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

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 α,β-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 SEM-protected 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.

List of scientific papers

I. Nakhai A, Bergman J (2009). Synthesis of hydrogenated indazole derivatives starting with alpha,beta-unsaturated ketones and hydrazine derivatives. Tetrahedron. 65: 2298-2306

II. Nakhai A, Rafterty J, Bergman J, Joule JA (2008). The reaction of cyclohexanone azine with cyanoacetic acid acetic anhydride. J Heterocycl Chem. 45: 1513-1516

III. Nakhai A, Bergman J (2009). Synthetic approaches to 3,3-biindolyl and 3,3-biindazolyl derivatives. [Manuscript]

IV. Nakhai A, Stensland B, Svensson PH, Bergman J (2009). Synthesis of benzotriazine and aryl-triazene derivatives starting with 2-azidobenzonitrile derivatives. [Manuscript]