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.