Synthetic studies of nitrogen containing heterocycles, particularly pyrazole and benzotriazine derivatives

University dissertation from Stockholm : Karolinska Institutet, Biosciences and Nutrition

Abstract: This thesis will mainly focus on the chemistry of nitrogen containing heterocyclic compounds, particularly pyrazole and benzotriazine and related ring systems to these compounds. The first part includes a short introduction to biologically important compounds as well as a description of reactivity and chemistry of benzo[c]pyrazole (indazole) and its derivatives. The second part features the synthesis of 3-substituted tetrahydroindazoles and hexahydroindazoles using alpha,beta-unsaturated ketones and hydrazine derivatives. Dehydrogenation of 3-substituted hexahydroindazoles and tetrahydroindazoles using different equivalents DDQ and p-chloranil is also discussed. The third part describes synthesis of a hitherto unknown spirocyclic dihydropyrazolone, namely 4-cyano-1-cyanoacetyl-2-(cyclohexen-1-yl)-1,2-diazaspiro[4.5]decan-3-one, whose structure was confirmed by an X-ray analysis. Mild hydrolysis of this compound resulted in isolation of a des-cyanoacetylated product. In addition, prolonged reflux time during hydrolysis delivered a fully hydrolysed product, namely 4-cyano-1,2-diazaspiro[4.5]decan-3-one, whose structure also was established by X-ray crystallography. The fourth part of this thesis deals with the syntheses of 3,3'-biindolyl and 3,3'-biindazolyl derivatives. A new method for the preparation of 3,3'-biindolyl derivatives via oxidative coupling induced by tellurium tetrachloride was successfully developed. Attempts to achieve 3,3'-biindazolyl derivatives using the same reaction conditions failed. However isolation of 3,3'-biindazolyl derivatives using palladium-catalyzed Stille cross-coupling reaction on SEMprotected derivatives (SEM=2-(trimethylsilyl)ethoxymethyl) is described. Upon preparation of 3,3'-biindazolyl, inconsistencies between the previously reported data promoted further investigations. Hence, the molecule was subjected to an X-ray analysis which gave conclusive evidence for the SEM-protected 3,3'-biindazolyl structure. The last part describes attempts to synthesize 3-substituted indazoles. The anticipated transformation involved treatment of o-azidobenzonitriles with Grignard or lithium reagents, which surprisingly delivered an unexpected product, namely benzotriazines, in good yields. It has also been clarified that substituents on 2-azidobenzonitriles have a clear impact on the formation of products and yields. Furthermore, when aryl Grignard or lithium reagents were used, the only isolable products were aryl-triazene derivatives.

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