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A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp3)–H amination

Nature Chemistry volume 7, pages 987–994 (2015)Cite this article

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Abstract

C–H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp3)–H bonds while displaying chemoselectivity (that is, tolerance of more oxidizable functionality) remains an unsolved problem. Here, we describe a catalyst, manganese tert-butylphthalocyanine [Mn(tBuPc)], that is an outlier to the reactivity–selectivity paradigm. It is unique in its capacity to functionalize all types of C(sp3)–H bond intramolecularly, while displaying excellent chemoselectivity in the presence of π functionality. Mechanistic studies indicate that [Mn(tBuPc)] transfers bound nitrenes to C(sp3)–H bonds via a pathway that lies between concerted C–H insertion, observed with reactive noble metals such as rhodium, and stepwise radical C–H abstraction/rebound, as observed with chemoselective base metals such as iron. Rather than achieving a blending of effects, [Mn(tBuPc)] aminates even 1° aliphatic and propargylic C–H bonds, demonstrating reactivity and selectivity unusual for previously known catalysts.

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Figure 1: The C–H oxidation reactivity/selectivity paradigm.
Figure 2: Mechanistic studies of manganese and iron C–H amination catalysts.
Figure 3: Late-stage diversification of complex molecules via [Mn(tBuPc)]-catalysed C–H amination.

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Acknowledgements

Financial support for this work was provided by the NIH/NIGMS (GM112492). S.M.P. was a NSF Graduate Research Fellow, J.R.G is a NSF Graduate Research Fellow and a Springborn Graduate Fellow, J.P.Z. is a R.C. Fuson graduate fellow, and S.M.M. is a UIUC Summer Undergraduate Research Fellow. The authors thank Bristol-Myers-Squibb for generous support with an unrestricted ‘Freedom to Discover’ grant to M.C.W. and acknowledge J.M. Howell, J.R. Clark and C.C. Pattillo for checking our experimental procedure. The authors thank J. Bertke and D. Gray for crystallographic analysis of compound 56, L. Zhu for assistance with NMR data analysis, and D. Loudermilk for creative graphic assistance.

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Author notes

  1. Shauna M. Paradine and Jennifer R. Griffin: These authors contributed equally to this work

  2. Shauna M. Paradine: Harvard University, Cambridge, Massachusetts, USA

Authors and Affiliations

  1. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

    Shauna M. Paradine, Jennifer R. Griffin, Jinpeng Zhao, Aaron L. Petronico, Shannon M. Miller & M. Christina White

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Contributions

S.M.P., J.R.G., J.P.Z., A.L.P. and S.M.M. conducted the experiments and analysed the data. S.M.P., J.R.G. and M.C.W. conceived and designed the project, analysed the data and prepared the manuscript.

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Correspondence to M. Christina White.

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Competing interests

The University of Illinois has filed a patent application on the [Mn(tBuPc)] catalyst for general C–H functionalizations. The [Mn(tBuPc)] catalyst (prod # 799688) will be offered by Aldrich through a licence from the University of Illinois.

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Crystallographic data for compound 56 (CIF 2960 kb)

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Paradine, S., Griffin, J., Zhao, J. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp3)–H amination. Nature Chem 7, 987–994 (2015). https://doi.org/10.1038/nchem.2366

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