Why is an experimental regioselectivity of Fischer Indole Syntheses observed: A Mechanistic Model DFT Study

Abstract The Fischer indole synthesis of the ketone 1 with phenylhydrazine is studied using DFT methods. A detailed reaction mechanism is proposed and evaluated, including different plausible diaza-Cope rearrangement pathways. Cis-/trans-stereochemistry of the substrate 1 leads to different pathways and products. In addition, the influence of hydrazine protonation on the mechanism is investigated. Only implicit solvation at the PCM-M06–2X/6–311++G(d,p) level of theory predicts correctly the product stability. Furthermore, the importance of nitrogen protonation resulting in lower (and feasible) activation energies for the key step is shown. In agreement with experimental data, the pathways leading to observed products possess the lowest activation barriers. With the proposed mechanism, the correct thermodynamic and kinetic control for this rather complicated reaction is calculated, and the procedure should be able further predict regioselectivity of related systems.