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Peer-reviewedCC BYThe Journal of organic chemistry

Aluminum Cation-Catalyzed C2-H Activation and Enantioselective Michael Addition of Indoles.

  • Ching-Pei Hsu1
  • Chu-Chiao Wen1
  • Chao-An Liu1
  • Li-Hui Hong1
  • Wan-Chi Liao1
  • Yi-Hung Liu1
  • Wei-Chih Chen2
  • Ching-Wen Chiu1,3
  1. 1Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei City10617, Taiwan.
  2. 2Department of Applied Chemistry, Providence University, No. 200, Sec. 7, Taiwan Boulevard, Taichung City43301, Taiwan.
  3. 3Center for Emerging Materials and Advanced Devices, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei City10617, Taiwan.
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Abstract

While C-H functionalization reactions are widely achieved using precious metal-based catalysts, such transformations are far less common for earth-abundant main-group metals. In this work, we demonstrate that prolinol-supported tetracoordinate aluminum cations can activate the C2-H bond of 3-substituted indoles and facilitate an enantioselective Michael addition to enones, furnishing alkylated indoles with good to excellent enantioselectivity. In contrast to transition-metal-catalyzed systems, the use of specially designed chelating enone substrates is no longer essential for the aluminum cation catalyst to induce stereoselectivity. Mechanistic studies suggest that the ligand-assisted concerted metalation-deprotonation of the C2-H bond is the rate-determining step (RDS). Stoichiometric NMR experiments provide direct evidence for an on-cycle aluminum complex, further supporting the proposed C2-H activation pathway. These findings are also consistent with the observed complete suppression of the C2-H activation when the amine basic site of the ligand was blocked or other Lewis acid catalysts were used. Our findings highlight the unique catalytic reactivity of prolinol-supported aluminum cations and provide a foundation for the future development of main-group catalysts for enantioselective C-H functionalization of heterocycles.

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Cite

BibTeXRIS
BibTeX
@article{hsu2026aluminum,
  title = {{Aluminum Cation-Catalyzed C2-H Activation and Enantioselective Michael Addition of Indoles.}},
  author = {Ching-Pei Hsu and Chu-Chiao Wen and Chao-An Liu and Li-Hui Hong and Wan-Chi Liao and Yi-Hung Liu and Wei-Chih Chen and Ching-Wen Chiu},
  journal = {The Journal of organic chemistry},
  year = {2026},
  month = oct,
  doi = {10.1021/acs.joc.6c01197},
  url = {https://europepmc.org/article/MED/42917575},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Aluminum Cation-Catalyzed C2-H Activation and Enantioselective Michael Addition of Indoles.
AU  - Ching-Pei Hsu
AU  - Chu-Chiao Wen
AU  - Chao-An Liu
AU  - Li-Hui Hong
AU  - Wan-Chi Liao
AU  - Yi-Hung Liu
AU  - Wei-Chih Chen
AU  - Ching-Wen Chiu
PY  - 2026
DA  - 2026/10/01
JO  - The Journal of organic chemistry
DO  - 10.1021/acs.joc.6c01197
UR  - https://europepmc.org/article/MED/42917575
AB  - While C-H functionalization reactions are widely achieved using precious metal-based catalysts, such transformations are far less common for earth-abundant main-group metals. In this work, we demonstrate that prolinol-supported tetracoordinate aluminum cations can activate the C2-H bond of 3-substituted indoles and facilitate an enantioselective Michael addition to enones, furnishing alkylated indoles with good to excellent enantioselectivity. In contrast to transition-metal-catalyzed systems, the use of specially designed chelating enone substrates is no longer essential for the aluminum cation catalyst to induce stereoselectivity. Mechanistic studies suggest that the ligand-assisted concerted metalation-deprotonation of the C2-H bond is the rate-determining step (RDS). Stoichiometric NMR experiments provide direct evidence for an on-cycle aluminum complex, further supporting the proposed C2-H activation pathway. These findings are also consistent with the observed complete suppression of the C2-H activation when the amine basic site of the ligand was blocked or other Lewis acid catalysts were used. Our findings highlight the unique catalytic reactivity of prolinol-supported aluminum cations and provide a foundation for the future development of main-group catalysts for enantioselective C-H functionalization of heterocycles.
SN  - 0022-3263
SN  - 1520-6904
ER  -