Directed metalation lateral lithiation

We have tried to summarize in this chapter the basic tendencies and mechanisms of directed metalation. DoM in presence of DMG(s) allows for the regioexhaustive functionalization of aromatics. DreM, frequently combined with migration of the DMG or rearrangement, gives a powerful tool for the synthesis of natural products. Peri and lateral lithiations have shown to further enable functionalization for aromatic scaffolds, and last but not least, when coordinated to and thus activated by a metal complex, aromatic ring systems can be subjected to enantiose-lective metalation reactions. Although such a chapter cannot cover the topic in an exhaustive manner, we hope to have found a compromise between scholarly presentation and citation of relevant literature. 

We therefore wished to avoid the formation of the 4-lithio species, and examined the use of a non-exchangeable group at the 4- position in place of the iodide. We chose to study the 4-chloropyridine derivative 45 based on the fact that chlorine is known to direct ortho-lithiations at -78 °C and does not undergo halogen-metal exchange. Chloropyridines are also susceptible to nucleophilic aromatic substitution with alkoxides, and as such this compound contains a handle for the introduction of the methoxy group at the 4-position as required later in the synthesis. 

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