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Intermolecular trans-bis-silylation of terminal alkynes

Nature Synthesis volume 2, pages 937–948 (2023)Cite this article

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Abstract

Addition of interelement compounds across alkynes is a straightforward strategy for the synthesis of densely functionalized alkenes, which are versatile units in numerous biologically active compounds. Of these processes the bis-silylation of alkynes is of particular interest, due to the synthetic use of the alkenyl silane reaction products. While cis-bis-silylation of alkynes is well known, trans-bis-silyation of alkynes is relatively underdeveloped. Here, we report the intermolecular trans-bis-silylation of terminal alkynes, using Pd-catalysis and disilane reagent 8-(2-substituted-1,1,2,2-tetramethyldisilanyl)quinoline (TMDQ), to selectively form trans-bis-silylated alkenes. The reaction process was found to be compatible with aryl and alkyl alkynes as well as those bearing electron-withdrawing groups and other alkenyl or alkynyl functionalities. The use of the reaction was displayed through late-stage functionalization of terminal alkynes bearing natural product or drug motifs and onward synthetic transformations of the trans-bis-silylated alkenes reaction products. Experimental and computational mechanistic studies reveal that the reaction probably proceeds through a combined cis-bis-silylation and Z/E isomerization process and that the use of TMDQ as the limiting reagent is key to the desired reactivity.

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Fig. 1: State-of-art of transition metal-catalysed E–Eʹ bond addition of alkynes and our reaction design.
Fig. 2: Late-stage functionalization of natural products and drug derivatives.
Fig. 3: Synthetic uses of these trans-bis-silylated alkenes.
Fig. 4: Mechanistic studies.
Fig. 5: Proposed catalytic cycle and DFT calculation.

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Data availability

Full experimental procedures and spectral data for this study are included in the Supplementary Information. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2217001 (3aa), 2217002 (3am) and 2217003 (6aa). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

D.Z. is grateful for the financial support from the National Natural Science Foundation of China (grant nos. 22022103, 21871146, 22188101 and 22221002, D.Z.), the National Key Research and Development Program of China (grant nos. 2019YFA0210500 and 2020YFA0711504, D.Z.), the ‘Frontiers Science Center for New Organic Matter’, Nankai University (grant no. 63181206, D.Z.) and the Fundamental Research Funds for the Central Universities and Nankai University (D.Z.). X.H. is grateful for the financial support from National Natural Science Foundation of China (grant nos. 21873081 and 22122109, X.H.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (grant no. SN-ZJU-SIAS-006, X.H.), Beijing National Laboratory for Molecular Sciences (grant no. BNLMS202102, X.H.), CAS Youth Interdisciplinary Team (grant no. JCTD-2021-11, X.H.), Fundamental Research Funds for the Central Universities (grant nos. 226-2022-00140 and 226-2022-00224, X.H.), the Center of Chemistry for Frontier Technologies and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province (grant no. PSFM 2021-01, X.H.), and the State Key Laboratory of Clean Energy Utilization (grant no. ZJUCEU2020007, X.H.). Calculations were performed on the high-performance computing system at Department of Chemistry, Zhejiang University.

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Author notes

  1. These authors contributed equally: Shuang Zhao, Yun Zhang, Rongkai Wu.

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Haihe Laboratory of Sustainable Chemical Transformations, Nankai University, Tianjin, China

    Shuang Zhao, Yun Zhang, Kailin Yin & Dongbing Zhao

  2. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China

    Rongkai Wu & Xin Hong

  3. Beijing National Laboratory for Molecular Sciences, Beijing, PR China

    Xin Hong

  4. Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, Hangzhou, China

    Xin Hong

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Contributions

S.Z., Y.Z. and K.Y. performed the experiments. X.H. and R.W. designed and carried out the DFT calculations. D.Z. conceived the concept, directed the project and wrote the paper.

Corresponding authors

Correspondence to Xin Hong or Dongbing Zhao.

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Nature Synthesis thanks Boris Maryasin, Akinobu Naka, John Spencer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Tables 1–5, Figs. 1–4, Methods, Text, Experiments, NMR spectra, HRMS spectra and References.

Supplementary Data 1

Crystallographic data for 3aa, CCDC 2217001.

Supplementary Data 2

Crystallographic data for 3am, CCDC 2217002.

Supplementary Data 3

Crystallographic data for 6aa, CCDC 2217003.

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Zhao, S., Zhang, Y., Wu, R. et al. Intermolecular trans-bis-silylation of terminal alkynes. Nat. Synth 2, 937–948 (2023). https://doi.org/10.1038/s44160-023-00325-3

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