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Aziridine synthesis by coupling amines and alkenes via an electrogenerated dication

Nature volume 596, pages 74–79 (2021)Cite this article

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Abstract

Aziridines—three-membered nitrogen-containing cyclic molecules—are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products1,2,3, and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity4,5,6. Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive7 amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach.

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Fig. 1: Development of an oxidative coupling strategy for aziridine synthesis.
Fig. 2: Scope of the aziridination reaction.
Fig. 3: Synthetic applications of the dication pool strategy.
Fig. 4: Mechanistic insight into adduct formation.

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Data availability

Crystallographic data for compounds 1 and 2 can be obtained free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk). All data supporting the findings of this paper are available within the paper and its Supplementary Information.

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Acknowledgements

We thank A. Wendlandt, M. Levin and. D. Weix for suggestions and manuscript proofreading. We also acknowledge A. Hoque and F. Wang in the Stahl laboratory for the use of, and technical assistance with, the electrochemical flow reactor. Additionally, we thank the Weix, Stahl, Yoon and Schomaker groups for sharing their chemical inventories. B. J. Thompson is acknowledged for his assistance with the design and fabrication of the power supply. T. Drier is acknowledged for the fabrication of electrochemical glassware. A. M. Wheaton is acknowledged for assistance with crystallographic studies. We also acknowledge support and suggestions from all members of the Wickens group throughout the investigation of this project. This work was supported financially by the Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin–Madison, with funding from the Wisconsin Alumni Research Foundation. Spectroscopic instrumentation was supported by a gift from P. J. and M. M. Bender, by National Science Foundation (NSF) grant CHE-1048642, and by National Institutes of Health (NIH) grants 1S10OD020022-1 and S10 OD01225. This study also made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41GM136463 (old number P41GM103399 (NIGMS)) and P41RR002301. Equipment was purchased with funds from the University of Wisconsin–Madison, the NIH (grants P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062 and S10RR029220), the NSF (DMB-8415048, OIA-9977486 and BIR-9214394), and the US Department of Agriculture (USDA). The Bruker D8 VENTURE Photon III X-ray diffractometer was partially funded by NSF award CHE-1919350 to the University of Wisconsin–Madison Department of Chemistry.

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  1. These authors contributed equally: Dylan E. Holst, Diana J. Wang

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Dylan E. Holst, Diana J. Wang, Min Ji Kim, Ilia A. Guzei & Zachary K. Wickens

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Contributions

Z.K.W., D.E.H. and D.J.W. designed the project. D.E.H., D.J.W. and M.J.K. performed the experiments and collected the data. I.A.G. collected and analysed X-ray data to provide crystal structures. Z.K.W., D.E.H., D.J.W. and M.J.K. analysed the data and contributed to writing the manuscript. D.E.H. and D.J.W. contributed equally.

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Correspondence to Zachary K. Wickens.

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Peer review information Nature thanks Louis-Charles Campeau and David Hickey for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

The file contains the following sections: 1. General Methods and Materials; 2. Supplementary Data; 3. Mechanistic Investigations; 4. Substrate preparation; 5. General Experimental Procedures; 6. Aziridine Product Isolation and Characterization; 7. Scale-Up Flow Electrolysis Set-Up and Procedure; 8. Aziridine Derivatization Reaction Isolation and Characterization; 9. X-Ray Diffraction Data; 10. References; and 11. NMR Spectra.

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Holst, D.E., Wang, D.J., Kim, M.J. et al. Aziridine synthesis by coupling amines and alkenes via an electrogenerated dication. Nature 596, 74–79 (2021). https://doi.org/10.1038/s41586-021-03717-7

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