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.