Regioselective Synthesis of 4,5-Diaryl-1-methyl-1H-imidazoles Including Highly Cytotoxic Derivatives by Pd-Catalyzed Direct C-5 Arylation of 1-Methyl-1H-imidazole with Aryl Bromides

A general and efficient three-step procedure for the highly regioselective synthesis of 1-methyl-1H-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-1H-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-1H-imidazoles with NBS, followed by a PdCl(2)(dppf)-catalyzed Suzuki-type reaction between 5-aryl-4-bromo-1-methyl-1H-imidazoles and arylboronic acids under phase-transfer conditions. Two 4,5-diaryl-1-methyl-1H-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. ( (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)