Directed lithiation of unprotected benzoic acids

Benzoic acid gives the ortho-lithiated species 1 under standard conditions (BusLi–TMEDA–THF, –90 °C). Reaction of 1 at –78 °C with either methyl iodide, dimethyl disulfide, hexachloroethane, or 1,2-dibromotetrachloroethane gives the ortho-substituted product. Intramolecular competition between the carboxylic acid and methoxy, chloro, fluoro, or diethylamido functions in ortho- and -para-substituted benzoic acids establishes the carboxylic acid group to be of intermediate capacity in directing metallation. Complimentarity of directing effects is observed with the chloro and fluoro groups in the meta-substituted benzoic acids but not with the methoxy and trifluoromethyl groups. Electrophile introduction into meta- and para-lithiated benzoates occurs with equal efficacy and comparable scope. The 2,4-dihalogenobenzoic acids undergo hydrogen/metal exchange at the position flanked by both halogen substituents. 2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid undergoes lithiation adjacent to the oxygen atom. By use of such methods, routes to benzoic acids contiguously tri- and tetra-substituted with a variety of functionalities have been developed.