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Deacylation-aided C–H alkylative annulation through C–C cleavage of unstrained ketones

Abstract

Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C–H bond on the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be synthetically appealing if a common native functional group can be used as a handle to enable a general C–H annulation with diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C–C bond via a pre-aromatic intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional group tolerance.

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Fig. 1: Alkylative annulation of aromatic C(sp2)–H bonds.
Fig. 2: Reaction design.
Fig. 3: Preliminary mechanistic consideration.
Fig. 4: Synthetic applications of the deacylative C–H annulation.

Data availability

Details about materials and methods, experimental procedures and characterization data are available in the Supplementary Information. Additional data are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by NIGMS (grant no. 2R01GM109054). X.Z. thanks the International Talent Training Project of Dalian Institute of Chemical Physics for financial support. Umicore AG & Co KG is acknowledged for a donation of Ir salts. We thank J. Wang for helpful discussions.

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X.Z, Y.X. and G.D. conceived and designed the experiments. X.Z. and Y.X. performed the experiments. X.Z., Y.X. and G.D. co-wrote the manuscript.

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Correspondence to Yan Xu or Guangbin Dong.

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Peer review information Nature Catalysis thanks Laurent Chabaud, Zhiwei Zuo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Methods, References, Figs. 1–4 and NMR spectra.

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Zhou, X., Xu, Y. & Dong, G. Deacylation-aided C–H alkylative annulation through C–C cleavage of unstrained ketones. Nat Catal 4, 703–710 (2021). https://doi.org/10.1038/s41929-021-00661-7

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