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Abstract
Site-specific isotopically labeled molecules have a wide variety of applications in medical imaging, drug development, and basic science. Despite this utility, isotope sources are expensive and potentially hazardous, especially in the case of radioactive isotopes; therefore, new strategies to quickly and efficiently incorporate isotopes into complex organic compounds are advantageous for expanding the scope of molecules that can be feasibly labeled. This thesis focuses on new methods to prepare arenes with a single carbon isotope. While aromatic rings are a common motif in medicinally relevant compounds, strategies to prepare labeled arenes site-selectively are limited and typically involve multi-step synthesis. Chapter 1 reviews the applications of molecules labeled with carbon isotopes as well as existing strategies to prepare labeled benzene compounds with a single carbon isotope. Chapter 2 demonstrates site-specific isotopic labeling of arenes using a new method to prepare phenols in one step from one-carbon isotope sources. This method relies on a highly reactive dilithiate precursor which is capable of quickly forming the labeled aromatic ring. The synthesis of carbon-13 labeled phenols was demonstrated as well as the first synthesis of a carbon-11 phenol directly from cyclotron-produced [11C]carbon dioxide. Chapter 3 expands on the applications of the carbon-13 labeled phenols and explores the development of [13C]fospropofol as a candidate hyperpolarized magnetic imaging probe. Chapter 4 details a new synthetic route to form an isotopically labeled aniline via cyanide as the isotope source. This route was used to prepare a labeled phenyl azide substrate for a carbon-to-nitrogen exchange reaction, and the isotopic label was used to perform mechanistic studies giving insight into the fate of the labeled carbon as well as the oxidation of a key azepine intermediate.