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Ruthenium‐Catalyzed Alkylation of Indoles with Tertiary Amines by Oxidation of a sp 3 CH Bond and Lewis Acid Catalysis
Author(s) -
Wang MingZhong,
Zhou CongYing,
Wong ManKin,
Che ChiMing
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200902387
Subject(s) - chemistry , iminium , alkylation , aniline , medicinal chemistry , ruthenium , catalysis , regioselectivity , lewis acids and bases , alkyl , coupling reaction , organic chemistry
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 t BuOOH 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 CH 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 t BuOOH as oxidant), determined through competition experiments, correlate linearly with the substituent constants σ ( R 2 =0.989), giving a ρ value of −1.09. This ρ 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 %).