The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate.
The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines.
In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones.
Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/26332 |
| Date | 23 February 2011 |
| Creators | Thansandote, Praew Petcharat |
| Contributors | Lautens, Mark |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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