Regioselective Functionalization of the Imidazole Ring via Transition Metal‐Catalyzed CN and CC Bond Forming Reactions

Abstract

Functionalized imidazole derivatives include compounds that are known to possess a broad range of significant biological properties or are important templates in medicinal chemistry. In the light of the importance of these heteroaromatic compounds a great deal of attention has been given to their synthesis and, in the past years, a number of methods has been described in the literature allowing for the construction of the heteroaromatic core of these substances by cyclization protocols. However, in recent years, much more attention has been focused on the design and development of efficient protocols that are based on the selective functionalization of the imidazole ring at the N-1, C-2, C-4 or C-5 position via transition metal-catalyzed reactions and enable the synthesis of imidazole derivatives, including bioactive and/or naturally occurring compounds, which cannot be accessed by other means. This critical review with 439 references covers developments in this hot area of research up to July 2009 and includes a description of synthetically important, regioselective transition metal-catalyzed IntroductionSubstituted imidazoles are important heteroaromatic compounds that are known to exhibit a broad range of biological activities such as antifungal properties, [1] analgesic activity, [2,3] anti-inflammatory activity inhibiting the p38 MAP kinase or cytokine release, [4,5] antiallergic activity, [6] antileishmanial activity, [7] and VEGF receptor I and II [I8] and neuropeptide Y antagonistic activities.[9] They are also important building blocks found in naturally occurring compounds [10] and versatile precursors to N-heterocyclic carbenes useful as ligands in various catalytically active transition metal complexes [11] and in organocatalysis. [12] Moreover, imidazolium salts can be used as environmentally friendly ionic solvents.[13] As a result, a number of methodologies for the preparation of variously substituted imidazoles has been intensively developed. [14] Methods for imidazole core synthesis include cyclocondensation reactions of a-hydroxy ketones, aamino ketones with formamide (Bredereck synthesis), [15] the base-promoted reaction of tosylmethyl isocyanide (TosMIC) and its substituted derivatives with aldimines, polymer-bound imines or imidoyl chlorides (van Leusen reaction), [16] reaction of amidines with ahalo ketones, [17] reaction of a-diketones with ammoAdv. Synth. Catal. 2010, 352, 1223 -1276 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1223 REVIEW nia and aldehydes (Debus-Radziszewski reaction), [18] condensation of a-hydroxy ketones with aldehydes and AcONH 4 in the presence of diacetoxyiodobenzene, [19] reaction of a-(hydroxyimino) ketones with 1,3,5-trisubstituted hexahydro-1,3,5-triazines, [20] cyclization reaction of a-halo ketones and N-acetylguanidine, [21] treatment of the sodium enolate salts of Nacyl-C-formylglycine esters with acid and KSCN, [22] pyrolysis of a-azido ketones, [23] condensation of aamino ketals with imidates followd by cyclization in refluxing 4 M HCl/dioxane...

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.…”

Unexpected Course of the Reaction of 2‐Unsubstituted 1H‐Imidazole 3‐Oxides with Ethyl Acrylate

“…The metal-catalyzed formation of new C,C-bonds in aromatic and heteroaromatic rings is a challenging task in modern organic synthesis, and the state of the art in the field of imidazole derivatives has recently been summarized [6]. A frequently studied reaction is the ethenylation with acrylates leading to 3-aryl propenoates.…”

Synthesis of New Imidazole 3-Oxides; Unexpected Deoxygenation of Some Derivatives in the Reaction with 2,2,4,4-Tetramethylcyclobutane-1,3-dithione

“…3 The condensation of α-hydroxyimino ketones of type (1) with primary amines and formaldehyde is widely applied for the synthesis of stable 2-unsubstituted imidazole 3-oxides (2) (Scheme 1). 4 These compounds are related in their structure with aldonitrones and display reactivities analogous to this type of 1,3-dipoles.…”