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.

NH‐Heterocyclic Aryliodonium Salts and their Selective Conversion into N1‐Aryl‐5‐iodoimidazoles

“…Progress made in recent years includes the usage of well-designed protection/deprotection strategies, [5] and the C5-selective CHborylation [6] and CH-arylation [7] reactions. Here we present a new route to a versatile class of precursors for 1,5-disubstituted imidazoles.…”

Total synthesis and cytotoxicity of Leucetta alkaloids

“…While this was encouraging, this meant that an exchange of imidazole N-substituents was necessary and that this had to be accomplished in a position selective manner. Fortunately, Robiette, 30 Sames 31 and more recently Knochel 17b have demonstrated that the DMAS-protecting group can be removed with a methyl group via the intermediacy of an imidazolium salt formed by reaction with methyl triflate or Meerwein’s salt. Given this encouraging precedent, the corresponding DMAS-protected 4,5-diiodoimidazole was used as a starting material.…”

4,5-Diiodo-2-phenyl-1H-imidazole

“…For the structures of various related compounds, see: Delest et al (2008); Poverlein et al (2007); Panday et al (2000); Phillips et al (1997); Terinek & Vasella (2003); Mukai & Nishikawa (2010a,b); Noland et al (2003); Dou & Weiss (1992); Nagatomo et al (1995). For the use of diiodoimidazoles as starting compounds for ligand synthesis, see: Haruki et al (1965); Ito & Uedaira (2004); Kim et al (1999); Zhang et al (2006).…”