Polysubstituted imidazole

Most substituted imidazoles are obtained via the condensation of non-cyclic fragments to form the desired imidazole. The majority of these condensation reactions has recently been reviewed by Grimmett8. The largest number of imidazoles obtained via condensation approaches is only of limited use for the development of histaminergic ligands as they are mainly polysubstituted imidazoles. For the histamine receptors proper substitution of the imidazole ring is usually limited to the 4(5)-position, with the exception of the histamine H]-receptor, where a broader range of substituents on the 2-position is tolerated. 

Several novel IOji bicyclic imidazoles (63 or 65), obtained from polysubstituted imidazoles, were reported during this period. The first synthesis of an imidazo[4 ,5 4,5]thieno[3,2-d]pyri-midine commences with l-benzyl-2-(methylthio)-4-bromo-5-cyanoimidazole (62) [95TL12807]. Sequential metallation, sulfurization, S-alkyiation, and Thorpe cyclization of 62 afforded the thienoimidazole intermediate 63. Precursor 62 was obtained from 1 -benzyl-2,4,5-tribromoimida-zole in a series of metallation-electrophile trapping protocols. Nitroimidazo[l,5-a]imidazoles (65) were readily obtained from l-(acylmethyl)-2-methyl-4-nitro-5-bromoimidazoles (64) by sequential amination and cyclization [94KGS490]. 

Karami, B., Eskandari, K., Farahi, M. and Barmas, A. 2012a. An effective and new method for the synthesis of polysubstituted imidazoles by the use of CrCl3-6H20 as a green and reusable catalyst Synthasis of some novel imidazole derivatives. J. Chin. Chem. Soc. 59(4) 473 79. 

A. Hasaninejad, A. Zare, M. Shekouhy, J. A. Rad, J. Comb. Chem. 2010, 12, 844—849. Catalyst-free one-pot four component synthesis of polysubstituted imidazoles in neutral ionic liquid l-butyl-3-methylimidazolium bromide. 

The pyridinylimidazoles are representative of a class of polysubstituted imidazoles which are potent inhibitors of p38 Mitogen-Activated Protein (MAP) kinase.(i, 2) (Figure 1) These con5)ounds have been indicated for the treatment of inflammatory diseases due to their mode of action which involves upstream regulation of several pro-inflammatory cytokines such as IL-1 (interleukin-1) and TNF (tumor necrosis factor).(J) Effective syntheses for this class of compounds have been described. 5)... 

Scheme 8.48 Cul-catalyzed synthesis of polysubstituted imidazole derivatives via intermolecular [3+2] cycloaddition reaction of nitroolefins and amidines.

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

The amine-imine and the lactam-lactim tautomerisms may, of course, be coupled with the shift of the imidazole proton on the purine skeleton. In polysubstituted derivatives, e.g., in 8-azaguanine, all the different types of tautomerisms may be intermingled. 

Path a is the preferred one. Polysubstitution (also when bromine is used in deficient amount) is due to the fact that unsubstituted imidazole is more basic than bromoimidazole and is therefore preferentially converted into the inactive protonated form. 

Michael/Henry/dehydration/aromatisation reaction of 2-(2-oxoethyl) benzal-dehydes and nitroalkenes mediated by pyrrolidine to obtain polysubstituted naphthalene derivatives. DBU catalysed the conjugate additions of alcohols to ot,p-unsaturated nitriles, esters and ketones. Perhaps more important are the aza-Michael addition reactions of amines to a,p-unsaturated ketones, nitriles and esters. Recently, Costa, Vilarrasa and coworkers described the addition of lactams, imides, 2-pyridone, pyrimidine-2,4-diones and inosines to methyl propiolate and other similar compounds, DABCO and DMAP being the best catalysts. As mentioned before, tertiary amines give zwitterionic species with activated allynes. It was as early as 1932 when Diels and Alder used the reaction of pyridine with dimethyl acetylenedicarbojylate (DMAD) for the synthesis of heterocycles. The interception of the corresponding intermediate with Al-tosylimines and activated olefins provided access to l-azadienes ° and highly substituted butadienes (Scheme 2.6). When the quenching species of the zwitterionic intermediate is a 1,2-diketone, dibenzoyl maleates or cyclopentenedione derivatives could be obtained (Scheme 2.6). The interception of the zwitterionic species of N-methyl imidazole (NMI) and DMAD with ketenes to obtain unsaturated esters has also been shown. ... 

---