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Catalytic C–H bond silylation of aromatic heterocycles

Toutov, Anton A. and Liu, Wen-Bo and Betz, Kerry N. and Stoltz, Brian M. and Grubbs, Robert H. (2015) Catalytic C–H bond silylation of aromatic heterocycles. Nature Protocols, 10 (12). pp. 1897-1903. ISSN 1754-2189. doi:10.1038/nprot.2015.118.

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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, H_2 is the only by-product generated. The procedure normally requires 48–75 h to be completed.

Item Type:Article
Related URLs:
URLURL TypeDescription ReadCube access
Toutov, Anton A.0000-0002-6561-0462
Liu, Wen-Bo0000-0003-2687-557X
Betz, Kerry N.0000-0001-9118-5909
Stoltz, Brian M.0000-0001-9837-1528
Grubbs, Robert H.0000-0002-0057-7817
Additional Information:© 2015 Macmillan Publishers. Published online 29 October 2015. 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. These authors contributed equally to this work. Anton A Toutov & Wen-Bo Liu. Contributions: 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. The authors declare no competing financial interests.
Group:Resnick Sustainability Institute
Funding AgencyGrant Number
Dow Chemical CompanyUNSPECIFIED
Natural Sciences and Engineering Research Council of Canada (NSERC)UNSPECIFIED
Shanghai Institute of Organic Chemistry (SIOC)UNSPECIFIED
Issue or Number:12
Record Number:CaltechAUTHORS:20151103-103452993
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Official Citation:Catalytic C–H bond silylation of aromatic heterocycles Anton A Toutov, Wen-Bo Liu, Kerry N Betz, Brian M Stoltz & Robert H Grubbs Nature Protocols 10, 1897–1903 (2015) doi:10.1038/nprot.2015.118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:61794
Deposited By: Heidi Rusina
Deposited On:03 Nov 2015 19:37
Last Modified:10 Nov 2021 22:54

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