Regioselectivity of glycoluril-directed Claisen condensations — A kinetic and mechanistic study of substituent effects in the nucleophilic acyl group

The Claisen-like condensation of a series of 1-arylacetyl-6-acetyl-3,4,7,8-tetramethylglycolurils (Ar = Ph, p-OMeC₆H₄, and p-ClC₆H₄) was studied in preparative experiments and by analysis of kinetic data. The reactions proceeded in virtually quantitative yield and were highly regioselective: the corresponding N-(2′-aryl-3′-ketobutanoyl)-3,4,7,8-tetramethylglycolurils were obtained in all cases, with none of the 4′-aryl regioisomers being detected. Clean bimolecular kinetics were observed for each conversion using UV spectroscopy. Reaction rates followed the order Ar = p-OMeC₆H₄ < Ph < p-ClC₆H₄. The results are explained by a mechanism in which the deprotonation of the substrates is rate-limiting; thus, deprotonation of the arylacetyl groups is favoured. The ensuing enolate reacts rapidly in the C–C bond-forming step.Key words: glycoluril, biomimetic, Claisen condensation, regioselectivity, kinetics, mechanism, substituent effects.