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Desymmetrization of cyclohexanes by site- and stereoselective C–H functionalization

Abstract

Carbon–hydrogen (C–H) bonds have long been considered unreactive and are inert to traditional chemical reagents, yet new methods for the transformation of these bonds are continually being developed1,2,3,4,5,6,7,8,9. However, it is challenging to achieve such transformations in a highly selective manner, especially if the C–H bonds are unactivated10 or not adjacent to a directing group11,12,13. Catalyst-controlled site-selectivity—in which the inherent reactivities of the substrates14 can be overcome by choosing an appropriate catalyst—is an appealing concept, and substantial effort has been made towards catalyst-controlled C–H functionalization6,15,16,17, in particular methylene C–H bond functionalization. However, although several new methods have targeted these bonds in cyclic alkanes, the selectivity has been relatively poor18,19,20. Here we illustrate an additional level of sophistication in catalyst-controlled C–H functionalization, whereby unactivated cyclohexane derivatives can be desymmetrized in a highly site- and stereoselective manner through donor/acceptor carbene insertion. These studies demonstrate the potential of catalyst-controlled site-selectivity to govern which C–H bond will react, which could enable new strategies for the production of fine chemicals.

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Fig. 1: Background to the C–H functionalization of unactivated alkanes and its relationship to the current work.
Fig. 2: Scope of the reaction with respect to substrates and aryldiazoacetates.
Fig. 3: Functionalization of disubstituted cyclohexanes.
Fig. 4: Rationalization of the observed selectivities.

Data availability

Crystallographic data for the structures reported have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1855619, 1855620 and 1855295. Copies of the data can be obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif. Complete experimental procedures and compound characterization data are available in the Supplementary Information, or from the corresponding author upon request.

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Acknowledgements

Financial support was provided by the National Science Foundation (NSF) under the CCI Center for Selective C–H Functionalization (CHE-1700982). D.G.M. gratefully acknowledges NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry Emerson Center for Scientific Computation. NMR and X-ray instrumentation used in this work was supported by the NSF (CHE-1531620 and CHE-1626172).

Reviewer information

Nature thanks V. Gevorgyan and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors

Contributions

J.F. performed the synthetic experiments. Z.R. and D.G.M. conducted the computational studies. J.B. conducted the X-ray crystallographic studies. J.F. and H.M.L.D. designed and analysed the synthetic experiments and prepared the manuscript.

Corresponding author

Correspondence to Huw M. L. Davies.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Structures of previously established catalysts.

We have previously shown that, through catalyst-directed C–H functionalization, the most accessible primary, secondary and tertiary C–H bonds within a linear alkane substrate could be selectively functionalized by using catalyst 2, 3 or 4.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data Sections 1-7.

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Fu, J., Ren, Z., Bacsa, J. et al. Desymmetrization of cyclohexanes by site- and stereoselective C–H functionalization. Nature 564, 395–399 (2018). https://doi.org/10.1038/s41586-018-0799-2

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