Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles.
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.
Delest
Bruno
B
Chemistry Department, Université catholique de Louvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium.
Nshimyumukiza
Prosper
P
Fasbender
Olivier
O
Tinant
Bernard
B
Marchand-Brynaert
Jacqueline
J
Darro
Francis
F
Robiette
Raphaël
R
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
D006847:Hydrocarbons, Iodinated; D007093:Imidazoles; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D013450:Sulfones