Ruthenium-catalyzed alkylation of indoles with tertiary amines by oxidation of a sp3 C-H bond and Lewis acid catalysis.
Ruthenium porphyrins (particularly [Ru(2,6-Cl(2)tpp)CO]; tpp=tetraphenylporphinato) and RuCl(3) 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 sp(3) 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(2)tpp)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 sigma (R(2)=0.989), giving a rho value of -1.09. This rho value and the magnitudes of the intra- and intermolecular deuterium isotope effects (k(H)/k(D)) 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%).
Wang
Ming-Zhong
MZ
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Zhou
Cong-Ying
CY
Wong
Man-Kin
MK
Che
Chi-Ming
CM
D000478:Alkylation; D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry*; D008665:Metalloporphyrins / Q000737:chemistry*; D008956:Models, Chemical; D010084:Oxidation-Reduction; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism
D000588:Amines; D007211:Indoles; D008665:Metalloporphyrins; D012428:Ruthenium