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Chemoselective chromium-catalysed cross-coupling enables three-component tertiary alkane synthesis

Nature Synthesis volume 2, pages 1046–1058 (2023)Cite this article

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Abstract

The development of multiple-component cross-coupling reactions is a challenge due to issues of selectivity and efficiency. In the present study, we report a chromium-catalysed, multicomponent cross-coupling reaction for the synthesis of tertiary hydrocarbons using two distinct electrophiles and one nucleophile. The tertiary alkane reaction products are important three-dimensional space structures and prevalent in a variety of drugs and bioactive molecules. The strategy comprises two cross-coupling processes of inactivated geminal C–O and C–H bonds with arylmagnesium reagents and several electrophiles, enabling the inhibition of competitive side couplings to achieve high selectivity and diversification by chromium catalysis. The synthetic scope of the multicomponent process was demonstrated through the selective synthesis of a range of diarylated tertiary silanes and difluoroallylated and alkylated alkanes. The process was also found to be readily scalable and could be applied to the synthesis of market-selling drugs, anticancer agents and bioactive molecules. Mechanistic studies revealed an amphipathic diheterometalloalkane intermediate by incorporating two distinct functional groups in the formation of tertiary hydrocarbons.

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Fig. 1: Transition metal-catalysed cross-couplings.
Fig. 2: Selective, three-component, silylative cross-coupling in forming silylated tertiary alkanes.
Fig. 3: Deuterium-labelling experiments.
Fig. 4: DFT calculations.
Fig. 5: Application of the couplings in preparing bioactive tertiary alkanes.
Fig. 6: Application in the synthesis of market-selling drugs and functionalization.

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Data availability

Experimental details, nuclear magnetic resonance spectra and theoretical studies files are included as Supplementary Information.

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Acknowledgements

We thank the National Key R&D Program of China (grant no. 2021YFA1500200 to H.C.), the National Natural Science Foundation of China (grant nos. 22125107 and 21971168 to X.Z. and 21871186 to M.L.) and Fundamental Research Funds for the Central Universities (grant no. 20826041D4117 to X.Z.) for financial support. We also thank D. Deng from the College of Chemistry at Sichuan University for nuclear magnetic resonance testing.

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Authors and Affiliations

  1. Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China

    Fei Fan, Liang Ling, Chao Li, Meiming Luo & Xiaoming Zeng

  2. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Photochemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Linhong Long & Hui Chen

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Contributions

X.Z. designed the overall research project. F.F., M.L. and X.Z. designed and conducted directed evolution experiments. F.F., L.L. and C.L. conducted the studies of substrate scope and mechanistic experiments. L.L. and H.C. performed the computational studies. All authors analysed the data and contributed to the preparation of the paper. X.Z. and H.C. wrote the paper.

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Correspondence to Meiming Luo, Hui Chen or Xiaoming Zeng.

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Nature Synthesis thanks Robert Pollice 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

Experimental details: Supplementary Sections 1–10, Tables 1–9 and Figs. 1–7.

Supplementary Data 1

Cartesian coordinates for the DFT calculations.

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Fan, F., Long, L., Ling, L. et al. Chemoselective chromium-catalysed cross-coupling enables three-component tertiary alkane synthesis. Nat. Synth 2, 1046–1058 (2023). https://doi.org/10.1038/s44160-023-00364-w

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