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

Abstract

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-position 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 step of the sequence involve the selective C-4 bromination of the resulting 5-aryl-1-methyl-1H-imidazoles with NBS followed by a PdCl2(dppf)-catalyzed Suzuki-type reaction between 5-aryl-4-bromo-1-methyl-1H-imidazoles and arylboronic acids under phase-transfer conditions. Two so prepared 4,5-diaryl-1-methyl-1H-imidazoles, which can be regarded as Z-restricted analogues of naturally-occurring combretastatin A-4 (CA-4), have proven 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 so far

Mild Palladium‐Catalyzed Regioselective Direct Arylation of Azoles Promoted by Tetrabutylammonium Acetate

“…Note that this new protocol for the regioselective 5‐arylation of 7 gave identical regioselectivities but higher isolated yields than the procedure reported by us in 2008, in which we employed 5 mol‐% Pd(OAc) 2 and 10 mol‐% P(2‐furyl) 3 as the catalyst system, 2 equiv. of K 2 CO 3 as the base, and DMF as solvent at 110 °C 16e. For comparison, imidazole 10b was obtained in 49 % yield by applying our older method, and ortho ‐substituted aryl bromides did not react at all.…”

Mechanistic Elucidation of the Arylation of Non-Spectator N-Heterocyclic Carbenes at Copper Using a Combined Experimental and Computational Approach

“…Our findings may also suggest a pathway for catalyst deactivation for Cu I -NHCs as catalysts in the presence of water, and offer a reason to why high catalyst loadings or stoichiometric quantities are often necessary. [4][5][6][7][8][9][10][11][12][13][14]18 Cu I -NHC complexes 8 and 9 were prepared by reaction of the corresponding imidazolium salts with Cu 2 O in anhydrous DCM (both formed in quantitative yield). Single crystals of complex 8 suitable for X-ray diffraction analysis were grown via the vapor diffusion of diethyl ether into a solution of the product in dichloromethane.…”

“…[6][7][8][9][10][11][12] Adenosine can be functionalized using a similar route, to give 8-aryladenosine (Scheme 1b). 13,14 The functionalization of a benzimidazole to give a 2-arylbenzimidazole has been shown to proceed in the absence of Pd and using stoichiometric quantities of CuI, though higher reaction temperatures were employed in this reaction (Scheme 1c).…”

Synthesis, Spectral, Thermal and Biological Studies of Some Metal Complexes Derived from Heterocyclic Mono Azo Dye Ligand 2'[(2'-Hydroxy-4-methyl phenyl)azo]imidazole

“…Moreover, increasing the efficiency in inhibiting the growth of cancer cells by using Ni(II) complex is more than that in the ligand because it includes two imidazole rings. These kind of imidazole compounds are used in treating blood cancer, lung cancer, hepatomegaly and breast cancer [64,65].…”