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 N-allyl-2-iodo-N-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.