Portland State University. Department of Chemistry
David R. Stuart
Term of Graduation
Date of Publication
Doctor of Philosophy (Ph.D.) in Chemistry
Polycyclic aromatic hydrocarbons, Ring formation (Chemistry), Pharmaceutical chemistry, Organic chemistry
1 online resource (xvii, 222 pages)
The benzenoid core is a frequent and irreplaceable component of biologically active molecules. Structure function relationship of these compounds has been broadly analyzed and presented in numerous literature reports. Herein, we augmented existing knowledge by a broad analysis of the benzenoid substitution patterns in small molecule active pharmaceutical ingredients approved by the FDA. Our findings reveal a strong correlation that the most represented substitution patterns are those achieved via SEAr. Despite the rapid development of methods to functionalize benzenoid rings, the lack of synthetic methodologies to access sterically and electronically unfavorable positions is highlighted. We sought to establish a protocol to fulfill the synthetic gap to inaccessible benzenoids. The realization of this goal was achieved through aryne enabled C-H functionalization. Disubstituted aryl(mesityl)iodonium tosylates were demonstrated to undergo aryne formation upon ortho-deprotonation under basic conditions. Functionalization of these intermediates with a broad scope of arynophiles resulted in a variety of sterically congested tetra-substituted benzenoids. The practicality of the established protocol was supported by a successful performance of a gram scale reaction. The compatibility with halogen substituents on the aryne precursor provided an opportunity for sequential functionalization of the coupling products in transition metal catalyzed reactions. With our focus on the application of diaryliodonium salts, the diverse mechanistic possibilities of aryl(2,4,6-trimethoxyphenyl)iodonium tosylates in arylation reactions were expanded and incorporated access to aryne intermediates. The choice of the reaction conditions depends on the electronic nature of the substituents. The exceptionally mild conditions for aryne formation via deprotonation of the corresponding aryl iodides are viable in a telescoped reaction through iodonium intermediate.
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Nilova, Aleksandra, "Aryne-Guided C-H Functionalization of Benzenoid Rings Using Diaryliodonium Salts" (2020). Dissertations and Theses. Paper 5602.