Metallation and Direct Pd-Activation

Metalation takes place preferentially at the C2 position in -substituted imidazoles. If the 2-position is occupied, then the C5 position is metallated followed by the C4 position. For the first metallation and addition of electrophile, a variety of electrophiles has been successfully used like methyl sulfate (68% yield, E= Me), Br2 (80% yield, E = Br), or DMF (65% yield, E = CHO). LDA can also be used to deprotonate the 2-position. 

There have been examples using Pd to couple aryl iodides directly to the 5 position of the imidazole ring. In the example shown, JV-benzyl imidazole coupled with phenyl- or methoxy-phenyliodides efficiently and was subsequently brominated at the 4-position to undergo further reaction.  

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