Imidazole 1-oxides direct arylation

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Protons at C2 of imidazole 1-oxides 228 are acidic and are exchanged with deuterium even in weakly acidic solution. The exchange rate increases with increasing pH (2004S2678). Although the mechanism is not fully understood, the palladium-catalyzed direct arylation of imidazole 1-oxides most likely involves deprotonation so that the observed regi-oselective arylation reflects the propensity to proton abstraction found to decrease in the order C2 > C5 > C4 (2009JA3291). 

The palladium-catalyzed and the copper-cocatalyzed direct arylation of imidazole 1-oxides 280 shown in Scheme 83 may involve transmetallation (2008JA3276, 2009JA3291). However, classical transmetallation like conversion of imidazolyllithium compounds to imidazolylzinc compounds has not been reported. 

Direct arylation of methyl imidazole with 2,7-dichloronaphthyridine leads to a potentially tetradentate and practically tridentate bis-carbene ligand on a naphthyridine scaffold [363]. Reaction of the bis-imidazolium salt with silver(l) oxide in the usual way yields a linear trinuclear silver carbene complex with this tris-bridging hgand (see Figure 3.115). 

Scheme 15 Imidazole (V-oxides in palladium-catalyzed direct arylation...

Direct C—H arylation of 1,3-azoles takes predominant place at C5-H (due to the TT-nucleophUicity of the C5-position) along with double arylation at C5/C2-H (C2-H is the most acidic proton) (Figure 6a). A reHable C2—H—C5—H—C4—H reactivity order for 1,3-azole functionaHzation, including thiazoles and 1 H-imidazoles, was developed by Fagnou in 2008 by transforming the 1,3-azoles into their N-oxides prior to C—H activation... 

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