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Palladium-catalysed anti-Markovnikov selective oxidative amination

Nature Chemistry volume 10, pages 333–340 (2018)Cite this article

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Abstract

In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep approach and require one reactant to be activated prior to the carbon–nitrogen bond formation. This leads to a reaction inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond, in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations are reported.

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Figure 1: Current strategies for the anti-Markovnikov oxidative amination of simple alkenes.
Figure 2: Mechanistic investigation of the anti-Markovnikov oxidative amination through reagent order determination and Hammett plot analysis.
Figure 3: Deuterium labelling studies as probes to distinguish between multiple mechanistic pathways.
Figure 4: A catalytic cycle proposal based on the mechanistic studies undertaken.

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Acknowledgements

The authors thank the University of Illinois and the National Institutes for Health (R35-GM125029) for their generous support.

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  1. Department of Chemistry, University of Illinois, Urbana-Champaign, 600 S. Mathews, Urbana, 61801, Illinois, USA

    Daniel G. Kohler, Samuel N. Gockel, Jennifer L. Kennemur, Peter J. Waller & Kami L. Hull

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  1. Daniel G. Kohler
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  2. Samuel N. Gockel
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  3. Jennifer L. Kennemur
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Contributions

D.G.K. and K.L.H. conceived and designed the experiments and wrote the manuscript. D.G.K. and P.J.W. discovered the reaction. D.G.K., J.L.K. and S.N.G. performed the experiments.

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Correspondence to Kami L. Hull.

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The authors declare no competing financial interests.

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Crystallographic data for the bis(tetrabutylammonium) tetrachloropalladate. (CIF 810 kb)

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Kohler, D., Gockel, S., Kennemur, J. et al. Palladium-catalysed anti-Markovnikov selective oxidative amination. Nature Chem 10, 333–340 (2018). https://doi.org/10.1038/nchem.2904

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