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Catalytic radical generation of π-allylpalladium complexes

Abstract

Transition metal catalysed allylic substitution is one of the most powerful and frequently used methods in organic synthesis. In particular, palladium-catalysed allylic functionalization has become a well-established strategy for constructing carbon–carbon or carbon–heteroatom bonds, and its utility has been demonstrated in natural product synthesis, drug discovery and materials science. Several methods have been developed to generate π-allylpalladium complexes through ionic mechanisms; however, these methods typically require either prefunctionalized starting materials or stoichiometric oxidants, which naturally limits their scope. Here, we show a radical approach for the generation of π-allylpalladium complexes by employing N-hydroxyphthalimide esters as bifunctional reagents in combination with 1,3-dienes. Using this strategy, we report the 1,4-aminoalkylation of dienes. The remarkable scope and functional group tolerance of this redox-neutral and mild protocol was demonstrated across >60 examples. The utility of this strategy was further demonstrated in radical cascade reactions and in the late-stage modification of drugs and natural products.

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Fig. 1: Development of a radical strategy for the generation of π-allylpalladium complexes and its application in the 1,4-aminoalkylation of dienes.
Fig. 2: Scope of palladium-catalysed 1,4-aminoalkylation of 1,3-dienes.
Fig. 3: Modification of complex architectures.
Fig. 4: Cascade reactions and manipulation of allylic amines.
Fig. 5: Preliminary mechanistic studies and proposed mechanism.

Data availability

Materials and methods, detailed optimization studies, experimental procedures, mechanistic studies, EPR spectra and NMR spectra are available in the Supplementary Information or from the corresponding author upon reasonable request. The atomic coordinates of the optimized models are provided in Supplementary Data 1. Crystallographic data for compound 20 are available free of charge from the Cambridge Crystallographic Data Centre under deposition number CCDC 1947092. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was generously supported by the Alexander von Humboldt Foundation (H.-M.H.), the European Union’s Horizon 2020 research and innovation programme, under Marie Skłodowska-Curie grant agreement number 843349-H2020-MSCA-IF-2018 (E.S.), and the Deutsche Forschungsgemeinschaft (SFB 858; Leibniz Award). We thank S. Klabunde for assistance with the EPR studies, B. Heidrich and U. Rodehorst for assistance with the X-ray photoelectron spectroscopy studies, K. Bergander for the NMR measurements and C. G. Daniliuc for the X-ray crystallographic analysis. We also thank M. van Gemmeren, F. Strieth-Kalthoff, F. Sandfort, M. J. James, T. Dalton, J. Ma, Z. Nairoukh, J.-H. Ye, T. Patra, C. Chen, Q. Sun, J. Li and M. Freitag (all at the University of Münster) for helpful discussions.

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H.-M.H. and F.G. directed the project. H.-M.H., M.K., E.S., J.L.S. and F.G. designed the experiments. H.-M.H., M.K. and E.S. performed all of the experiments and analysed all of the data. P.M.P. performed all of the computational studies. H.-M.H. and F.G. wrote the manuscript with contributions from all authors.

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Correspondence to Frank Glorius.

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Supplementary information

Supplementary Information

Supplementary methods, Figs. 1–13, Tables 1–5 and references.

Supplementary Data 1

Calculated atomic coordinates.

Compound 20

Crystallographic data for compound 20.

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Huang, HM., Koy, M., Serrano, E. et al. Catalytic radical generation of π-allylpalladium complexes. Nat Catal 3, 393–400 (2020). https://doi.org/10.1038/s41929-020-0434-0

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