Strategic atom replacement enables regiocontrol in pyrazole alkylation

Alexander Fanourakis, Yahia Ali, Liao Chen, Patrick Q. Kelly, Abigail J. Bracken, Christopher B. Kelly () and Mark D. Levin ()
Additional contact information
Alexander Fanourakis: University of Chicago
Yahia Ali: University of Chicago
Liao Chen: University of Chicago
Patrick Q. Kelly: University of Chicago
Abigail J. Bracken: University of Chicago
Christopher B. Kelly: Johnson & Johnson Innovative Medicine
Mark D. Levin: University of Chicago

Nature, 2025, vol. 641, issue 8063, 646-652

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08951-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:641:y:2025:i:8063:d:10.1038_s41586-025-08951-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08951-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().