Synthesis of Nitrogen Heterocycles via 1,3-Dipolar Cycloadditions - Method Development and Applications

Licentiatavhandling, 2012

Because of the diverse properties displayed by nitrogen heterocycles, they are one of the most commonly used structural elements in drug discovery. Due to this variation in properties, however, the chemistry and synthetic pathway to each heterocycle is unique. This is one of the reasons why heterocyclic chemistry is still an important and interesting research field for organic chemists today. This Licentiate Thesis is focused on the synthesis of two types of nitrogen heterocycles, 1,2,3-triazoles and the pyrrolidines, via 1,3-dipolar cycloadditions. In the first part of this thesis, the development of an experimentally simple and safe sequential one-pot procedure for the ruthenium catalyzed azide-alkyne 1,3-dipolar cycloaddition (RuAAC), to form 1,5-disubstituted 1,2,3-triazoles, is presented. The method uses microwave heating to enable shorter reaction time compared to conventional heating. The use of [RuClCp*(PPh3)2 and [RuCl2Cp*]x as catalysts has been studied, and the solvent compatibility of the reaction has been investigated. A broad range of functional groups present on the substrates is tolerated, such as alcohols, esters, chlorides, amides, carbamates, nitro compounds, fluorides, sulfides, pyridines, imidazoles, and the reaction affords the 1,5-disubstituted 1H-1,2,3-triazole in good to excellent yield. The 1,5-substitution pattern was verified by 2D NOESY experiments. In the second part of the thesis, the 1,3-dipolar cycloaddition of azomethine ylides to dipolarophiles has been applied for the covalent functionalization of carbon nanotubes (CNTs) on a silicon-metal chip. The azomethine ylide was formed in situ by condensation of glycine with benzaldehyde. The covalent functionalization of active azide groups on the CNTs was carried out via a two step process and verified by the introduction of fluorine via a copper catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. The functionalized CNTs on chip were analysed by SEM equipped with an EDS detector. The results point toward successful covalent attachment of active azide functional groups on the CNTs on chip. This platform looks promising for future applications such as biosensors