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Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer

Nature volume 539, pages 268–271 (2016)Cite this article

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Abstract

Despite advances in hydrogen atom transfer (HAT) catalysis1,2,3,4,5, there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen–hydrogen (N–H) bonds of N-alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination6,7,8,9,10,11 and directed carbon–hydrogen (C–H) bond functionalization12,13,14,15,16. In the latter process—a subset of the classical Hofmann–Löffler–Freytag reaction—amidyl radicals remove hydrogen atoms from unactivated aliphatic C–H bonds17,18,19,20,21. Although powerful, these transformations typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon–carbon (C–C) bonds. Here we report an approach that overcomes these limitations by homolysing the N–H bonds of N-alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C–H abstraction and radical alkylation steps. This C–H alkylation represents a catalytic variant of the Hofmann–Löffler–Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C–C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

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Figure 1: Design and development of a catalytic amidyl-mediated C–H alkylation.
Figure 2: Proposed catalytic cycle.
Figure 3: Optimization studies.
Figure 4: Substrate scope.

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Acknowledgements

We thank the NIH (R01 GM113105) for financial support. R.R.K. is a Sloan Foundation Research Fellow and Amgen Young Investigator Award recipient. We also thank M. Rauch for assistance with quantum yield measurements and D. G. Oblinsky for assistance in measuring excited-state lifetimes. We thank E. Alexanian and R. Quinn (UNC Chapel Hill) for discussions. We thank T. Rovis (Colorado State University) for sharing results before publication.

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  1. Qilei Zhu and David C. Miller: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, 08544, New Jersey, USA

    Gilbert J. Choi, Qilei Zhu, Qilei Zhu, David C. Miller, Carol J. Gu & Robert R. Knowles

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Contributions

R.R.K. and G.J.C. conceived of the research. G.J.C., Q.Z. and D.C.M. carried out experiments and analysed results with R.R.K. C.J.G. assisted with substrate synthesis. R.R.K. wrote the manuscript with input from all of the authors.

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Correspondence to Robert R. Knowles.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks A. Studer and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Choi, G., Zhu, Q., Miller, D. et al. Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer. Nature 539, 268–271 (2016). https://doi.org/10.1038/nature19811

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