Direct Lithiation of Alkoxyphenols: Metalation vs Demethylation. An Experimental and Theoretical (MNDO) Study

Article abstract of DOI:10.1021/jo00299a038

The direct lithiation of simple alkoxyphenols has been studied both from a theoretical and an experimental viewpoint.Efficient lithiations were achieved by using a 2:1 tBuLi-tBuOLi mixture (LICLIOR) in THF at room temperature.In most cases alkoxy groups are responsible for the regioselectivity observed, although for the case of 2-methoxyphenol both the OMe and OLi groups actually act as ortho-directing groups during lithiation.Demethylation has been shown to be a common side reaction of lithiation of phenolic or nonphenolic alkoxy aromatics.MNDO calculations provide good support for all the experimental observations.Thus, lithiation and demethylation are shown to be competing pathways, the former being kinetically favored whereas the latter leads to the thermodynamically more stable compounds.Calculations also show that the so-called geminal demethylations are more favored processes than the alternative vicinal demethylations.Moreover, MNDO allows the measurement of the extent of agostic activation of the ortho hydrogens with respect to the OMe and OLi groups involved in lithiation.Finally, MNDO nicely predicts the important role of reaction temperature in successful direct lithiation of simple alkoxyphenols.