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Three-dimensional divergent hydroheteroarylation of internal alkynes with indolizines

Nature Synthesis (2025)Cite this article

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Abstract

Divergent synthesis approaches generate all isomers of a molecule, but typically focus on single-dimensional selectivity control. The more challenging two-dimensional divergent synthesis dictating two types of selectivity to achieve all four isomers has recently received some attention. As such, three-dimensional divergent synthesis through dictation of three types of selectivity to prepare eight isomers or analogues is very challenging. Here we report a catalyst-controlled three-dimensional divergent protocol for the synthesis of eight types of diaryl allyl skeleton (through combinations of E/Z and R/S stereochemistry and 1,1-/1,3-substitution patterns) from the reaction of alkynes and heteroarenes. Good geometric selectivity, regioselectivity and enantioselectivity are observed for the hydroheteroarylation process of internal alkynes with indolizines via Pd and Rh catalysis. Experimental data and density functional theory calculations reveal that the Pd and Rh catalysts have differing mechanistic pathways for the hydroarylation of the internal alkynes and corresponding allene intermediates.

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Fig. 1: Different stages of divergent synthesis.
Fig. 2: Rh-catalysed hydroheteroarylation of alkynes to prepare (E)-1,1-diaryls.
Fig. 3: Divergent hydroheteroarylation of alkynes.
Fig. 4: Three-dimensional divergent synthesis, gram-scale test and transformations.
Fig. 5: Mechanistic elucidation of Rh- and Pd-catalysed hydrofunctionalizations of internal alkynes.
Fig. 6: DFT calculations on the origin of different mechanistic pathways.

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Data availability

All relevant data are available with the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2463493 (3r) and 2381076 (6p). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Z.-T.H acknowledges the National Natural Science Foundation of China (grant no. 22371292), Ningbo Natural Science Foundation (grant no. 2023J036), Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB0610000), State Key Laboratory of Organometallic Chemistry and Shanghai Institute of Organic Chemistry for financial support. X.-S.X. acknowledges the funding from the National Natural Science Foundation of China (grant no. 22193012), the CAS Project for Young Scientists in Basic Research (grant no. YSBR-095) and the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB0590000).

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Author notes

  1. These authors contributed equally: Ao Huang, Hao-Ran Xu.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China

    Ao Huang, Zi-Jiang Yang & Zhi-Tao He

  2. State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China

    Hao-Ran Xu & Xiao-Song Xue

  3. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Xiao-Song Xue & Zhi-Tao He

  4. Ningbo Zhongke Creation Center of New Materials, Ningbo, China

    Zhi-Tao He

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Contributions

Z.-T.H. conceived the project. A.H. and Z.-J.Y. performed the experiments. H.-R.X. and X.-S.X. conducted the computations. Z.-T.H. and X.-S.X. supervised the project and wrote the manuscript with the feedback from all authors.

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Correspondence to Xiao-Song Xue or Zhi-Tao He.

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Nature Synthesis thanks Zhihui Shao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Stephanie Greed, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Supplementary Sections 1–13 and Supplementary Fig. 1.

Supplementary Data 1

X-ray crystallographic data for 3r. CCDC 2463493.

Supplementary Data 2

X-ray crystallographic data for 6p. CCDC 2381076.

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Huang, A., Xu, HR., Yang, ZJ. et al. Three-dimensional divergent hydroheteroarylation of internal alkynes with indolizines. Nat. Synth (2025). https://doi.org/10.1038/s44160-025-00870-z

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