A reported skeletal-editing strategy tackles pyrazole alkylation by changing the order of the chemistry: rather than forcing a reaction to choose between two tautomerically related nitrogens, it uses an asymmetric isothiazole to encode the substitution pattern first, then converts that ring into a pyrazole. The approach offers a way to address a stubborn selectivity problem, though its multistep sequence and reported substrate limitations may constrain wider use.
Why alkylating a pyrazole selectively is difficult
Pyrazoles have two adjacent nitrogen atoms. In a neutral pyrazole, the hydrogen can move between them, making the nitrogens tautomerically related. As Mark Levin, an organic chemist at the University of Chicago and co-corresponding author, explains, “The two nitrogens in the neutral pyrazole are tautomerically related.” Because each nitrogen can occupy the basic or aromatic position as the tautomer changes, both can act as nucleophiles.
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That makes it hard for a direct alkylation to distinguish one nitrogen from the other. A reaction can produce regioisomers—products with the new carbon–nitrogen bond at different positions—which may be difficult to separate. The issue is not simply whether the pyrazole can be alkylated; it is how to control which nitrogen receives the substituent.
How the isothiazole route controls the substitution pattern
The reported method avoids asking the pyrazole itself to make that choice. It begins with an asymmetric isothiazole, whose unequal starting structure helps determine where a substituent will end up in the pyrazole formed at the end.
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- Amidate the ring nitrogen. The researchers first introduce an amino group at the isothiazole ring nitrogen.
- Oxidize sulfur and expand the ring. Oxidation of the adjacent sulfur triggers a rearrangement that expands the ring, producing an isolable 1,2,3-thiadiazine-S-oxide intermediate.
- Alkylate the differentiated intermediate. The two nitrogens in this intermediate are no longer equivalent in their reactivity. The nitrogen adjacent to sulfur has sulfonamide-like character and is more acidic; the other is more imine-like. Standard alkylation conditions therefore favor the more acidic nitrogen.
- Heat to contract the ring. Heating the alkylated intermediate releases sulfur monoxide and contracts the ring, yielding a functionalized pyrazole.
The key design move is to create a chemically differentiated intermediate before the pyrazole is formed. In the direct route, tautomerism complicates selective alkylation of the pyrazole; in the reported sequence, the intermediate’s different nitrogen environments guide alkylation before ring contraction. This is a strategic alternative, not evidence that the new route is superior to established methods in yield, cost or breadth.
What kinds of alkylation can the strategy accommodate?
The report describes the method as not limited to SN2 chemistry. Christopher Kelly, a Johnson & Johnson collaborator and co-corresponding author, says that SNAr and Mitsunobu approaches can also be used. That indicates possible ways to grow the chemistry, but it does not establish that those modes have equal scope or provide general operating conditions for them.
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Why the work matters beyond pyrazole synthesis
Skeletal editing changes the atoms or connectivity of a molecule’s framework, rather than only attaching a new group to an unchanged structure. It is often associated with late-stage functionalisation. Levin argues that it can also be used earlier to resolve selectivity challenges: “You can solve selectivity challenges and I think that may be an underappreciated aspect of it.”
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What could limit broader adoption
The expert assessments in Chemistry World describe promise alongside practical constraints. Indrajeet Sharma, a synthetic chemist at 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 limitation may restrict late-stage use.
Richmond Sarpong, an organic chemist at the University of California, Berkeley, called the approach conceptually interesting but noted that it is multistep. He suggested that carrying out the transformation in one pot, in one solvent, with a single reagent could make it more attractive to medicinal chemists. This is an expert assessment of what might improve adoption, not a measured comparison with other methods.
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Chemistry World’s account does not provide reaction yields, substrate counts or detailed experimental conditions. Those figures should not be inferred from the conceptual description. The report identifies the underlying paper as A. Fanourakis and colleagues, Nature (2025), DOI 10.1038/s41586-025-08951-x.
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Sources
- Victoria Atkinson, Chemistry World, April 17, 2025: “Reimagining synthetic strategy with skeletal editing ticks box on chemists’ wish list”.
- University of Chicago Physical Sciences Division, May 5, 2025: “Chemists solve longstanding selectivity problem in complex pyrazole synthesis”.
- Underlying paper, A. Fanourakis and colleagues, Nature (2025): https://doi.org/10.1038/s41586-025-08951-x.
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