Ruthenium-catalyzed alkylation of indoles with tertiary amines by oxidation of a sp3 CH bond and lewis acid catalysis

Ming Zhong Wang, Cong Ying Zhou, Man Kin Wong, Chi Ming Che

Research output: Journal article publicationJournal articleAcademic researchpeer-review

94 Citations (Scopus)

Abstract

Ruthenium porphyrins (particularly [Ru(2,6-Cl2tpp)CO]; tpp = tetraphenylporphinato) and RuCl3 can act as oxidation and/or Lewis acid catalysts for direct C-3 alkylation of indoles, giving the desired products in high yields (up to 82% based on 60-95% substrate conversions). These ruthenium compounds catalyze oxidative coupling reactions of a wide variety of anilines and indoles bearing electron-withdrawing or electron-donating substituents with high regioselectivity when using tBuOOH as an oxidant, resulting in the alkylation of N-arylindoles to 3{[(N-aryl-N-alkyl)amino]methyl} indoles (yield: up to 82%, conversion: up to 95%) and the alkylation of N-alkyl or N-H indoles to 3-[p-(dialkylamino)benzyl]indoles (yield: up to 73%, conversion: up to 92%). A tentative reaction mechanism involving two pathways is proposed: an iminium ion intermediate may be generated by oxidation of an sp3 C-H bond of the alkylated aniline by an oxoruthenium species; this iminium ion could then either be trapped by an N-arylindole (pathway A) or converted to formaldehyde, allowing a subsequent three-component coupling reaction of the in situ generated formaldehyde with an N-alkylindole and an aniline in the presence of a Lewis acid catalyst (pathway B). The results of deuterium-labeling experiments are consistent with the alkylation of N-alkylindoles via pathway B. The relative reaction rates of [Ru(2,6-Cl 2tpp)CO] catalyzed oxidative coupling reactions of 4-X-substituted N,N-dimethylanilines with N-phenylindole (using tBuOOH as oxidant), determined through competition experiments, correlate linearly with the substituent constants o (R2=0.989), giving a ρ value of -1.09. This ρ value and the magnitudes of the intra- and intermolecular deuterium isotope effects (kH/kD) suggest that electron transfer most likely occurs during the initial stage of the oxidation of 4-X-substituted N,N-dimethylanilines. Ruthenium-catalyzed three-component reaction of N-alkyl N-H indoles, paraformaldehyde, and anilines gave 3-[p-(dialkylamino)benzyl] indoles in up to 82% yield (conversion: up to 95%). KGaA.
Original languageEnglish
Pages (from-to)5723-5735
Number of pages13
JournalChemistry - A European Journal
Volume16
Issue number19
DOIs
Publication statusPublished - 17 May 2010

Keywords

  • Alkylation
  • Indoles
  • Lewis acids
  • Oxidation
  • Ruthenium

ASJC Scopus subject areas

  • Chemistry(all)

Cite this