Ones, Thiones, andN-Oxides: An Exercise in Imidazole Chemistry

Abstract

Regioselective synthetic approaches to tetrasubstituted imidazoles (see picture) are reported. These highly substituted heterocycles are potent inhibitors of cytokine release and therefore interesting candidates for anti‐inflammatory drugs.

Reactions of 2-Unsubstituted 1H-Imidazole 3-Oxides with 2,2-Bis(trifluoromethyl)ethene-1,1-dicarbonitrile: A Stepwise 1,3-Dipolar Cycloaddition

“…For this reason, the reaction was repeated using anhydrous N-oxides 1, which were prepared by drying the corresponding hydrates with activated molecular sieves in CHCl 3 . Under these conditions, the (imidazol-2-ylidene)malononitriles 11 were formed in high yield (Scheme 4).…”

“…their applications as building blocks of imidazole derivatives [1][2][3] and for their diverse biological activities [4][5][6]. Convenient syntheses of 2-unsubstituted imidazole N-oxides are condensations of α-(hydroxyimino)ketones with in situ generated methylidenamines [7], of α-aminooximes with orthoformates [8], and of diimines with formaldoxime [9].…”

Non-covalent interactions of N-phenyl-1,5-dimethyl-1H-imidazole-4-carboxamide 3-oxide derivatives—a case of intramolecular N-oxide hydrogen bonds

“…For example, the N-oxide group forms very strong hydrogen bonds with isocyanide with an energy close to 16 kcal/mol (DFT-B3LYP/aug-ccpVTZ). The corresponding energy value for (H 3 C) 2 O and H 2 C=O molecules as oxygen proton acceptors is of about half of that, ∼7 and ∼9 kcal/mol, respectively. Interestingly, we recently found that imidazole N-oxide is able to interact with proton donors not only in strong intermolecular but also in intramolecular hydrogen bonds with energies of about 12 kcal/mol [19].…”

“…Because of regioselective reactivity, many N-oxide derivatives are used in the synthesis of a number of organic compounds [1][2][3][4][5][6][7]. Imidazole N-oxides act as precursors of biologically active molecules, transition metal chelating agents [8,9], and inhibitors of the release of interleukin-1, cytokine release, and protein kinase p38 [10,11].…”

One-Pot Synthesis of Polysubstituted Imidazoles From Arylaldehydes in Water Catalyzed by NHC Using Microwave Irradiation

“…General methods relay on the synthesis of trisubstituted imidazoles followed by installation of the fourth substituent via N-alkylation [11] , metal activated coupling 12 , or imidazole-N-oxides 13 to generate tetrasubstituted imidazoles.…”