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

Nature Chemistryvolume 10pages583591 (2018) | Download Citation

Abstract

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

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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.

Author information

Author notes

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

Affiliations

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

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

Authors

  1. Search for Joseph R. Clark in:

  2. Search for Kaibo Feng in:

  3. Search for Anasheh Sookezian in:

  4. Search for M. Christina White in:

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.

Competing interests

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

Corresponding author

Correspondence to M. Christina White.

Supplementary information

  1. Supplementary information

    Supplementary experimental data, synthetic procedures and chemical compound characterization data

  2. Crystallographic data

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

  3. Crystallographic data

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

  4. Crystallographic data

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

  5. Crystallographic data

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

  6. Crystallographic data

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

  7. Crystallographic data

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

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DOI

https://doi.org/10.1038/s41557-018-0020-0