Effects of protecting group and counter‐anion on fluorination, bromination, and intramolecular cyclization of phenethylamine diaryliodonium salts: Quantum chemical analysis

AbstractWe analyze the effects of protecting group(s) and counter‐anion on the relative efficiency of fluorination, bromination and intramolecular cyclization of phenethylamine diaryliodonium salts (1) for nucleophilic fluorination using CsF as a model system for the synthesis of radiopharmaceuticals such as 18F‐dopa and 18F‐dopamine. We demonstrate by quantum chemical analysis that protection of –NH2 by –Boc groups strongly influences the relative yields of nucleophilic fluorination versus side reactions (bromination and intramolecular cyclization) through intricate interactions with iodonium, counter‐anion (Br−, F−, or OMs−) to iodonium, and counter‐cation Cs+ to the nucleophile F−. Protection of the amino by one or two –Boc group(s) render fluorination to be strongly favored over bromination/cyclization. Possibility of direct attack by counter‐anion is assessed. We propose that mesylate (–OMs−) would be much better counter‐anion than Br− because of its much weaker nucleophilicity. F− is also preferred as a counter‐anion, because using it would exclusively give fluorinated product. We also estimate the capability of crown ether (18‐crown‐6) as a Lewis base promoter for enhancing the rates of fluorination.