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.
Lehrstuhl für Organische Chemie I and Catalysis Research Center, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Lei
L
Jiao
Eberhardt
E
Herdtweck
Thorsten
T
Bach
D000478:Alkylation; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D006859:Hydrogen / Q000737:chemistry*; D026121:Indole Alkaloids / Q000138:chemical synthesis; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D009636:Norbornanes / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D011804:Quinolines / Q000138:chemical synthesis; D013237:Stereoisomerism; D013379:Substrate Specificity
D026121:Indole Alkaloids; D007211:Indoles; D009636:Norbornanes; D011804:Quinolines; C409672:aspidospermidine; C526621:goniomitine; C046060:2-norbornene; D010165:Palladium; D002244:Carbon; D006859:Hydrogen