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Metalloradical approach for concurrent control in intermolecular radical allylic C−H amination

Nature Chemistry volume 15, pages 498–507 (2023)Cite this article

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Abstract

Although they offer great potentials, the high reactivity and diverse pathways of radical chemistry pose difficult problems for applications in organic synthesis. In addition to the differentiation of multiple competing pathways, the control of various selectivities in radical reactions presents both formidable challenges and great opportunities. To regulate chemoselectivity and regioselectivity, as well as diastereoselectivity and enantioselectivity, calls for the formulation of conceptually new approaches and fundamentally different governing principles. Here we show that Co(II)-based metalloradical catalysis enables the radical chemoselective intermolecular amination of allylic C−H bonds through the employment of modularly designed D2-symmetric chiral amidoporphyrins with a tunable pocket-like environment as the supporting ligand. The reaction exhibits a remarkable convergence of regioselectivity, diastereoselectivity and enantioselectivity in a single catalytic operation. In addition to demonstrating the unique opportunities of metalloradical catalysis in controlling homolytic radical reactions, the Co(II)-catalysed convergent C–H amination offers a route to synthesize valuable chiral α-tertiary amines directly from an isomeric mixture of alkenes.

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Fig. 1: Radical pathways for direct functionalization of allylic C–H bonds: challenges, opportunities and solution.
Fig. 2: Convergent radical amination of allylic C−H bonds with organic azides via Co(II)-based MRC.
Fig. 3: Mechanistic studies on the Co(II)-based metalloradical system for convergent amination of allylic C–H bonds.
Fig. 4: Synthetic applications of the resulting chiral α-tertiary amines from Co(II)-catalysed allylic C–H amination.

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Data availability

All the data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information. CIF crystallographic data files and xys coordinates of the optimized structures are available as Supplementary Data. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2160224 (3as), 2160223 (3aaa) and 2160225 (3da). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We are grateful for financial support from NIH (R01-GM132471) and in part from NSF (CHE-1900375 and CHE-2154885). We also thank the financial support from NIH (S10-OD026910) and NSF (CHE-2117246) for the purchases of NMR spectrometers at the Magnetic Resonance Center of Boston College.

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Boston, MA, USA

    Pan Xu, Jingjing Xie, Duo-Sheng Wang & X. Peter Zhang

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Contributions

P.X. conducted the experiments. J.X. conducted the DFT calculations. D.-S.W. assisted the project. X.P.Z. conceived the work and directed the project. P.X. and X.P.Z. designed the experiments. P.X. and X.P.Z. wrote the manuscript.

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Correspondence to X. Peter Zhang.

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Nature Chemistry thanks Wei Guan, Forrest Michael and Tanguy Saget for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary information on experimental methods, synthetic procedures and compound characterizations, additional discussion, computational details, X-ray crystallographic data, NMR spectra and HPLC traces.

Supplementary Data 1

Crystallographic data for compound 3as; CCDC reference 2160224.

Supplementary Data 2

Crystallographic data for compound 3aaa; CCDC reference 2160223.

Supplementary Data 3

Crystallographic data for compound 3da; CCDC reference 2160225.

Supplementary Data 4

Energies and coordinates in Xys format of DFT computations.

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Xu, P., Xie, J., Wang, DS. et al. Metalloradical approach for concurrent control in intermolecular radical allylic C−H amination. Nat. Chem. 15, 498–507 (2023). https://doi.org/10.1038/s41557-022-01119-4

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