The application of n-butyl lithium for the rapid synthesis of methoxy-substituted aromatic carboxylic acids is reported. New compounds associated with this study are described.
YNTHETIC STUDIES by the authors on isoquino-S lines as potential cardiovascular agents (1-4) were patterned on the D and E rings of reserpine particularly incorporating the 3,4,5-trimethoxybenzoyl radical. The marked antiarrhythmic activity observed with decahydroisoquinoline compounds possessing this moiety (4), as well as the documented importance of the 3,4,5-trimethoxybenzoyl radical for neurosedative and analgesic activity (5), led the authors to investigate the synthesis of other methoxy-substituted aromatic carboxylic acids in order to ascertain the biological effects induced by various methoxy substitutions in the above series of compounds. The authors report improved, rapid syntheses for some methoxy benzoic acids and a new direct synthesis for tetramethoxyterephthalic acid, using n-butyl lithium as the key reactant.
Many studies have been carried out on the applications and anomalies of lithiation of aromatic systems (6). In general, metalation with n-butyl lithium occurs ortho to ether functions, i.e., -OCH3. The authors have demonstrated that treatment of 1,2,4,5-tetramethoxybenzene with 2 moles n-butyl lithium for 40 min. in tetrahydrofuran, under standard metalation conditions, followed by carbonation