Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles.
(2008) The Journal of Organic Chemistry — Vol. 73, n° 17, p. 6816-6823 (2008)
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- 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.
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Unibioscreen SA Belgium
Citations
Delest, B., Nshimyumukiza, P., Fasbender, O., Tinant, B., Marchand-Brynaert, J., Darro, F., & Robiette, R. (2008). Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles. The Journal of Organic Chemistry, 73(17), 6816-6823. https://doi.org/10.1021/jo801256b (Original work published 2008)