Improvements of C–H Radio-Iodination of N-Acylsulfonamides toward Implementation in Clinics

Abstract

An improved protocol to perform C–H radio-iodination is described. These new conditions allow rapid and clean formation of radio-iodinated N-acylsulfonamides using [125I]NIS and catalytic amounts of palladium acetate and para-toluenesulfonic acid. No pre-functionalized precursors are required and the products are obtained with radiochemical conversions (RCC) of 27–84%.

Recent Advances in Synthetic Methods for Radioiodination

“…The reaction was then extended to other directing groups such as anilides and carboxamides derivatives, N-Boc-protected anilines, urea, pyrrazolyl, carboxylic acids, and nitriles. In 2019, an improvement of this methodology was reported, 50 allowing reduced amounts of palladium acetate (2 mol %) and PTSA (3 mol %), while maintaining RCCs. This new protocol led to an improvement in the purity of the crude mixture through abolition of nonradioactive side reactions, as well as an easier implementation, with palladacycle formation in several minutes instead of 24 h. Radioiodine can be introduced into aliphatic groups using nucleophilic substitution reactions involving the displacement of typical leaving groups with radioiodide under Finkelstein conditions.…”

Ligand-Enabled Copper-Mediated Radioiodination of Arenes

“…These include the click-type reaction of azides and alkynes in the presence of [ 125 I]­iodide, a Sandmeyer radioiodination of diazonium salts, and the use of silver­(I)-based Lewis acids for the radioiodination of electron-rich arenes . Methods using transition metals have also been reported, such as a nickel-mediated radioiodination of aryl bromides, arene C–H radioiodination using palladium acetate, and radio-iododecarboxylation of aryl carboxylic acids using gold­(I) intermediates . The widespread availability of aryl boronic acids and esters has meant that these have also been investigated as precursors for transition-metal-mediated radioiodination methods .…”

Gold(I)-Mediated Radioiododecarboxylation of Arenes

“…In 2018, our group explored palladiummediated C−H radioiodination. 10,11 Additionally, these methodologies can be interoperable with other radioisotopes, an option often precluded with S E Ar and S N Ar approaches. For example, Cu-catalyzed boron exchange has been used with fluorine-18, 9,12 carbon-11, 13 or astatine-211, 14 while palladiummediated C−H activation has been used with tritium 15,16 or fluorine-18.…”

“…In 2016, the groups of both Zhang and Gouverneur described Cu-catalyzed B­(OR) 2 /I exchange. In 2018, our group explored palladium-mediated C–H radioiodination. , Additionally, these methodologies can be interoperable with other radioisotopes, an option often precluded with S E Ar and S N Ar approaches. For example, Cu-catalyzed boron exchange has been used with fluorine-18, , carbon-11, or astatine-211, while palladium-mediated C–H activation has been used with tritium , or fluorine-18. − However, despite being currently the most innovative methods for introducing iodine radionuclides into organic substrates, they still have limitations and drawbacks.…”