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Organocatalytic asymmetric arylation of indoles enabled by azo groups

Nature Chemistry volume 10, pages 58–64 (2018)Cite this article

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Abstract

Arylation is a fundamental reaction that can be mostly fulfilled by electrophilic aromatic substitution and transition-metal-catalysed aryl functionalization. Although the azo group has been used as a directing group for many transformations via transition-metal-catalysed aryl carbon–hydrogen (C–H) bond activation, there remain significant unmet challenges in organocatalytic arylation. Here, we show that the azo group can effectively act as both a directing and activating group for organocatalytic asymmetric arylation of indoles via formal nucleophilic aromatic substitution of azobenzene derivatives. Thus, a wide range of axially chiral arylindoles have been achieved in good yields with excellent enantioselectivities by utilizing chiral phosphoric acid as catalyst. Furthermore, highly enantioenriched pyrroloindoles bearing two contiguous quaternary chiral centres have also been obtained via a cascade enantioselective formal nucleophilic aromatic substitution–cyclization process. This strategy should be useful in other related research fields and will open new avenues for organocatalytic asymmetric aryl functionalization.

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Figure 1: Direct arylation via formal nucleophilic aromatic substitution.
Figure 2: Control experiments and proposed reaction mechanism.

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Acknowledgements

The authors acknowledge financial support from the National Natural Science Foundation of China (grant no. 21572095), Shenzhen special funds for the development of biomedicine, the Internet, new energy and new material industries (JCYJ20150430160022510). B.T. acknowledges the Thousand Young Talents Program for financial support. Dedicated to Scott J. Miller for his great contribution to the construction of axially chiral compounds via peptide catalysis. Dedicated to Professor Shizheng Zhu on the occasion of his 70th birthday. Dedicated to Professor Chi-Ming Che on the occasion of his 60th birthday.

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  1. Liang-Wen Qi and Jian-Hui Mao: These authors contributed equally to this work.

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  1. Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, China

    Liang-Wen Qi, Jian-Hui Mao, Jian Zhang & Bin Tan

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  1. Liang-Wen Qi
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Contributions

B.T. conceived and designed the experiments. L.-W.Q. and J.-H.M. performed experiments and prepared the Supplementary Information. J.Z. helped with collecting some new compounds and analysing the data. B.T. wrote the paper. L.-W.Q. and J.-H.M. contributed equally to this work. All authors discussed the results and commented on the manuscript.

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Correspondence to Bin Tan.

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Supplementary information

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Supplementary information (PDF 16466 kb)

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Crystallographic data for compound 3o (CIF 1099 kb)

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Crystallographic data for compound 5d (CIF 1565 kb)

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Crystallographic data for compound 7 (CIF 1565 kb)

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Qi, LW., Mao, JH., Zhang, J. et al. Organocatalytic asymmetric arylation of indoles enabled by azo groups. Nature Chem 10, 58–64 (2018). https://doi.org/10.1038/nchem.2866

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