Aromatization of differently substituted 3,4-dihydropyrimidinone derivatives

Lesjak Kolarović, Danijela (2016) Aromatization of differently substituted 3,4-dihydropyrimidinone derivatives. Doctoral thesis, Faculty of Science > Department of Chemistry.

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Abstract

Differently substituted 3,4-dihydropyrimidinones were prepared using a three component Biginelli reaction. By using a model compound 124-I-b, extensive preliminary research was done in order to find a new appropriate 3,4-dihydropyrimidinone aromatization method. A wide range of reaction conditions, reagents, catalysts and solvents were examined. The scope of the preliminary examination supports the literature known fact that this kinds of compounds are very difficult to be aromatized. The research in the context of this PhD thesis has resulted in four new, so far unknown methods of 3,4-dihydropyrimidinone aromatization. Efficient, rapid and selective aromatization method was developed using molecular iodine and potassium t-butoxide in dry tetrahydrofuran at room temperature (conversion 80 % - 100 %). 3,4-Dihydropyrimidinone aromatization mechanism was proposed. It includes the formation of t-butil hypoiodite as an active species during aromatization. The second aromatization method is catalytic modification of the previously described method - aromatization of 3,4-dihydropyrimidinones using t-butyl hydroperoxide, molecular iodine and potassium t-butoxide in t-butyl acetate at reflux temperature (conversion 98 % - 100 %). The series of differently substituted derivatives were oxidized using on efficient method that includes t-butyl hydroperoxide as an oxidant, potassium hydroxide as a base and potassium iodide as a catalyst. Reactions were carried out in methanol at room temperature (conversion 98 % - 100 %). In the last aromatization method, the 4-aryl-pyrimidin-2(1H)-one derivatives were dehydrogenated to the corresponding 4-aryl-pyrimidine-ones using tetracyanoethylene in acetonitrile at elevated temperatures (conversion 100 %). The final stage was “one pot synthesis” of the first three steps in the synthesis of rosuvastatin calcium. This synthesis includes 3,4-dihydropyrimidinone aromatization, the “activation” of dehydrogenated product and a substitution reaction with an appropriate nucleophile. All three stages were carried out in a single reaction flask without isolation of intermediates. The corresponding products were obtained in a yield of 12 % - 71 %, depending on the derivative.

Item Type: Thesis (Doctoral thesis)
Keywords: aromatization, Biginelli reaction, 3,4-dihydropyrimidinones, oxidation, pharmacological activity, rosuvastatin
Supervisor: Litvić, Mladen and Vinković, Vladimir
Date: 2016
Number of Pages: 202
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Branka Maravic
Date Deposited: 06 Sep 2016 16:16
Last Modified: 28 Sep 2016 07:51
URI: http://digre.pmf.unizg.hr/id/eprint/5040

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