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Site-selective and stereoselective functionalization of unactivated C–H bonds

Nature volume 533, pages 230–234 (2016)Cite this article

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Abstract

The laboratory synthesis of complex organic molecules relies heavily on the introduction and manipulation of functional groups, such as carbon–oxygen or carbon–halogen bonds; carbon–hydrogen bonds are far less reactive and harder to functionalize selectively. The idea of C–H functionalization, in which C–H bonds are modified at will instead of the functional groups, represents a paradigm shift in the standard logic of organic synthesis1,2,3. For this approach to be generally useful, effective strategies for site-selective C–H functionalization need to be developed. The most practical solutions to the site-selectivity problem rely on either intramolecular reactions4 or the use of directing groups within the substrate5,6,7,8. A challenging, but potentially more flexible approach, would be to use catalyst control to determine which site in a particular substrate would be functionalized9,10,11. Here we describe the use of dirhodium catalysts to achieve highly site-selective, diastereoselective and enantioselective C–H functionalization of n-alkanes and terminally substituted n-alkyl compounds. The reactions proceed in high yield, and functional groups such as halides, silanes and esters are compatible with this chemistry. These studies demonstrate that high site selectivity is possible in C–H functionalization reactions without the need for a directing or anchoring group present in the molecule.

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Figure 1: Site-selective C–H functionalization by donor/acceptor carbenes.
Figure 2: Synthesis of TPCP carboxylate dirhodium catalysts.
Figure 3: Catalyst optimization studies.
Figure 4: C–H functionalization of alkanes and substituted n-alkanes.
Figure 5: Structural information about the dirhodium catalysts.

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Data deposits

The crystal data have been deposited in the The Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk) under accession number 1445448.

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Acknowledgements

Financial support was provided by the National Science Foundation (NSF) through the CCI Center for Selective C–H Functionalization (CHE-1205646). We thank Novartis and AbbVie for supporting our research in C–H functionalization. We thank D. Guptill for conducting some preliminary studies on this project. D.G.M. gratefully acknowledges an NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry Emerson Center for Scientific Computation.

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Authors and Affiliations

  1. Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, 30322, Georgia, USA

    Kuangbiao Liao, Solymar Negretti, John Bacsa & Huw M. L. Davies

  2. Cherry L. Emerson Center for Scientific Computation, Emory University, 1521 Dickey Drive, Atlanta, 30322, Georgia, USA

    Djamaladdin G. Musaev

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  1. Kuangbiao Liao
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  2. Solymar Negretti
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Contributions

K.L. performed and analysed the majority of the synthetic experiments. S.N. prepared the first meta-disubstituted catalyst, D.G.M. conducted the computational studies and J.B. conducted the X-ray crystallographic studies. K.L. and H.M.L.D. designed the synthetic experiments and prepared the manuscript.

Corresponding author

Correspondence to Huw M. L. Davies.

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Competing interests

H.M.L.D. is a named inventor on a patent entitled “Dirhodium Catalyst Compositions and Synthetic Processes Related Thereto” (US 8,975,428, issued 10 March 2015). The other authors have no competing financial interests.

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Liao, K., Negretti, S., Musaev, D. et al. Site-selective and stereoselective functionalization of unactivated C–H bonds. Nature 533, 230–234 (2016). https://doi.org/10.1038/nature17651

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