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Organocatalytic aromatization-promoted umpolung reaction of imines

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Abstract

The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Strong nucleophiles are often required to react with the N-electrophiles without catalytic and stereochemical control. Here we show an effective strategy to realize umpolung of imines promoted by organocatalytic aromatization. The attachment of strongly electron-withdrawing groups to imines could enhance the umpolung reactivity by both electronegativity and aromatic character, enabling the direct amination of (hetero)arenes with good efficiencies and stereoselectivities. Additionally, the application of chiral Brønsted acid catalyst furnishes (hetero)aryl C–N atropisomers or enantioenriched aliphatic amines via dearomative amination from N-electrophilic aromatic precursors. Control experiments and density functional theory calculations suggest an ionic mechanism for the umpolung reaction of imines. This disconnection expands the options to forge C–N bonds stereoselectively on (hetero)arenes, which represents an important synthetic pursuit, especially in medicinal chemistry.

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Fig. 1: Motivation and design for umpolung of imines.
Fig. 2: The synthesis of atropisomeric N-heteroaryls via catalytic asymmetric umpolung reaction of iminoquinones with C-2 substituted indoles.
Fig. 3: Mechanistic investigations.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under numbers CCDC 2181457 (E-1a), 2092420 (1), 2181572 (27), 2252804 (45), 2261521 (49), 2153493 (73), 1937417 (84) and 2252823 (102). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data supporting the findings of this work are provided in the Supplementary Information including experimental procedures and characterization of new compounds.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (nos. 21825105 and 22231004 to B.T. and no. 22271135 to S.-H.X.), National Key R&D Program of China (nos. 2022YFA1503703 and 2021YFF0701604 to B.T.), National Science Foundation (CHE-1764328 to K.N.H.), Guangdong Innovative Program (no. 2019BT02Y335 to B.T.), Shenzhen Science and Technology Program (KQTD20210811090112004 and JCYJ20210324120205016 to B.T. and JCYJ20210324105005015 to S.-H.X.). Computational work was supported by the Center for Computational Science and Engineering at Southern University of Science and Technology, and the Extreme Science and Engineering Discovery Environment, which is supported by the National Science Foundation (OCI-1053575 to K.N.H.). The authors appreciate the assistance of SUSTech Core Research Facilities.

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Author notes

  1. These authors contributed equally: Ye-Hui Chen, Meng Duan.

Authors and Affiliations

  1. Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Ye-Hui Chen, Si-Li Lin, Yu-Wei Liu, Jun Kee Cheng, Shao-Hua Xiang, Peiyuan Yu & Bin Tan

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Meng Duan & Kendall N. Houk

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Contributions

B.T. conceived and directed the project. Y.-H.C. designed and performed experiments. S.-L.L, Y.-W.L., J.K.C. and S.-H.X. helped with the collection of some new compounds and data analysis. M.D. and P.Y. performed the DFT calculations and mechanism analysis. K.N.H. directed the DFT calculations and mechanism analysis. B.T., Y.-H.C., M.D., J.K.C., S.-H.X. and K.N.H. wrote the paper with input from all other authors. All authors discussed the results and commented on the manuscript. Y.-H.C. and M.D. contributed equally to this work

Corresponding authors

Correspondence to Kendall N. Houk or Bin Tan.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–797, Tables 1–5, experimental procedures, synthetic procedures, characterization data and DFT calculations.

Supplementary Data 1

Crystallographic data for compound E-1a; CCDC reference 2181457.

Supplementary Data 2

Structure factors of compound E-1a; CCDC reference 2181457.

Supplementary Data 3

Crystallographic data for compound 1; CCDC reference 2092420.

Supplementary Data 4

Structure factors of compound 1; CCDC reference 2092420.

Supplementary Data 5

Crystallographic data for compound 27; CCDC reference 2181572.

Supplementary Data 6

Structure factors of compound 27; CCDC reference 2181572.

Supplementary Data 7

Crystallographic data for compound 45; CCDC reference 2252804.

Supplementary Data 8

Structure factors of compound 45; CCDC reference 2252804.

Supplementary Data 9

Crystallographic data for compound 49; CCDC reference 2261521.

Supplementary Data 10

Structure factors of compound 49; CCDC reference 2261521.

Supplementary Data 11

Crystallographic data for compound 73; CCDC reference 2153493.

Supplementary Data 12

Structure factors of compound 73; CCDC reference 2153493.

Supplementary Data 13

Crystallographic data for compound 84; CCDC reference 1937417.

Supplementary Data 14

Structure factors of compound 84; CCDC reference 1937417.

Supplementary Data 15

Crystallographic data for compound 102; CCDC reference 2252823.

Supplementary Data 16

Structure factors of compound 102; CCDC reference 2252823.

Supplementary Data 17

Calculations archive files in XYZ format.

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Chen, YH., Duan, M., Lin, SL. et al. Organocatalytic aromatization-promoted umpolung reaction of imines. Nat. Chem. 16, 408–416 (2024). https://doi.org/10.1038/s41557-023-01384-x

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