This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis. Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination. Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis. Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)-complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap. Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-242259 |
| Date | January 2015 |
| Creators | Fardost, Ashkan |
| Publisher | Uppsala universitet, Institutionen för läkemedelskemi, Uppsala |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 194 |
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