Photochemical permutation of thiazoles, isothiazoles and other azoles

Baptiste Roure, Maialen Alonso, Giovanni Lonardi, Dilara Berna Yildiz, Cornelia S. Buettner, Thiago Santos, Yan Xu, Martin Bossart, Volker Derdau, María Méndez, Josep Llaveria, Alessandro Ruffoni () and Daniele Leonori ()
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Baptiste Roure: University of Manchester
Maialen Alonso: RWTH Aachen University
Giovanni Lonardi: RWTH Aachen University
Dilara Berna Yildiz: RWTH Aachen University
Cornelia S. Buettner: RWTH Aachen University
Thiago Santos: RWTH Aachen University
Yan Xu: RWTH Aachen University
Martin Bossart: Sanofi Germany
Volker Derdau: Sanofi Germany
María Méndez: Sanofi Germany
Josep Llaveria: Johnson & Johnson Innovative Medicine
Alessandro Ruffoni: RWTH Aachen University
Daniele Leonori: RWTH Aachen University

Nature, 2025, vol. 637, issue 8047, 860-867

Abstract: Abstract Thiazoles and isothiazoles are privileged motifs in drug and agrochemical discovery1,2. The synthesis of these derivatives is generally approached, designed and developed on a case-by-case basis. Sometimes, the lack of robust synthesis methods to a given target can pose considerable difficulties or even thwart the preparation of specific derivatives for further study3,4. Here we report a conceptually different approach in which photochemical irradiation can be used to alter the structure of thiazoles and isothiazoles in a selective and predictable manner. On photoexcitation, these derivatives populate their π,π* singlet excited states that undergo a series of structural rearrangements, leading to an overall permutation of the cyclic system and its substituents. This means that once the initial heteroaromatic scaffold has been prepared, it can then function as an entry point to access other molecules by selective structural permutation. This approach operates under mild photochemical conditions that tolerate many chemically distinct functionalities. Preliminary findings also show the potential for extending this method to other azole systems, including benzo[d]isothiazole, indazole, pyrazole and isoxazole. This strategy establishes photochemical permutation as a powerful and convenient method for the preparation of complex and difficult-to-access derivatives from more available structural isomers.

Date: 2025
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DOI: 10.1038/s41586-024-08342-8

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