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Updated: Jun 13, 2026
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Skeletal Editing of 4-Substituted Isothiazoles to Pyrazoles Via a Two-Atom N-S to N-N Swap
Bao-Qin Huang1, Jin-Zhen Xu1, Zi-Cheng Huang1
1State Key Laboratory of Anti-Infective Drug Discovery and Development; Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University; Guangzhou, 510006, China.
Abstract:
We report a Tf2O-promoted skeletal editing of 4-substituted isothiazoles to pyrazoles via a two-atom N-S to N-N swap. The reaction proceeds via activation of the isothiazole ring by Tf2O, followed by a nucleophilic addition/Dimroth rearrangement cascade in a one-pot process under mild conditions. A range of 4-substituted isothiazoles bearing various electronic and steric substituents are compatible, affording the corresponding pyrazoles in moderate to good yields. The method is scalable to gram-scale synthesis and allows late-stage modification of drug-derived isothiazole derivatives, demonstrating its utility for scaffold hopping in medicinal chemistry. This work establishes Tf2O activation as a viable platform for skeletal editing of five-membered heteroarenes, providing a mild and modular entry to pyrazoles from isothiazoles.
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