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Strategic atom replacement enables regiocontrol in pyrazole alkylation

Nature volume 641, pages 646–652 (2025)Cite this article

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Abstract

Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike1,2. Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization3. This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, we here describe a prototypical example of an alternative conceptual approach, ‘strategic atom replacement’, in which we synthesize N-alkyl pyrazoles from isothiazoles. The net forward transformation is a ‘swap’ of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole4,5. Linking the two azoles is an orphaned heterocycle class, 1,2,3-thiadiazine-S-oxides, whose synthetic potential has yet to be tapped6. By proceeding through these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.

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Fig. 1: Background and concept.
Fig. 2: TDSO synthesis, alkylation and mechanism.
Fig. 3: Substrate scope for NH-TDSO alkylation.
Fig. 4: Selective synthesis of minimally differentiated N-alkyl pyrazoles and demonstration of further C–N bond-forming reactions.

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Data availability

All data are in the Supplementary Information. NMR data are provided in image and peaklist format; original NMR spectra files are available from the corresponding author (M.D.L.) upon request. Crystallographic data have been deposited to the CCDC (2394327, 2394342, 2394344, 2394373, 2394381 and 2394383).

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Acknowledgements

The research reported in this work was supported by the Packard Foundation, the Bristol Myers Squibb Unrestricted Research Grant, and by Johnson and Johnson Innovative Medicine. University of Chicago Research Computing Center is thanked for computational resources. L.C. was supported by a University of Chicago Quad Scholars Grant for summer research funding. A.J.B. thanks the NSF Graduate Research Fellowship Program (grant no. 2140001) for fellowship support. P.Q.K. thanks the Seymour Goodman fund for fellowship support. Enamine is thanked for a generous donation of chemicals and B. Egle (Johnson & Johnson) is thanked for conducting safety testing.

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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Alexander Fanourakis, Yahia Ali, Liao Chen, Patrick Q. Kelly, Abigail J. Bracken & Mark D. Levin

  2. Discovery Process Research, Johnson & Johnson Innovative Medicine, Spring House, PA, USA

    Christopher B. Kelly

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  1. Alexander Fanourakis
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Contributions

A.F., Y.A., L.C. and C.B.K. designed and conducted experiments, and collected and analysed the data. P.Q.K. and A.J.B. conducted computations of the mechanism. P.Q.K and A.J.B. conducted crystallographic measurements and analyses. M.D.L. and A.F. conceived of the project and wrote the manuscript with input from all authors. M.D.L. and C.B.K. supervised the research.

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Correspondence to Christopher B. Kelly or Mark D. Levin.

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Supplementary Sections 1–25, including Figs. 1–31 and Tables 1–9. See the Table of Contents for details.

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Fanourakis, A., Ali, Y., Chen, L. et al. Strategic atom replacement enables regiocontrol in pyrazole alkylation. Nature 641, 646–652 (2025). https://doi.org/10.1038/s41586-025-08951-x

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