Density Functional Study of Indole Formation by an Intramolecular Heck Reaction

The mechanism of an intramolecular palladium-catalyzed Heck–Mizoroki reaction to form indole derivatives was studied using density functional theory (DFT). Starting from the <i>N</i>-allyl-2-iodo-<i>N</i>-methylaniline, four routes were detailed: two lead to five-membered rings and two to six-membered rings. In agreement with previous studies, oxidative addition was found to be the rate-determining step with a rather small activation free enthalpy of 10.2 kcal/mol. The five-membered ring is both kinetically and thermodynamically favored: the activation barriers for the ring closure differ by more than 4 kcal/mol, and the obtained five-membered product is more stable than the six-membered product by 1 kcal/mol . Because of its aromatic character, indole is more stable than the other three products by more than 20 kcal/mol: in agreement with experiments, it is the main product of this reaction. This study also revealed that the nitrogen atom does not play any role in the indole formation, while it discriminates between the two six-membered rings