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Discovery of N–X anomeric amides as electrophilic halogenation reagents

Nature Chemistry (2024)Cite this article

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Abstract

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

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Fig. 1: Electrophilic halogenation is a useful C–H functionalization tool: state of the art and design of reagents based on anomeric amides.
Fig. 2: Application of 6 and 7 in other reactivity modes and flow chemistry.
Fig. 3: DFT calculation-based mechanistic study.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2270492 (5), 2238041 (6), 2252734 (7), 2247860 (16-Cl), 2287564 (28-Cl), 2252735 (34-Cl), 2263724 (38-Cl), 2255203 (39-Cl), 2287572 (3-Br), 2263723 (23-Br), 2257302 (25-Br), 2261009 (38-Br), 2278375 (39-Br) and 2261010 (43-Br). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support for this work was provided by the National Institutes of Health (grant no. GM-118176, P.S.B.). We thank D.-H. Huang and L. Pasternack (Scripps Research) for assistance with NMR spectroscopy; M. A. Schmidt (BMS) for insightful discussion on computational studies; M. Gembicky and E. Samolova (UCSD) for X-ray crystallographic analysis; and J. Chen, B. Sanchez and Q. N. Wong (Scripps Research ASF) for high-resolution mass spectrometry.

Author information

Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Yu Wang, Cheng Bi, Yu Kawamata & Phil S. Baran

  2. Chemical Process Development, Bristol Myers Squibb, New Brunswick, NJ, USA

    Lauren N. Grant & Shasha Zhang

  3. Chemical Research and Development, Pfizer Inc., Groton, CT, USA

    Lacey Samp

  4. Oncology Medicinal Chemistry Department, Pfizer Medicine Design, San Diego, CA, USA

    Paul F. Richardson, Michael R. Collins & Doris Chen

  5. AbbVie Process Research and Development, North Chicago, IL, USA

    Kaid C. Harper

  6. Small Molecule Drug Discovery, Bristol Myers Squibb, Cambridge, MA, USA

    Maximilian D. Palkowitz & Jennifer X. Qiao

  7. Advanced Chemistry Technologies Group, AbbVie Inc., North Chicago, IL, USA

    Aristidis Vasilopoulos

  8. Small Molecule Discovery Chemistry, Bristol Myers Squibb Research and Early Development, Princeton, NJ, USA

    Martins S. Oderinde

  9. Pfizer Medicine Design, Groton, CT, USA

    Chet C. Tyrol & Erik A. LaChapelle

  10. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA

    Jake B. Bailey

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Contributions

Y.W., C.B., Y.K., L.N.G. and P.S.B. conceptualized the study. Y.W. and C.B. developed the reagents and conducted reaction optimization. Y.W., C.B., M.D.P., M.R.C., M.S.O., C.C.T., D.C., E.A.L. and J.X.Q. contributed to the substrate scope and analysed the data. K.C.H. and A.V. designed and performed flow chemistry scale-up. L.N.G. performed the DFT calculations. L.S., P.F.R. and S.Z. performed the safety experiments. J.B.B. performed the X-ray crystallographic analysis. Y.W., C.B., Y.K., L.N.G., L.S., K.C.H. and P.S.B. wrote the paper. P.S.B. supervised this work. All authors contributed to discussions.

Corresponding author

Correspondence to Phil S. Baran.

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The authors declare no competing interests.

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Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–23, Schemes 1–3, experimental procedures, product characterization and NMR spectra.

Supplementary Data 1

Computational data.

Supplementary Data 2

Crystallographic data for compound 3-Br (CCDC reference 2287572).

Supplementary Data 3

Crystallographic data for compound 5 (CCDC reference 2270492).

Supplementary Data 4

Crystallographic data for compound 6 (CCDC reference 2238041).

Supplementary Data 5

Crystallographic data for compound 7 (CCDC reference 2252734).

Supplementary Data 6

Crystallographic data for compound 16-Cl (CCDC reference 2247860).

Supplementary Data 7

Crystallographic data for compound 23-Br (CCDC reference 2263723).

Supplementary Data 8

Crystallographic data for compound 25-Br (CCDC reference 2257302).

Supplementary Data 9

Crystallographic data for compound 28-Cl (CCDC reference 2287564).

Supplementary Data 10

Crystallographic data for compound 34-Cl (CCDC reference 2252735).

Supplementary Data 11

Crystallographic data for compound 38-Br (CCDC reference 2261009).

Supplementary Data 12

Crystallographic data for compound 38-Cl (CCDC reference 2263724).

Supplementary Data 13

Crystallographic data for compound 39-Br (CCDC reference 2278375).

Supplementary Data 14

Crystallographic data for compound 39-Cl (CCDC reference 2255203).

Supplementary Data 15

Crystallographic data for compound 43-Br (CCDC reference 2261010).

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Wang, Y., Bi, C., Kawamata, Y. et al. Discovery of N–X anomeric amides as electrophilic halogenation reagents. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01539-4

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