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Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Nature Chemistry volume 10, pages 583–591 (2018)Cite this article

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Abstract

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C–H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base–metal-catalysed C–H aminations and provide new opportunities for tunable selectivities.

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Fig. 1: Converting C–H bonds to C–N bonds.
Fig. 2: Intermolecular benzylic C–H amination substrate scope.
Fig. 3: Late-stage benzylic C–H amination of bioactive molecules.
Fig. 4: Late-stage benzylic C–H amination of natural products.
Fig. 5: Mechanism of [MnIII(ClPc)]-catalysed benzylic C–H amination.

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Acknowledgements

Financial support for this work was provided by the NIGMS Maximizing Investigators’ Research Award MIRA (R35 GM122525). J.R.C. is an NIH Ruth Kirschstein Postdoctoral Fellow (1 F32GM112501-01A1). The authors thank D.L. Gray and T.J. Woods for crystallographic analysis of compounds 36, 37, 38 and 44. The authors thank L. Zhu for assistance with NMR spectroscopy and T. Nanjo, R. Ma, W. Liu and J. Griffin for checking the experimental procedures.

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Author notes

  1. These authors contributed equally: Kaibo Feng and Anasheh Sookezian.

Authors and Affiliations

  1. Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL, USA

    Joseph R. Clark, Kaibo Feng, Anasheh Sookezian & M. Christina White

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  1. Joseph R. Clark
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Contributions

M.C.W. and J.R.C. conceived and designed the project. J.R.C., K.F. and A.S. conducted the experiments and, with M.C.W., analysed the data. M.C.W. and J.R.C. prepared the manuscript with input from K.F. and A.S.

Corresponding author

Correspondence to M. Christina White.

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Competing interests

The University of Illinois has filed a patent application on the [Mn(ClPc)] catalyst for intermolecular C–H functionalization. The [Mn(ClPc)] catalyst (product # 901425) will be offered by MilliporeSigma through a licence from the University of Illinois.

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Supplementary information

Supplementary information

Supplementary experimental data, synthetic procedures and chemical compound characterization data

Crystallographic data

CIF for compound (±)-36 with embedded structure factors; CCDC reference: 1587014

Crystallographic data

CIF for compound (±)-37 with embedded structure factors; CCDC reference: 1587015

Crystallographic data

CIF for compound (-)-38; CCDC reference: 1587016

Crystallographic data

Structure factors for compound (-)-38; CCDC reference: 1587016

Crystallographic data

Description: CIF for compound (-)-44; CCDC reference: 1587017

Crystallographic data

Structure factors for compound (-)-44; CCDC reference: 1587017

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Clark, J.R., Feng, K., Sookezian, A. et al. Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization. Nature Chem 10, 583–591 (2018). https://doi.org/10.1038/s41557-018-0020-0

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