Functionalization of aromatic organic molecules through thermal decomposition of diaryliodonium salts

Abstract

In recent years, the DiMagno lab has focused on expanding the scope of ¹⁸F radiotracer synthetic techniques and broadening the range of accessible radiotracers and radiopharmaceuticals. Nucleophilic fluorination is the reaction of choice for ¹⁸F radiotracer synthesis. Fluorination through thermal decomposition of diaryliodonium salts is investigated. We have established that the use of a nonpolar solvent system reduces the propensity of ArI(III) species to undergo deleterious disproportionation and electron transfer reaction. Suppression of these unwanted decomposition pathways in diaryliodonium salts leads to a significantly improvement of the yields of fluoroarenes from these precursors. Its successful application for n.c.a. radiosynthesis of [ ¹⁸F]-6-fluorodopamine will be discussed. A similar preparation of [¹⁸F]-FDOPA provided the labeled compound (38% RCY) in amounts suitable for animal imaging studies.

We have also developed a mild synthetic methodology for hypervalent iodine(III) compounds mediated by Selectfluor™ BF₄. This methodology also allows the in situ preparation of diaryliodonium salts in one pot. Traditional preparations of diaryliodonium salts require the use of acidic reagents and/or heavy-metal precursors. Our elegant synthetic methodology is compatible with densely functionalized iodoarenes featuring acid sensitive moieties. Furthermore, this convenient diaryliodonium salt preparation eliminates the use of heavy-metal reagents.

Diaryliodonium salts can also be used to functionalize arenes with a variety of nucleophiles. Thermal decomposition of diaryliodonium azides has been demonstrated as an efficient route into aromatic azides and is independant of solvent choice. Our computational and experimental data show that destabilization of the reductive-elimination transition state can be achieved by steric influence. The steroselectronic control of unidirectional reductive elimination (SECURE) is made possible by the use of cyclophane as a directing group. Extension of this methodology to fluorinate highly electron-rich arenes may be necessary when unidirectional control of the transition state is not possible by electronics alone. The work in this dissertation aims at expanding the scope of PET by providing access to previously difficult or unknown radiotracers.