Metallation of Alkylarenes and Alkyl-hetarenes

When alkylbenzene derivatives are submitted to metallation, the metal may displace either a benzylic (a) or a ring hydrogen atom (preferably at the sterically unhindered meta or para positions). To avoid contamination by the ring-metallated derivative, a-deprotonation of toluene needs to be done with Schlosser s base18 191,192 while, for example, TMEDA-activated butyllithium gives rise to some contamination by ring-metallated products.193,194 Examples of mono- and dimetallation of alkylbenzenes are reported in Table 8. 

The relative reactivity of different alkyl groups on a phenyl ring parallels the one encountered in alkenes methyl methylene methine. This discrimination between benzylic position has been used to design a one-pot synthesis of ibuprofene, an analgesic with both anti-inflammatory and anti-rheumatic properties. The synthesis has been accomplished196 by sequential LIC-KOR deprotonation-alkylation starting with /wra-xylene. 

Analog results have been obtained in the metallation of fluoro-substituted diphenylmetanes. 

An additional example is constituted by 2,2-difluoro-4-methyl-l,3-benzodioxole which is deprotonated by sec-butyllithium exclusively at the 7-position, whereas only derivatives of the benzylmetal species are isolated after treatment with LIDA-KOR.204 

Despite these outstanding features, superbases have not been exploited in full potential yet future developments in this field are expected in the next years particularly concerning selective metallation of aromatic and heteroaromatic compounds. 

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