O-Methylarenehydroxamates as Ortho-Lithiation Directing Groups. Ti(III)-Mediated Conversion of O-Methyl Hydroxamates to Primary Amides

Article abstract of DOI:10.1021/jo00066a014

Reaction of O-methyl benzohydroxamates 2a-c with sec-butyllithium in the presence of TMEDA at -40 deg C regiospecifically generates the highly reactive N,ortho-dilithiated species (e.g. 3).These dilithio species react avidly with a wide spectrum of electrophilic reagents, including alkyl halides, givind adducts which on reduction with TiCl3 are converted into ortho-substituted primary benzamides in excellent yields.Ortho lithiation of O-methyl benzohydroxamates is thus formally equivalent to ortho lithiation of primary benzamides themselves.The utility of these synthetic operations is enhanced by the well-known facility with wich the primary amide moiety can be transformed into other useful functional groups.The conversion of O-methyl hydroxamates to primary amides is shown to be general, as exemplified by transformation of 14a-f to 15a-f.O-Methyl-2-methylbenzohydroxamate (4a) undergoes regiospecific dilithiation on nitrogen and on the methyl group when treated with sec-butyllithium at -70 deg C.These dilithio species react with DMF or "Weinreb-type" amides to give condensation products wich 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 exemplified 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 from O-methyl 2-methylbenzohydroxamate (4a).