Metalation in hydrocarbon solvents: the mechanistic aspects of substrate-promoted ortho-metalations

The methoxy-substituted aromatic reagents 1,2- and 1,3-dimethoxybenzene (1,2-DMB and 1,3-DMB) and 1,2,4-trimethoxybenzene (1,2,4-TMB) each undergo directed ortho-metalation in high yield in n-BuLi/hydrocarbon media without the aid of a catalyst. These reactions, coined ‘substrate-promoted ortho-metalations’, proceed with the methoxy aromatic substrate functioning as both the directing metalation group (DMG) and as the deoligomerization agent. Evidence that the substrates themselves serve to deoligomerize n-BuLi comes from 13C NMR. The relative extent of metalated product formed as a function of time for each of the three aromatics directly correlates with the substrateʹs time-dependent ability to coordinate to n-BuLi as measured by 13C NMR. The interpretation of NMR results from experiments involving 1,2,4-TMB is consistent with the metalation proceeding via the activated complex [(1,2,4-TMB)2·(n-BuLi)2]. Finally, conclusions from solubility experiments are that for every substrate-promoted metalation investigated, a precipitate forms in the hydrocarbon solvent, and this precipitate mostly contains the ortho-lithiated aryl intermediate.