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Site-selective and versatile aromatic C−H functionalization by thianthrenation

Abstract

Direct C–H functionalization can quickly increase useful structural and functional molecular complexity1,2,3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1,2,3,4—in the absence of such functionality, most aromatic C–H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C–H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C–H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C–H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

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Fig. 1: Selectivity of thianthrenation.
Fig. 2: Substrate scope of thianthrenation.
Fig. 3: Application of thianthrenation for functionalizing complex arenes.
Fig. 4: Proposed reaction mechanism and mechanistic experiments.

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Acknowledgements

We thank M. van Gastel (Max Planck Institute for Chemical Energy Conversion) for the acquisition of electron paramagnetic resonance spectra, as well as S. Marcus and D. Kampen (Max-Planck-Institut für Kohlenforschung) for mass spectrometry analysis. We thank G. Berger for assistance with the construction of a photoreactor. We thank UCB Biopharma and the Max-Planck-Institut für Kohlenforschung for funding.

Reviewer information

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

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Authors

Contributions

F.B. designed reagent 1, developed the reaction chemistry and investigated the mechanism. J.R., F.B. and M.H. explored the substrate scope. F.B., M.B.P., W.Y. and J.R. optimized the cross-coupling and photoredox reactions. M.B.P. investigated the selectivity of bromination. F.B., S.S., N.F. and J.R. developed the synthesis of reagent 1. T.R. and F.B. wrote the manuscript. T.R. directed the project.

Corresponding author

Correspondence to Tobias Ritter.

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Competing interests

A patent application (number EP18204755.5, Germany), dealing with the use of thianthrene and its derivatives for C–H functionalization and with reagent 1, has been filed and F.B. and T.R. may benefit from royalty payments.

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Berger, F., Plutschack, M.B., Riegger, J. et al. Site-selective and versatile aromatic C−H functionalization by thianthrenation. Nature 567, 223–228 (2019). https://doi.org/10.1038/s41586-019-0982-0

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