Study of Meldrum's Acid Cyclization Reactions

On the basis of the cyclization reactions reported by Danishefsky et al. of Meldrum's acid hydroxylethyl and anilinoethyl derivatives, the cyclization of the sulfamidomethylene and ureidomethylene derivatives was attempted without success. To understand the lack of reactivity of these compounds versus the successful cyclization of the ethyl derivatives, the corresponding mechanisms of reaction for both processes have been explored by means of MP2/6-311+G(d,p) calculations in an aqueous environment. The conformational analysis of all of these structures revealed that, while for the ethyl derivatives the minimum energy conformation corresponds to that of the cyclization initiating structure, for the methylene analogues the entrance channel conformations are substantially less stable than the energy minimum. Intramolecular hydrogen bonds were found in all of the energy minima as well as in the cyclization initiating conformations as determined by analysis of their electron density. The potential energy surfaces for the successful and unsuccessful cyclization processes were obtained at room temperature and 100 °C. Comparison of both processes allows rationalization that the lack of reactivity of the methylene derivatives can be thermodynamically explained based not only on the strength of the intramolecular hydrogen bond formed in their energy minima but also by the energy penalty needed to reach the entrance channel conformation and by the calculated energy barriers.The authors would like to acknowledge the essential contribution of the late Professor Manfredo Stud (Instituto de Química Médica, CSIC, Madrid, Spain) whose original idea was behind the synthetic pathway here studied. We acknowledge the School of Chemistry at Trinity College Dublin for financial support. Thanks are given to the Irish Centre for High-End Computing (ICHEC) and the Trinity Center for High-Performance Computing (TCHPC) for the provision of computational facilities. We are indebted to Dr. Goar Sánchez from the UCD School of Chemistry for AIM analysis and for helpful discussions.Peer Reviewe