Directed ortho-halogen exchange

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. 

When pyridine is heated to 165 °C in MeONa-MeOD, H-D exchange occurs at all positions via small concentrations of deprotonated species, at the relative rates a (3 7, 1 9.3 12. However, using the combination n-butyllithium/potassium t-butoxide, efficient formation of 2-pyridylpotassium or 4-pyridylpotassium has been achieved." Some pyridines have been selectively lithiated at C-2 via complexes with hexafluoroacetone " complexation removes the lone pair (cf. section 5.5.1) and additionally provides inductive and chelation effects to assist the regioselective metallation. In practice, simple lithiopyridines are generally prepared by metal-halogen exchange, however the presence of chlorine or fluorine, or other substituents which direct ortho metallation, allows direct lithiation (section 5.5.1). 

Tandem Directed ortho Metalation-Metal - Halogen Exchange Route to Antitumor Ellipticine Alkaloids and Analogues... 

Now comes the clever bit. Lithiation of 63 with LDA occurs next to Br at the only remaining free position 64 but the halogen dance (chapter 32) exchanges Br and Li so that Li is next to the excellent ortho-directing carbamate 65. Protonation with EtOH gives 66 ready for introduction of the fourth and last OH group. 

Ortho lithiation of arenes directed by CONRj, OCONRj, OMOM, or NHCOR (Eq. 5), or the halogen-lithium exchange reaction (Eq. 6) provides various aryllithiums regioselectively. In situ treatment of these lithium intermediates with trimethyl- or tri(isopropyl) borate gives variously functionalized arylboronic acids. Trapping aryl-lithium or aryl-magnesium intermediates with trimethylchlorosilane, followed by transmetallation to BClj or is a convenient alterna-... 

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