Aromatic dienophiles. 1. A theoretical study of an inverse-electron demandDiels-Alder reaction between 2-aminopyrrole and 1,3,5-triazine

This study is devoted to a detailed theoretical study of an inverse-electro n demand Diels-Alder reaction (IDA) with 1,3,5-triazine as the diene and 2- aminopyrrole 1A(alpha) as the dienophile, which is a key step in a cascade reaction for the one-pot synthesis of purine analogues. Geometries were opt imized with the B3LYP/6-31G* method and energies were evaluated with the MP 2/6-311++G** method. This IDA reaction occurs through a stepwise mechanism, where the first step corresponds to the nucleophilic attack of 2-aminopyrr ole to triazine to form a zwitterionic intermediate, which is in equilibriu m with a neutral intermediate through a hydrogen transfer process, followed by a rate-determining ring-closure step. It is shown that the B3LYP method significantly overestimates the activation energy, whereas the MP2 method offers a reasonable activation barrier of 27.9 kcal/mol in the gas phase. T he solvation effect has been studied by the PCM model. In DMSO, the calcula ted activation energy of the IDA reaction is decreased to 24.0 kcal/mol wit h a strong endothermicity of 17.4 kcal/mol due to the energy penalty of tra nsforming two aromatic reactants into a nonaromatic IDA adduct. The possibl e stepwise [2+2] pathway is ruled out based on its higher activation and re action energies than those of the [4+2] pathway. By comparing the IDA react ions of triazine to 2-aminopyrrole and pyrrole, we address two crucial role s of the alpha -amino substituent in lowering activation and reaction energ ies and controlling the reaction regiochemistry.