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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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.
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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