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Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

Abstract

Transition-metal-catalysed direct C–H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. Several methods have been developed for the direct sp3 C–H functionalization of secondary and tertiary aliphatic amines, but site-selective functionalization of primary aliphatic amines in remote positions remains a challenge. Here, we report the direct, highly site-selective γ-arylation of primary alkylamines via a palladium-catalysed C–H bond functionalization process on unactivated sp3 carbons. Using glyoxylic acid as an inexpensive, catalytic and transient directing group, a wide array of γ-arylated primary alkylamines were prepared without any protection or deprotection steps. This approach provides straightforward access to important structural motifs in organic and medicinal chemistry without the need for pre-functionalized substrates or stoichiometric directing groups and is demonstrated here in the synthesis of analogues of the immunomodulatory drug fingolimod directly from commercially available 2-amino-2-propylpropane-1,3-diol.

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Figure 1: Transition-metal-catalysed C–H functionalization of alkylamines.
Figure 2: Synthetic applications of palladium-catalysed arylation of alkylamines.
Figure 3: Insights into the reaction mechanism of palladium-catalysed arylation of alkylamines.

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Acknowledgements

The authors acknowledge Indiana University–Purdue University Indianapolis and NSF CHE-1350541 for financial support. The authors thank J. Miao and K. Yang for discussions on this project.

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Y.L. and H.G. conceived and designed the experiments. Y.L. performed the experiments. Y.L. and H.G. analysed the data. H.G. wrote the manuscript.

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Correspondence to Haibo Ge.

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The authors declare no competing financial interests.

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Crystallographic data for compound 6. (CIF 687 kb)

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Liu, Y., Ge, H. Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nature Chem 9, 26–32 (2017). https://doi.org/10.1038/nchem.2606

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