Intramolecular nucleophilic addition of phenolate oxygen to double bonds activated by carboxyl and carboxylate groups. Relative reactivity, stereochemistry, and mechanism

The cyclization reactions of substituted 4-methyl-4-(2-hydroxyphenyl)pent-2-enoic acid derivatives (7) in water involve intramolecular nucleophilic attack of phenolate oxygen on the activated double bond. Activation by COO^- and COOH groups gives rate enhancements over a hydrogen substituent of 4000 and 10⁸, respectively, for the unsubstituted acid. Both mono- and dianion reactions are general-acid-catalyzed by protonated amines (α ≈ 0.2). The stereochemistry of these latter reactions (syn addition of phenol O and general-acid H) is in remarkable contrast with the trans addition observed for the water-catalyzed reaction, and the (primary) solvent deuterium isotope effects (less than 2 for buffer acids, compared with ~ 5 for water) are also very different. The most likely mechanisms involve rate-determining protonation of mono- or dianions of carboxylic acid enolates, thus formally, reverse (E1cB)_I reactions.