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A steric tethering approach enables palladium-catalysed C–H activation of primary amino alcohols

Abstract

Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C–H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C–H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C–H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.

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Figure 1: C–H activation on aliphatic amines.
Figure 2: Conceptual approach and preliminary studies towards C–H activation of amino alcohols.
Figure 3: Synthetic applications of functionalized amino alcohol derivatives.

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Acknowledgements

The authors acknowledge the Marie Curie Foundation (D.P. and J.C.), the Engineering and Physical Sciences Research Council (EPSRC) (T.W.G. and M.J.G.) and European Research Council (V.D. and M.J.G.). The authors thank A. Smalley for density functional theory calculations and Y. Shimidzu for assistance with optimization of the C–H acetoxylation reaction. Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.

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J.C., T.W.G., D.P., V.D. and B.H. discovered and developed the reactions. M.J.G. conceived, designed and directed the investigations and wrote the manuscript.

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Correspondence to Matthew J. Gaunt.

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The authors declare no competing financial interests.

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Crystallographic data for compound int-IV-1a (CIF 374 kb)

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Calleja, J., Pla, D., Gorman, T. et al. A steric tethering approach enables palladium-catalysed C–H activation of primary amino alcohols. Nature Chem 7, 1009–1016 (2015). https://doi.org/10.1038/nchem.2367

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