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

We 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 18 F‐dopa and 18 F‐dopamine. We demonstrate by quantum chemical analysis that protection of –NH 2 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.