: Present address: Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir Prelog Weg 2, CH-8093 Zürich, Switzerland.,

  2. Anton A. Toutov and Wen-Bo Liu: These authors contributed equally to this work.

Authors and Affiliations

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

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

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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.

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

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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). https://doi.org/10.1038/nature14126

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