Synthesis of aza-aromatic hydroxylamine-O-sulfonates and their application to tandem nucleophilic addition-electrophilic 5-endo-trig cyclization |
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Authors: | Jaroslaw Saczewski Maria GdaniecPatrick J Bednarski Anna Makowska |
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Institution: | a Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, Gdańsk 80-416, Poland b Faculty of Chemistry, Adam Mickiewicz University, Ul. Grunwaldzka 6, Poznań 60-780, Poland c Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, D-17487 Greifswald, Germany |
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Abstract: | Hydroxylamine-O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine-O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition-electrophilic 5-endo-trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine-O-sulfonates and N-(5-methoxy-2H-1,2,4]thiadiazolo2,3-a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2H-1,2,4]thiadiazolo3,2-a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC50 in the range 1.47-2.97 μM). |
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Keywords: | Hydroxylamine-O-sulfonic acid HOSA 5-endo-trig Cyclization Nucleophilic addition Aza-aromatic hydroxylamine-O-sulfonic acids Cytostatic activity |
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