The reactivity of tetrahydropyrrolo[1,2- b ]isothiazol-3(2 H )-one 1,1-dioxides
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ORIGINAL PAPER
The reactivity of tetrahydropyrrolo[1,2‑b]isothiazol‑3(2H)‑one 1,1‑dioxides Taras V. Omelian1,2 · Alexey V. Dobrydnev1,2 · Oleksandr Yu. Utchenko1 · Eugeniy N. Ostapchuk1,2 · Irina S. Konovalova3 · Yulian M. Volovenko2 Received: 13 April 2020 / Accepted: 23 September 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract The present work is devoted to the study of the reactivity of tetrahydropyrrolo[1,2-b]isothiazol-3(2H)-one 1,1-dioxide framework. This scaffold possesses two reaction centers: the EWG-activated methylene group and the carbonyl functionality, which are the basic variation points. At the same time, the attached 3a-substituent had a significant impact on the course of the explored reactions and its role was also investigated. In this regard, the corresponding 3a-unsubstituted and 3a-methylated tetrahydropyrrolo[1,2-b]isothiazol-3(2H)-one 1,1-dioxides were chosen as model substances involved in chemical properties evaluation. With a view to pre-assess the activity of the model compounds, a deuteration study was conducted. Furthermore, the interaction with a variety of electrophilic and nucleophilic agents was explored. The most striking difference in the chemical behavior was observed in the reaction with the Wittig reagent triphenylcarbethoxymethylenephosphorane (Ph3P=CHCO2Me). In particular, unlike the 3a-unsubstituted substrate, the 3a-methylated one gave the unusual phosphonium betaine, namely 3a-methyl-2-[2-(triphenylphosphonio)acetyl]-3a,4,5,6-tetrahydropyrrolo[1,2-b]isothiazol-3-olate 1,1-dioxide. The proposed mechanistic insights of this reaction have been discovered. Graphic abstract
Keywords Sulfonamides · Heterocycles · Nucleophilic substitutions · Electrophilic substitutions · X-ray structure determination
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00706-020-02694-3) contains supplementary material, which is available to authorized users. * Alexey V. Dobrydnev [email protected] 1
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
2
Taras Shevchenko National University of Kyiv, Lva Tolstoho Street 12, Kyiv 01033, Ukraine
3
SSI “Institute for Single Crystals” NAS of Ukraine, Nauky Avenue 60, Kharkiv 61072, Ukraine
Sulfonamide motif is popular within medicinal chemistry, since it serves as a bioisosteric equivalent of the carboxamide group. The similarity between these two functionalities is based on the convergence of electronic and conformational aspects [1]. Another reason for remarkable applications of sulfonamide motif in the pharmaceutical industry [2–6] and materials science is their stability under physiological conditions. Only a few known enzymes can hydrolyze the S O2–N bond [7]. The most well-known example of successful utilization of bioisosteric replacement in medical chemistry is prontosil [8], the first representative of marketed sulfa drugs
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that treat bacterial infections. Prontosil earned its creator Gerha
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