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Atom Replacement Strategy Achieves Precise Regiocontrol in Pyrazole Alkylation

28 July 2025

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Selectivity represents one of the fundamental principles in organic synthesis. From a retrosynthetic perspective, the conventional approach to addressing selectivity challenges involves identifying the determinant bonds and subsequently attempting to control their formation. While this strategy has provided synthetic solutions across numerous domains, it proves inadequate for many significant reactions, necessitating the development of innovative approaches to address these persistent challenges.

Pyrazole represents a common heterocyclic structure widely found in agrochemicals and pharmaceutically active compounds[1, 2]. These compounds are typically synthesized through N-alkylation of free NH-pyrazoles, but the tautomerism of unsymmetrical starting materials (along with the resonance of the deprotonated pyrazole anion) renders such kinetically controlled processes non-selective. Moreover, the chromatographic separation of the two regioisomers is often extremely challenging. These dual challenges of selectivity and separation collectively constitute the “pyrazole alkylation problem,” which has been explicitly identified by medicinal chemists as a critical issue requiring urgent resolution.

Current strategies to address this problem still rely on traditional retrosynthetic logic, including electrophile design, cleavable steric-directing auxiliaries, and biocatalysis, aiming to control the formation of peripheral C–N bonds. The team of Mark D. Levin at the University of Chicago proposed an innovative approach—"strategic atom replacement"—by substituting the sulfur atom in isothiazoles with a nitrogen atom and its alkyl fragment, successfully achieving regioselective alkylation of pyrazoles and opening new avenues for drug molecule design [3] (Figure 1).The core of this method involves using a sulfur atom as a "placeholder," which is later replaced with the target atom in subsequent steps. A key intermediate in this transformation is 1,2,3-thiadiazine-S-oxide (TDSO), serving as a bridge between isothiazoles and pyrazoles. The synthesis and functionalization of TDSO provide crucial support for regioselective control.

Figure 1. This Work

Key Methodological Steps

The authors first developed a method to synthesize unprotected NH-TDSOs starting from isothiazoles (Figure 2). The isothiazole was initially converted into an N-aminoisothiazolium salt via electrophilic amination, then transformed to the NH-TDSO by oxidative ring expansion. Since isothiazoles exhibit significantly lower nucleophilicity compared to other basic heterocycles (pKaH < 0), the authors designed a new reagent—N-Boc-O-(3,5-bis(trifluoromethyl)phenylsulfonylhydroxylamine (1). This reagent undergoes in situ deprotection to generate a highly reactive NH₂⁺ transfer species. Reagent 1 can be prepared stably on a 100 mmol scale and purified via trituration (Figure 3). Under the conditions of 1 and trifluoroacetic acid (TFA) in trifluoroethanol (TFE), isothiazoles reacted efficiently to afford N-aminoisothiazolium salts (3) in high yields. After N-amination, volatile components were removed, and the crude product underwent oxidative ring expansion with NaBO₃·4H₂O and acetic acid (AcOH), converting smoothly into TDSO (4). Using this protocol, the authors successfully synthesized 19 mono-, di-, and tri-substituted NH-TDSOs bearing diverse functional groups, two of which were characterized by single-crystal X-ray diffraction.

Figure 2. TDSO Synthesis

Figure 3. Large-Scale Preparation of Electrophilic Aminating Agent 1

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Applications and Scope:

The researchers conducted an extensive investigation of alkylation reactions between various TDSO substrates and electrophiles. They successfully synthesized a diverse array of asymmetric N-alkyl pyrazoles, including structurally complex molecules of significant medicinal importance. The methodology demonstrates considerable synthetic versatility, accommodating a wide range of substituents (Figure 4).

Nevertheless, certain limitations were identified:

· Isothiazoles bearing oxidation-sensitive functionalities proved incompatible with the N-amination process.

· TDSO derivatives containing core halogen substituents underwent decomposition under basic alkylation conditions.

· C5-unsubstituted TDSO generated sulfur-containing pyrazole derivatives upon thermal treatment.

Figure 4. Substrate Scope for NH TDSO Alkylation

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References

[1]Niu H., Yunfei D. et al. Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies. RSC Med. Chem., 2022, 13, 1300–1321.

[2]Perwaiz A. et al. Current status of pyrazole and its biological activities. J Pharm Bioallied Sci. 2016, 8(1):2-17.

[3]Chen L. et al. Strategic atom replacement enables regiocontrol in pyrazole alkylation. Nature, 2025, 641, 646–652.

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