Metallation of aromatic compounds either via DoM or by metal-halogen exchange is usually carried out at cryogenic temperatures and if there is a carbonyl or nitrile in the molecule temperatures down to -100°C are usually required.  However 2 recent publications have started to challenge this requirement and/or find alternative methodology to get to the same intermediate without the cryogenic requirement.

In the first paper¹ the generation of lithiated benzonitriles via the lithium-bromine exchange reaction was investigated.  Under standard conditions the reaction is carried out by adding butyl lithium to the bromobenzonitrile at -100°C.  However if the order of addition is reversed, i.e. addition of the bromobenzonitrile to the butyl lithium the reaction can be carried out at -70°C and clean conversion to the lithiobenzonitrile is achieved.  This still requires low temperatures but -70°C is more easily attained than -100°C on plant scale.

In the second paper² the investigators from Novartis examined a variety of reagents for effecting the metal-bromine exchange using 4-bromoanisole as the substrate.  Butyl lithium worked well at -78°C but at higher temperatures the most promising reagents were lithium trialkylmagnesiates – LiR₃Mg, however this requires preformation of the LiR₃Mg reagent.  An alternative protocol was devised in which a branched alkyl magnesium halide is added to the substrate under non-cryogenic conditions followed by the controlled addition of an alkyl lithium that results in a transient aryl lithium intermediate that is rapidly transmetallated by the Grignard reagent.  The reaction is carried out at 0-5°C and works well for a variety substrates RC₆H₄Br where R = Me, OMe, F, Cl, Br, CF₃, and OH.  The reaction does not work for R = CN or CO₂Et or for 2-bromophenol, or 1,2-dibromobenzene.


1. S. Luliński et al, J. Org. Chem., 2008, 73, 7785-7788.
2.  F. Gallou et al, Tet. Letts., 2008, 49, 5024-5027.