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Catalytic asymmetric umpolung reactions of imines

Nature volume 523, pages 445–450 (2015)Cite this article

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Abstract

The carbon–nitrogen double bonds in imines are fundamentally important functional groups in organic chemistry. This is largely due to the fact that imines act as electrophiles towards carbon nucleophiles in reactions that form carbon–carbon bonds, thereby serving as one of the most widely used precursors for the formation of amines in both synthetic and biosynthetic settings1,2,3,4,5. If the carbon atom of the imine could be rendered electron-rich, the imine could react as a nucleophile instead of as an electrophile. Such a reversal in the electronic characteristics of the imine functionality would facilitate the development of new chemical transformations that convert imines into amines via carbon–carbon bond-forming reactions with carbon electrophiles, thereby creating new opportunities for the efficient synthesis of amines. The development of asymmetric umpolung reactions of imines (in which the imines act as nucleophiles) remains uncharted territory, in spite of the far-reaching impact such reactions would have in organic synthesis. Here we report the discovery and development of new chiral phase-transfer catalysts that promote the highly efficient asymmetric umpolung reactions of imines with the carbon electrophile enals. These catalysts mediate the deprotonation of imines and direct the 2-azaallyl anions thus formed to react with enals in a highly chemoselective, regioselective, diastereoselective and enantioselective fashion. The reaction tolerates a broad range of imines and enals, and can be carried out in high yield with as little as 0.01 mole per cent catalyst with a moisture- and air-tolerant operational protocol. These umpolung reactions provide a conceptually new and practical approach to chiral amino compounds.

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Figure 1: Design of a catalytic C–C bond-forming umpolung reaction of imines.
Figure 2: Gram-scale reaction and synthetic applications.
Figure 3: Asymmetric umpolung reactions of aryl and unsaturated aldimines.

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Acknowledgements

We are grateful for financial support from the National Institute of General Medical Science (NIH, GM-61591). We thank M. Bezpalko and B. Foxman for X-ray crystallographic characterizations of structures. C. Fei and B. Hu are acknowledged for the help in substrate preparation.

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  1. Department of Chemistry, Brandeis University, 415 South Street, Waltham, 02454, Massachusetts, USA

    Yongwei Wu, Lin Hu, Zhe Li & Li Deng

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  1. Yongwei Wu
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  3. Zhe Li
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  4. Li Deng
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Contributions

Y.W., L.H. and Z.L. performed the experiments and analysed data. Y.W. and L.D. conceived the idea and prepared this manuscript with feedback from L.H. and Z.L.

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Correspondence to Li Deng.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Text and Methods, NMR Spectra for new compounds, HPLC Spectra for chiral products and additional references (see Table of Contents for more details). (PDF 24203 kb)

Supplementary Data

This zipped file contains the 'cif' files for the X-ray crystallographic data for compounds 24Aa and 24Ge. (ZIP 10 kb)

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Wu, Y., Hu, L., Li, Z. et al. Catalytic asymmetric umpolung reactions of imines. Nature 523, 445–450 (2015). https://doi.org/10.1038/nature14617

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