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Enantioconvergent copper-catalysed difluoromethylation of alkyl halides

Nature Catalysis volume 7, pages 1372–1381 (2024)Cite this article

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Abstract

Stereochemically controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF2H) groups at chiral centres are emerging as pivotal components in pharmaceuticals owing to their distinct hydrogen-bonding property. However, a general approach for introducing CF2H groups in an enantioselective manner has remained elusive. Here we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a strategy for constructing CF2H-containing stereocentres. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic CF2H-zinc reagent. This method allows the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF2H analogues with excellent enantioselectivity. Mechanistic studies reveal a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantiodetermining steps. This copper-catalysed difluoromethylation process opens an avenue for the efficient preparation of CF2H-containing pharmaceuticals.

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Fig. 1: Development of Cu-catalysed enantioconvergent difluoromethylation of alkyl halides.
Fig. 2: Scope for Cu-catalysed enantioconvergent difluoromethylation of alkyl halides.
Fig. 3: Synthetic applications of enantioconvergent difluoromethylation reaction.
Fig. 4: Mechanistic studies and proposed catalytic cycle.
Fig. 5: DFT calculations on the Cu-catalysed enantioconvergent difluoromethylation reaction at the B3LYP-D3BJ/def2-TZVP//B3LYP-D3BJ/def2-SVP level of theory.
Fig. 6: Other families of alkyl electrophiles investigated in this enantioconvergent difluoromethylation reaction.

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Data availability

The data generated in this study are provided in Supplementary Information and related files provided with this paper. Data are also available from the corresponding author upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers 2300997 and 2303333. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Acknowledgements

This work was supported by the National Institute of General Medical Science (R35GM146765). Mechanistic studies were supported by National Science Foundation under grant CHE-2237757. W.L. also thanks the ACS Herman Frasch Foundation (926-HF22) for the financial support. NMR experiments were performed using a Bruker AVANCE NEO 400 MHz NMR spectrometer, funded by NSF-MRI grant CHE-1726092. Funding for the D8 Venture diffractometer was through NSF-MRI grant CHE-1625737.

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Authors and Affiliations

  1. Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA

    Decai Ding, Lingfeng Yin, Jeanette A. Krause & Wei Liu

  2. Department of Chemistry, Purdue University, West Lafayette, IN, USA

    Andrew T. Poore, Stephen C. Yachuw, Rachael M. Knieser & Shiliang Tian

  3. Department of Chemistry, National Cheng Kung University, Tainan, Taiwan

    Yeu-Shiuan Ho, Yu-Ho Cheng, Chi-Tien Hsieh & Mu-Jeng Cheng

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Contributions

D.D. and W.L. designed experiments. D.D. and L.Y. performed the synthetic experiments and prepared the supplementary information. A.T.P., S.C.Y., R.M.K. and S.T. performed EPR experiments. M.-J.C., Y.-H.C. and C.-T.H. conducted DFT calculations. J.A.K. performed X-ray diffraction analysis. W.L. conceived and supervised the project. W.L. wrote this manuscript with contributions from all authors.

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Correspondence to Wei Liu.

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Nature Catalysis thanks Al Postigo, Nigam Rath, Qilong Shen, Beatrice Tuccio-Lauricella and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–396, Tables 1–17, Notes, Methods and References.

Supplementary Data 1

Crystallographic data for compound 24.

Supplementary Data 2

Crystallographic Information File check report for compound 24.

Supplementary Data 3

Crystallographic data for compound L*Cu(OAc)2.

Supplementary Data 4

Crystallographic Information File check report for compound compound L*Cu(OAc)2.

Supplementary Data 5

Tables of energy and coordinates for optimized structures.

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Ding, D., Yin, L., Poore, A.T. et al. Enantioconvergent copper-catalysed difluoromethylation of alkyl halides. Nat Catal 7, 1372–1381 (2024). https://doi.org/10.1038/s41929-024-01253-x

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