Ion pairing effects on the regioselectivity of arylic versus benzylic C–O bond reductive cleavage: synthetic applications

The regioselectivity of the reductive cleavage of 3,4,5-trimethoxybenzyl methyl ether strongly depends on the alkali metal employed as a reducing agent and solvent effects. Reactions run using Na as a reducing agent led to aromatic C(4)–O bond cleavage, whilst reductions run in the presence of Na/15-crown-5, or using Li as a reducing agent, led to highly regioselective benzylic C–O bond cleavage. This regioselectivity turnaround is discussed in terms of major solvent effects affecting the fragmentation paths of a common reaction intermediate. Synthetic applications of these findings led to the synthesis of biologically active compounds, like 2,5-dialkyl-substituted resorcinols, or 1-(3,4,5-trimethoxyphenyl)-2-arylethanes structurally related to combretastatin.