General acid–base catalysed cyclisation reactions of a strained ω-phenylhydantoic acid

Abstract

In relation to model studies on the carboxylation of biotin, the nucleophilic reactivity of a weakly basic urea towards COOH and COO– was characterised by means of the ring-closure of (3) to (4). Owing to the strain introduced by the two methyl groups the reaction was rapid over the whole pH range, being reversible at pH > 9. Three general acid–base-catalysed reactions and one uncatalysed reaction were identified, corresponding to a change of the predominant form of catalysis and/or reactive form of the substrate with changing pH. The additional barrier for anionic nucleophilic attack on COO–versus attack on COOH was estimated as ca. 9 kcal mol–1. A comparison between the reactivity of the phenylureido and methylureido anion towards COO– indicated better nucleophilicity by phenylureido anion, despite its lower basicity. The results obtained with the model compound (3) illustrated the possibility of a change to a different rate-determining step for intramolecular reactions of compounds activated by ground-state strain.