Directed ortho Metalation isocoumarin

N-Methylbenzamides have been used as isocoumarin precursors (71T6171). Directed ortho metallation followed by reaction with ethylene oxide gave the dihydroisocoumarin via the alcohol (Scheme 184). 

The directed metalation of aromatic systems that was discussed in Section 2.1.3.3 has one ramification that was not mentioned there the directed lithiation of an o-methyl group. Although the resultant species is formally a resonance-stabilized anion, and therefore covered in Volume 2 of this series, we mention it here for consistency with the other topics covered. In particular, the examples that have appeared in recent years involve substrates having a methyl ortho to a tertiary amide. Intentional use of such a directed lithiation has been used in the synthesis of the isocoumarin natural products hydrangenol and pyllodul-cin.137,138 Interestingly, the directed metalation of 5-methyl-oxazoles and -thiazoles occurs in preference to deprotonation at a 2-methyl group (azaenolate) (Scheme 33). ... 

Many commercial sulfonylureas contain an ortho ester, therefore, preparation of tied-back ester was of great interest. We could use the target intermediate monomethylamide 2 (Scheme X), as both a directing group for metallation and as the latent lactone group. The sulfonamide handle could be added via metallation and quenched with propyl disulfide. Sulfide 2Q can also be prepared via a nucleophilic displacement of the chlorobenzamide 21. A second metallation of 2Q gave the ethanol derivative 22. Base hydrolysis to the amide to the carboxylate, then lactonization under acidic conditions, gave the isocoumarin 22. Oxidative chlorination and amination proceeded without a problem. 

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