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.
Imidazole derivatives R 0190Divergent and Regioselective Synthesis of 1,2,4-and 1,2,5-Trisubstituted Imidazoles. -Treatment of imidazole (I) with MeOTf allows a regiospecific access to the 1,2,5-trisubstituted derivative (IV) which can smoothly be converted into diverse analogues. In contrast, slow addition of (II) to an excess of Me3OBF4 provides a selective route to 1,2,4-trisubstituted imidazoles. -(DELEST, B.; NISHIMYUMUKIZA, P.; FASBENDER, O.; TINANT, B.; MARCHAND-BRYNAERT, J.; DARRO, F.; ROBIETTE*, R.; J. Org. Chem. 73 (2008) 17, 6816-6823; Dep. Chim., Univ. Cathol. Louvain, B-1348 Louvain-la-Neuve, Belg.; Eng.) -Jannicke 02-135
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