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Regioselective Synthesis of 4,5‐Diaryl‐1‐methyl‐1 H ‐imidazoles Including Highly Cytotoxic Derivatives by Pd‐Catalyzed Direct C‐5 Arylation of 1‐Methyl‐1 H ‐imidazole with Aryl Bromides
Author(s) -
Bellina Fabio,
Cauteruccio Silvia,
Di Fiore Annarita,
Rossi Renzo
Publication year - 2008
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200800738
Subject(s) - chemistry , regioselectivity , imidazole , aryl , catalysis , stereochemistry , halogenation , medicinal chemistry , combinatorial chemistry , organic chemistry , alkyl
A general and efficient three‐step procedure for the highly regioselective synthesis of 1‐methyl‐1 H ‐imidazoles possessing electron‐rich, electron‐neutral, and/or electron‐deficient aryl moieties at their 4‐ and 5‐positions is described. The first step involves the Pd‐catalyzed direct C‐5 arylation of commercially available 1‐methyl‐1 H ‐imidazole with aryl bromides, and the second and third steps of the sequence involve the selective C‐4 bromination of the resulting 5‐aryl‐1‐methyl‐1 H ‐imidazoles with NBS, followed by a PdCl 2 (dppf)‐catalyzed Suzuki‐type reaction between 5‐aryl‐4‐bromo‐1‐methyl‐1 H ‐imidazoles and arylboronic acids under phase‐transfer conditions. Two 4,5‐diaryl‐1‐methyl‐1 H ‐imidazoles so prepared, which can be regarded as Z ‐restricted analogues of naturally occurring combretastatin A‐4 (CA‐4), proved to be highly cytotoxic against a variety of human tumor cell lines, and one of these derivatives has been shown to be more cytotoxic than CA‐4 and all of the imidazole derivatives investigated in the literature thus far. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)