Metalation of the Di- and Tri-Methoxybenzenes

Hydrocarbon solvents are known to be unreactive towards organolithium reagents and also to afford little support for ortho-metalation reactions. In contrast, both m- and odimethoxybenzene afford 80% ion-multiple specific monometalation in hydrocarbon solvent (n-hexane, cyclohexane, toluene) without the addition of any catalyst (ether or amine). These observations are, in part, attributed to the 1,2- and 1,3- formation of the n-BuLi dimer, the most reactive form of n-BuLi. In other words these substrates are acting in a substrate-catalyzed manner. Extensions of these concepts to 1,2,3-, 1,2,4- and 1,3,5-trimethoxybenzenes have led to further unusual observations. In particular, the 1,2,3-system affords an interesting nucleophilic aromatic substitution reaction. This autocatalytic mode of ortho-metalation offers additional insight into the controversy regarding the participation of a dimer intermediate in the mechanism of the directed ortho-metalation reaction