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Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles

Nature volume 510, pages 129–133 (2014)Cite this article

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A Corrigendum to this article was published on 20 August 2014

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Abstract

The development of new chemical transformations based on catalytic functionalization of unactivated C−H bonds has the potential to simplify the synthesis of complex molecules dramatically. Transition metal catalysis has emerged as a powerful tool with which to convert these unreactive bonds into carbon−carbon and carbon−heteroatom bonds1,2,3,4,5,6, but the selective transformation of aliphatic C−H bonds is still a challenge. The most successful approaches involve a ‘directing group’, which positions the metal catalyst near a particular C−H bond, so that the C−H functionalization step occurs via cyclometallation7. Most directed aliphatic C−H activation processes proceed through a five-membered-ring cyclometallated intermediate8,9,10. Considering the number of new reactions that have arisen from such intermediates, it seems likely that identification of distinct cyclometallation pathways would lead to the development of other useful chemical transformations11. Here we report a palladium-catalysed C−H bond activation mode that proceeds through a four-membered-ring cyclopalladation pathway. The chemistry described here leads to the selective transformation of a methyl group that is adjacent to an unprotected secondary amine into a synthetically versatile nitrogen heterocycle. The scope of this previously unknown bond disconnection is highlighted through the development of C−H amination and carbonylation processes, leading to the synthesis of aziridines and β-lactams (respectively), and is suggestive of a generic C−H functionalization platform that could simplify the synthesis of aliphatic secondary amines, a class of small molecules that are particularly important features of many pharmaceutical agents.

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Figure 1: Palladium-catalysed directed C–H activation modes.
Figure 2: A new amine-directed, palladium-catalysed directed C–H activation mode.
Figure 3: Scope of the palladium-catalysed C–H aziridination process.
Figure 4: Palladium-catalysed C–H carbonylation of aliphatic amines.
Figure 5: Towards a general strategy for C–H activation of aliphatic amines.

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Acknowledgements

We thank the EPSRC (A.M.), GSK (for a Case Award to B. H.) and the University of Cambridge (B.S.L.C.) for financial support, and the ERC and EPSRC for Fellowships (M.J.G.). Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.

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  1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK,

    Andrew McNally, Benjamin Haffemayer, Beatrice S. L. Collins & Matthew J. Gaunt

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  1. Andrew McNally
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Contributions

A.M., B.H. and B.S.L.C. discovered and developed the reactions. M.J.G. conceived, designed and directed the investigations and wrote the manuscript with revisions provided by A.M. and B.S.C.L.

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Correspondence to Matthew J. Gaunt.

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The authors declare no competing financial interests.

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McNally, A., Haffemayer, B., Collins, B. et al. Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510, 129–133 (2014). https://doi.org/10.1038/nature13389

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