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UBC Theses and Dissertations

Studies on radical reactions for the syntheses of pharmaceutically relevant organic motifs Zhang, Wei


Organic synthesis plays a significant role in the pharmaceutical industry, particularly in providing a large array of pharmaceutically active molecules for drug discovery. In spite of numerous methods developed, there are still many limitations in the existing synthetic methodologies for pharmarceutically important organic motifs. Two such motifs are organofluorine derivatives and nitrogen heterocycles. This thesis focuses on my research on the development of new and efficient methodologies for the syntheses of these two motifs. Chapter 2 describes the development of a new radical fluorodecarboxylation method using xenon difluoride. This method can efficiently convert 2-aryl-2-fluoroacetic acids with different substitutents to difluoromethyl aryl ethers in good to excellent yields (53-80%). Chapter 3 details studies on the mechanism of fluorine transfer in radical fluorinations by N-F reagents, including Selectfluor and N-fluorobenzenesulfonimide (NFSI). Two strategies, carbocation rearrangement and carbocation trapping, were applied to identify the possible carbocation intermediates during the fluorinations of alkyl radicals. The results of our studies are consistent with a fluorine atom transfer pathway between alkyl radicals and either Selectfluor or NFSI. Mechanistic studies into silver-catalyzed radical fluorination method indicated the formation of carbocations, presumably via a single electron transfer pathway between alkyl radicals and the silver catalyst. The carbocation formation was supported by the detection of the products from carbocation rearrangement as well as carbocation trapping by nucleophiles. Chapter 4 describes the development of a novel 6-endo-trig radical cyclization onto hydrazones for the regio-controlled and stereoselective syntheses of tetrahydrophthalazines. Two synthetic protocols using this radical cyclization were developed, including one-pot or stepwise processes, to access substituted tetrahydrophthalazines. These protocols showed good efficiency and robustness, and were able to afford high yields (50-98%) of the desired products with excellent functional group tolerance. This radical cyclization is also the first method to achieve excellent trans-diastereoselectivity in the syntheses of 1,4-disubstituted tetrahydrophthalazines. Chapter 5 describes the applications of the 6-endo-trig radical cyclization for the syntheses of other nitrogen-containing motifs, such as tetrahydroazaphthalazines, tetrahydropyradizines, dihydrophthalazines, aromatic phthalazines, and pyrazolo phthalazine diones. Additionally, we have developed a Pt-catalyzed hydrogenation for the cleavage of N-N bonds of the tetrahydrophthalazines, as a new route to 1,4-diamines.

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