Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Abstract

Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, the development of methods to functionalize the α-methylene C–H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (–)-sparteine followed by Pd(0) catalysed cross-coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalysed enantioselective α-C–H coupling of a wide range of amines, which include ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C–H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.

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Figure 1: Examples of important chiral α-arylated cyclic amines and approaches for the construction of α-stereocentres.
Figure 2: Removal of the thioamide directing group.

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Acknowledgements

We acknowledge The Scripps Research Institute and the National Institutes of Health (NIGMS, 2R01GM084019) for their financial support.

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P.J. developed the enantioselective arylation reaction. P.V. and G.X. expanded the substrate scope. J.-Q.Y. conceived and supervised the project. J.-Q.Y. and P.J. wrote the manuscript.

Corresponding author

Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Jain, P., Verma, P., Xia, G. et al. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nature Chem 9, 140–144 (2017). https://doi.org/10.1038/nchem.2619

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