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Organocatalyst-controlled site-selective arene C–H functionalization

Nature Chemistry volume 13, pages 982–991 (2021)Cite this article

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Abstract

Over the past three decades, organocatalysis has emerged as a powerful catalysis platform and has gradually been incorporated into the routine synthetic toolbox to obtain chiral molecules. However, its application in the site- and enantioselective functionalization of inactive aryl C–H bonds remains in its infancy. Here, we present an organocatalyst-controlled para-selective arene C–H functionalization strategy that addresses this issue, which remains an enduring challenge in arene functionalization chemistry. By emulating enzyme catalysis, the chiral phosphoric acid catalyst offers an ideal chiral environment for stereoinduction, and the projecting substituents give control of chemo- and site-selectivity. Various types of nucleophile are compatible with this method, affording more than 100 para-selective adducts with stereodefined carbon centres or axes in viable molecular contexts. This protocol is expected to provide a general strategy for para-selective functionalization of arene C–H bonds in a controlled manner.

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Fig. 1: Selective functionalization of C–H bonds and our design blueprint.
Fig. 2: Condition optimization and transformations.
Fig. 3: Proposed reaction pathways and mechanistic studies.

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Data availability

The X-ray crystallographic coordinates for the products reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. CCDC 1992074 (12j), CCDC 1992075 (12r), CCDC 1992076 (12s), CCDC 1992068 (14), 1992069 (16) and 1992073 (18). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Experimental procedures and characterization of new compounds are available in the Supplementary Information.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (grants 21825105 to B.T. and 21801121 to Y.-B.W.), Guangdong Provincial Key Laboratory of Catalysis (grant 2020B121201002 to B.T.), Guangdong Innovative Program (grant 2019BT02Y335 to B.T.), Shenzhen Special Funds (grants JCYJ20180305123508258 to S.-H.X. and JCYJ20180302174106405 to Y.-B.W.), Shenzhen Nobel Prize Scientists Laboratory Project and SUSTech Special Fund for the Construction of High-Level Universities (grant G02216402, B.T.). We dedicate this paper to the 100th Anniversary of Xiamen University.

Author information

Author notes

  1. These authors contributed equally: Jian-Hui Mao, Yong-Bin Wang, Limin Yang.

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Jian-Hui Mao, Yong-Bin Wang, Quan-Hao Wu, Yuan Cui, Qian Lu, Jie Lv & Bin Tan

  2. College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, China

    Limin Yang

  3. Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China

    Shao-Hua Xiang & Shaoyu Li

Authors
  1. Jian-Hui Mao
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Contributions

B.T. conceived and directed the project. J.-H.M. and Y.-B.W. designed and performed experiments. L.Y. performed the density functional theory calculations and mechanism analysis. S.-H.X., S.L., Q.-H.W., Y.C., Q.L. and J.L. helped with the collection of some new compounds and data analysis. B.T., S.-H.X., Y.-B.W., S.L. and L.Y. wrote the manuscript with input from all other authors. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Yong-Bin Wang or Bin Tan.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Chemistry thanks Debabrata Maiti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–3, Figs. 1–14, experimental data, synthesis and characterization data, NMR spectra, X-ray crystallographic data and density functional theory calculation data.

Supplementary Data 1

Crystallographic data for compound 12j. CCDC reference 1992074.

Supplementary Data 2

Structure factors file for compound 12j. CCDC reference 1992074.

Supplementary Data 3

Crystallographic data for compound 12r. CCDC reference 1992075.

Supplementary Data 4

Structure factors file for compound 12r. CCDC reference 1992075.

Supplementary Data 5

Crystallographic data for compound 12s. CCDC reference 1992076.

Supplementary Data 6

Structure factors file for compound 12s. CCDC reference 1992076.

Supplementary Data 7

Crystallographic data for compound 14. CCDC reference 1992068.

Supplementary Data 8

Structure factors file for compound 14. CCDC reference 1992068.

Supplementary Data 9

Crystallographic data for compound 16. CCDC reference 1992069.

Supplementary Data 10

Structure factors file for compound 16. CCDC reference 1992069.

Supplementary Data 11

Crystallographic data for compound 18. CCDC reference 1992073.

Supplementary Data 12

Structure factors file for compound 18. CCDC reference 1992073.

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Mao, JH., Wang, YB., Yang, L. et al. Organocatalyst-controlled site-selective arene C–H functionalization. Nat. Chem. 13, 982–991 (2021). https://doi.org/10.1038/s41557-021-00750-x

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