Halobenzoic acids

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-... 

Six- and seven-membered rings (dihydroisoquinolines 178, isoquinolinones 179, 180 and benzazepines 181) were obtained starting from orf/io-halobenzaldehydes or orf/to-halobenzoic acids [144, 145]. In all the cases, the exo-trig cyclization mode was strongly favoured. However, for 178 and 180, isomerization of the double bond from exocyclic to endocyclic occurred spontaneously under the Heck conditions. 

Carbonylations of 6>-dihalobenzenes and o-halobenzoic acids catalysed by Co2(CO)8 in aqueous NaOH and under photostimulation were also described213 to give moderate yields of the diacids. 

Another system which leads to ring closure reaction is o-halobenzoic acids. For instance, the reaction of o-iodobenzoate ion (288) with acetone enolate ion gives the substitution product 289, which leads to the isocoumarin 290 in acidic conditions, in high overall yield (80%) (equation 178)329. 

The cyclodehydration of 2-arylaminobenzoic acids, which are readily available from anilines and 2-halobenzoic acids by the Jourdan-Ullmann reaction, involving formation of the bond y to the hetero-atom (C-9 - C-9a), is the most versatile and important route to 9-acridones and it continues to attract attention. 

Whilst electron-withdrawing groups on the amine component are considered to inhibit the Jourdan-Ullmann condensation (see J.M.F. Gagan in Chemistry of Heterocyclic Compounds, vol. 9, Acridines ed. R. M. Acheson, Wiley-Interscience, New York, 1973), anthranilic acid reacts quantitatively with 2-halobenzoic acids to... 

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. 

Reaction of m- and p-nitrohalobenzenes with CN leading to o- and m-halobenzoic acids with loss of the N02 group (see 1st edition). 

For such reactions to succeed with aryl halides the halogen must be particularly reactive. For example, o-halobenzoic acids give o-mercaptobenzoic acid when heated with an alkali hydrogen sulfide in the presence of copper powder under pressure 265 and / -chloronitrobenzene gives / -aminothiophenol when heated with an excess of sodium sulfide in aqueous solution, the nitro group being simultaneously reduced.266... 

N-PhenylanthranUic acids. Copper halobenzoic acids by aniline may be peifn Ullmann coupling. This classic re sis. Unsymmetrical biphenyls are obtainer salicyl alcohol unit), thus rendering the rei a-Amino esters and ketones. a-Dia. amines in refluxing toluene under the inft ketones or esters in one step. A Stevens rea such products. 

N-Phenylanthranilic acids. Copper-catalyzed displacement of halogen in o-halobenzoic acids by aniline may be performed in refluxing water. 

The acids 22 are obtained by an Ullmann reaction between o-halobenzoic acids and primary arylamines in the presence of Cu powder in a basic medium. They are also prepared from A -aryl-A -benzoyl-o-aminobenzoates 24 which are accessible by a Chapman rearrangement of imidates 26. 

Replacing the Cul with ZnCl2 affords primarily isocoumarins [30]. The direct reaction of o-halobenzoic acids with copper acetylides also affords phthalides [22-24]. The reaction of (Z)-3-halopropenoic acid and terminal alkynes in the presence of a palladium catalyst and catalytic amounts of Cul provides a convenient synthesis of alkylidene butenolides (Eq. 8) [31,32]. 

Having observed the improvement using ultrasound in the cross-coupling of o-halobenzoic acids and substituted benzoamines with copper, or Cu/Zn under probe sonication, Galy and co-workers successfully synthesized acridine... 

Even though the Jourdan-Ullmann condensation has been known for more than a century, the mechanism is still not quite clear. On the one hand, the reaction may proceed via a free-radical mechanism, pertaining to the reductive dehalogenation of aryl halides and the acceleration of the reaction rate by ultraviolet irradiation, as outlined in Scheme 1. On the other hand, the reaction may involve halonium and proceed as a simple aromatic nucleophilic substitution, as displayed in Scheme 2. However, for the reaction of 6>-halobenzoic acid, it is believed that the copper ion coordinates with both carboxyl and... 

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 use of A/ -heterocychc carbenes (NHC) as catalysts in the preparation of3,4-dihydro-2H-pyran-2-ones (14EJ05631),the copper-catalyzed synthesis of 3-substimted isocoumarins from o-halobenzoic acids and 1,3-diketones (14JOC8507) and the synthesis and reactivity of pyridine-flised 3-substituted 2-amino-4-arylchromenes (14H(89)1557) have been reviewed. 

Disubstituted isocoumarins arise from the copper(II)-catalyzed addition of o-halobenzoic acids to active internal alkynes (13JOC1660), rhodium(III)-mediated oxidative coupling ofbenzoic acids with disubsti-tuted alkynes (13T4454), palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone (13T8626), and nickel(II)-promoted t-butyl isocyanide insertion in 2-(o-bromophenyl)-1-ethanones followed by hydrolysis (Scheme 69) (13SC3262). 

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

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