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Palladium-catalysed transannular C–H functionalization of alicyclic amines

Nature volume 531, pages 220–224 (2016)Cite this article

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Abstract

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C–H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development1,2,3,4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited6,7. Here we report a transannular approach to selectively manipulate the C–H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

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Figure 1: Relevance of alicyclic amines and strategies for their late-stage functionalization.
Figure 2: Design and realization of transannular C–H activation of alicyclic amines.
Figure 3: Transannular C–H arylation of 3-azabicyclo[3.1.0]hexane core.
Figure 4: Transannular C–H arylation of alicyclic amines.

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Acknowledgements

We acknowledge J. W. Kampf for X-ray crystallographic analyses of 4a, 11b, an analogue of 11g, 11h and 14a. J.T.T. was supported by an NIH post-doctoral fellowship (F32 GM109479). This work was supported by NIGMS grant GM073836. We acknowledge funding from NSF grant CHE-0840456 for X-ray instrumentation.

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Author notes

  1. Joseph J. Topczewski and Pablo J. Cabrera: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Joseph J. Topczewski, Pablo J. Cabrera, Noam I. Saper & Melanie S. Sanford

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  1. Joseph J. Topczewski
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  2. Pablo J. Cabrera
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  3. Noam I. Saper
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Contributions

J.T.T., P.J.C. and N.I.S. discovered and developed the reaction. J.T.T., P.J.C. and M.S.S. conceived and designed the investigations. M.S.S. directed and supported the research. J.T.T., P.J.C. and M.S.S. wrote and revised the manuscript.

Corresponding author

Correspondence to Melanie S. Sanford.

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The authors declare no competing financial interests.

Additional information

Metrical parameters for the structures are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC-1401221, 1401222, 1440132, 1416579 and 1416516.

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This file contains Supplementary Text and Data – see contents page for details. (PDF 14418 kb)

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Topczewski, J., Cabrera, P., Saper, N. et al. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016). https://doi.org/10.1038/nature16957

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