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Skeletal editing offers a way around a stubborn selectivity problem in pyrazole synthesis: rather than trying to alkylate one of two tautomerically related nitrogens directly, the reported method encodes the desired substitution pattern in an asymmetric isothiazole and converts that ring into a pyrazole. The approach is a promising strategy, not yet a universal replacement for established routes; its multistep sequence and reported scope limit how broadly it may be useful.
Why is selective pyrazole alkylation difficult?
Pyrazoles are five-membered rings containing two adjacent nitrogen atoms. In a neutral pyrazole, those nitrogens are tautomerically related: the hydrogen can move between them, and the two positions can reversibly take on the basic or aromatic role. As Mark Levin, an organic chemist at the University of Chicago and co-corresponding author, put it, “The two nitrogens in the neutral pyrazole are tautomerically related.”
That interchangeability complicates direct N-alkylation. Both nitrogens can behave as nucleophiles, so an alkylating reaction may produce regioisomers—products that have the same atoms and bonds overall but differ in which nitrogen carries the new substituent. Separating such mixtures can be difficult. The researchers’ alternative is to avoid asking the pyrazole ring to distinguish the two sites at the moment of alkylation.
How does the isothiazole route control the substitution pattern?
The strategy begins with an asymmetric isothiazole, a ring whose starting-material structure already differentiates the positions that will become the pyrazole nitrogens. A sequence of ring editing and selective alkylation preserves that distinction through the conversion.
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- Amine the ring nitrogen. The isothiazole is first aminated at its ring nitrogen.
- Oxidize sulfur and expand the ring. Oxidation of the adjacent sulfur triggers a rearrangement that expands the ring to an isolable 1,2,3-thiadiazine-S-oxide intermediate.
- Alkylate the differentiated intermediate. In this intermediate, the nitrogen adjacent to sulfur has sulfonamide-like character and is more acidic; the other nitrogen is more imine-like. Standard alkylation conditions therefore favor the more acidic nitrogen, rather than relying on a distinction between the two tautomerically related nitrogens of a pyrazole.
- Heat to form the pyrazole. Heating the alkylated intermediate expels sulfur monoxide and contracts the ring, producing the functionalized pyrazole.
The order matters: the starting isothiazole’s asymmetry is translated into a chemically differentiated intermediate, selective alkylation sets the substituent position, and only then does ring contraction deliver the pyrazole. The key contribution is thus strategic control of selectivity before the target ring is formed.
Does the method require one kind of alkylation?
No single alkylation mode defines the concept. Christopher Kelly, a Johnson & Johnson collaborator and co-corresponding author, said the process is “agnostic to the alkylation mode,” citing SN2, SNAr and Mitsunobu approaches as possible ways to grow the chemistry. That flexibility should not be read as proof that each mode works equally well across substrates; the report does not establish general operating conditions or comparable scope for all of them.
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What is the broader significance of the skeletal-editing idea?
Skeletal editing is often associated with changing the framework of a complex molecule late in a synthesis. Levin argues that it can also solve a selectivity problem earlier in route design: instead of adding a substituent to an already formed pyrazole and confronting its two reactive nitrogens, chemists can edit a different ring into the pyrazole after installing the substituent selectively.
The authors have discussed whether this way of thinking might extend to other challenging heterocycles. That is a research direction, not evidence that the reported transformation is already a general platform for other ring systems.
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What are the method’s limits?
The report presents a promising conceptual approach, but outside chemists identify practical considerations that matter for adoption. Indrajeet Sharma of the University of Oklahoma praised the protocol’s practicality and manageable reagents, while cautioning that the substrate scope is limited to carbon-based groups that tolerate the alkylation conditions. That constraint may reduce its usefulness for late-stage modification of more complex molecules.
Richmond Sarpong of the University of California, Berkeley, likewise described the strategy as interesting but noted that its multistep nature could hinder broad use. He said a version that ran in the same pot, in the same solvent, with a single reagent would be more attractive to medicinal chemists. These are expert assessments of the method’s prospects, not measured comparisons against other synthesis routes.
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The Chemistry World report by Victoria Atkinson, published April 17, 2025, cites the underlying paper by A. Fanourakis and colleagues in Nature (2025), DOI 10.1038/s41586-025-08951-x. The report does not provide reaction yields, substrate counts or detailed experimental conditions, so those figures should not be inferred from the conceptual description.
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