Skeletal Editing of 4-Substituted Isothiazoles to Pyrazoles Via a Two-Atom N-S to N-N Swap.

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.