2-halobenzoic acid derivatives

Scheme 2.157 Palladium-catalyzed cyclization of 2-halobenzoic acid derivatives.

Although the thermal cyclization step in the Gould-Jacobs method proceeds with good yield for simple quinolones, the yields in multisubstituted analogues are low and unsatisfactory. In order to bypass the thermal cyclization step, a second method was introduced in the late 1980s and early 1990s via o-halobenzoic acid derivatives. This method, which is now the most pop-... 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

The procedure has also been applied to halobenzoic acids.3 Thus p-bromo-benzoic acid (6) was converted into the corresponding 2-oxazoline (7) as usual, and then into the Grignard derivative (8). This is, in effect, an aryl Grignard reagent with a protected carboxyl function. Reaction with an electrophile, for example benzonitrile, gives (9). The final step is hydrolysis. If carried out in 5-7% ethanolic sulfuric acid, the ester (10b) is obtained if carried out in an aqueous medium, the free acid (10a) is obtained. 

Miyano s approach was effective also in the synthesis of ( )-6,6 -dinitrodiphenic acid (556) from 3-nitro-2-halobenzoic acids 557 or 558, via diesters 559 and 560, derived from (Ti)-binaphthol (4), in moderate yield and good optical purity, 80-85% d.e. [14],... 

The pyrrole ring can also be constructed starting from an 7V-vinyl-2-halobenzoic amide. The /V-(2-iodobcnzoyl)-1,4-dihydropyndine derivative shown in 3.19. underwent palladium catalysed ring closure to give a condensed isoindolone derivative. The use of formic acid as co-solvent led to the reduction of the intermediate palladium complex formed in the insertion step, instead of / -hydride elimination. The transfer of the stereochemical information from the starting material to the product was poor.25... 

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