Journal of the American Chemical Society 2012-09-05

Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C-H activation: mechanism and applications.

Lei Jiao, Eberhardt Herdtweck, Thorsten Bach

Index: J. Am. Chem. Soc. 134(35) , 14563-72, (2012)

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Abstract

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.