O-METHYLARENEHYDROXAMATES AS ORTHO-LITHIATION DIRECTING GROUPS - TI(III)-MEDIATED CONVERSION OF O-METHYL HYDROXAMATES TO PRIMARY AMIDES

Reaction of O-methyl benzohydroxamates 2a-c with sec-butyllithium in t he presence of TMEDA at -40-degrees-C regiospecifically generates the highly reactive N,ortho-dilithiated species (e.g. 3). These dilithio s pecies react avidly with a wide spectrum of electrophilic reagents, in cluding alkyl halides, giving adducts which on reduction with TiCl3 ar e converted into ortho-substituted primary benzamides in excellent yie lds. Ortho lithiation of O-methyl benzohydroxamates is thus formally e quivalent to ortho lithiation of primary benzamides themselves. The ut ility of these synthetic operations is enhanced by the well-known faci lity with which the primary amide moiety can be transformed into other useful functional groups. The conversion of 0-methyl hydroxamates to primary amides is shown to be general, as exemplified by transformatio n of 14a-f to 15a-f. O-Methyl 2-methylbenzohydroxamate (4a) undergoes regiospecific dilithiation on nitrogen and on the methyl group when tr eated with sec-butyllithium at -70-degrees-C. These dilithio species r eact with DMF or ''Weinreb-type'' amides to give condensation products which cyclize to N-methoxyisoquinolin-1(2H)-ones under mildly acidic conditions. Removal of the N-methoxy moiety under conditions analogous to those used for O-methyl benzohydroxamate provides N-unsubstituted isoquinolin-1(2H)-ones with high overall efficiency. This process is e xemplified by the synthesis of isoquinolin-1(2H)-one 9a, its 3-n-butyl congener 9b, and the tricyclic isoquinolin-1 (2H)-ones 20a and 20b fr om O-methyl 2-methylbenzohydroxamate (4a).