title: Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles.
abstract: A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily available (two steps) common intermediate has been developed. This methodology is based on the regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1H-imidazole (10). When this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding 1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein's salt, isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-imidazole with a high selectivity. The general character of this methodology has been illustrated by showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling, whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic substitution.
authors.affiliation: Chemistry Department, Université catholique de Louvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Delest
authors.forename: Prosper
authors.initials: P
authors.lastname: Nshimyumukiza
authors.forename: Olivier
authors.initials: O
authors.lastname: Fasbender
authors.forename: Bernard
authors.initials: B
authors.lastname: Tinant
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
authors.forename: Francis
authors.initials: F
authors.lastname: Darro
authors.forename: Raphaël
authors.initials: R
authors.lastname: Robiette
mesh_terms: D000478:Alkylation; D006847:Hydrocarbons, Iodinated / Q000737:chemistry*; D007093:Imidazoles / Q000138:chemical synthesis*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry
chemical_list: D006847:Hydrocarbons, Iodinated; D007093:Imidazoles; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D013450:Sulfones