Pd(II)-Catalyzed Regioselective 2‑Alkylation of Indoles via a Norbornene-Mediated C–H Activation: Mechanism and Applications

A palladium-catalyzed direct 2-alkylation reaction of
free N-H indoles was developed based on a norbornene-mediated
regioselective cascade C–H activation. The detailed reaction
mechanism was investigated by NMR spectroscopic analyses, characterization
of the key intermediate, deuterium labeling experiments, and kinetic
studies. The results indicate that a catalytic cycle operates, in
which an N-norbornene type palladacycle is formed
as the key intermediate. Oxidative addition of alkyl bromide to the
Pd­(II) center in this intermediate is the rate-determining step of
the reaction. The synthetic utility of this indole 2-alkylation method
was demonstrated by its application in natural product total synthesis.
A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction
as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in
concise routes.