Abstract
The pursuit of increasingly complex, three-dimensional molecules is pushing the boundaries of modern organic synthesis, particularly in drug discovery where rigid, saturated scaffolds such as cyclobutanes, azetidines and oxetanes are in high demand. Here we outline a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of nickel-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have been nearly impossible to access before without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry and related fields.
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Data availability
All data are available in the main text or Supplementary Information. Experimental procedures in graphical form, additional experimental results, NMR characterization data and X-ray crystallographic details for all new compounds prepared in this study are provided in Supplementary Information. The X-ray crystallographic coordinates for compound Ni(L10)Cl2 have been deposited at the Cambridge Crystallographic Data Centre with the accession code 2388490. Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
Financial support for this work was provided by the NSF Center for Synthetic Organic Electrochemistry (CHE-2002158). L.M. thanks the Swedish Research Council (Vetenskapsrådet, VR-2023-00499) and the Stiftelsen Bengt Lundqvists Minne for postdoctoral fellowships. P.N. thanks the Kellogg Family for a graduate research fellowship. We thank L. Pasternack and G. J. Kroon for assistance with NMR spectroscopy; J. B. Bailey for X-ray crystallographic analysis; J. Chen, B. Sanchez, Q. N. Wong and J. Lee for assistance with high-resolution mass spectrometry; and M. Costantini, Á. Péter, M. Nassir, A. Pollatos, G. Laudadio, T. El-Hayek Ewing and G. Leoni for helpful discussions.
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L.M., P.N. and P.S.B. conceived the project. All authors were involved in designing, performing and analysing the experiments and writing the paper. P.S.B. directed the project.
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P.S.B. is a paid consultant at Bristol Myers Squibb. The other authors declare no competing interests.
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General procedures with visual guides, Supplementary discussion on reaction optimization, Tables 1–22, Figs. 1 and 2, Schemes 1 and 2, Discussion on limitations, and Characterization data.
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Massaro, L., Neigenfind, P., Feng, A. et al. Triply convergent Ni-electrocatalytic assembly of 1,1-diaryl cyclobutanes, azetidines and oxetanes. Nat. Chem. 18, 326–334 (2026). https://doi.org/10.1038/s41557-025-01990-x
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DOI: https://doi.org/10.1038/s41557-025-01990-x
