Heterocyclic phthalides

One of the more complex local anthetics in fact comprises a basic ether of a bicyclic heterocyclic molecule. Condensation of 1-nitropentane with acid aldehyde, 79, affords the phthalide, 81, no doubt via the hydroxy acid, 80. Reduction of the nitro group... 

Phthalic anhydride condenses with the aniline derivative in the presence of zinc or aluminum chlorides to yield the intermediate benzoyl-benzoic acid, which subsequently reacts with l,3-bis-V,V-dimethylaniline in acetic anhydride to yield the phthalide. The above compound gives a violet-gray image when applied to a clay developer. Clearly this synthesis is also very flexible and variations in shades of color formers have been obtained by varying the aniline components and also by using phthalic anhydrides substituted, for example, by nitro groups or chlorine atoms. Such products have excellent properties as color formers and have been used commercially. Furthermore, this synthetic route is of great importance for the preparation of heterocyclic substituted phthalides, as will be seen later. 

Dimerizations have, in addition, been reported in heterocyclic systems containing an exocyclic carbon-carbon double bond. The pseudooxazolone (242) is, in this way, converted into the dimer (243),227 and a similar transformation has been observed on irradiation of 3-benzilidene phthalide.228... 

The intramolecular reaction of alkenes with various O and N functional groups offers useful synthetic routes to heterocycles [69-71]. The isocoumarin 83 is prepared by the intramolecular reaction of 2-(2-propenyl)benzoic acid (81) with one equivalent ofPdCl2(MeCN)2. However, the (Z)-phthalide 82 is obtained from the same acid with a catalytic amount of Pd(OAc)2 under 1 atm of 02 in DMSO. 02 alone is remarkably efficient in reoxidizing Pd(0) in DMSO. The isocoumarin 83 is obtained by the reaction of 2-(l-propenyl)benzoic acid (84) under the same conditions [2]. 2-Vinylbenzoic acid was converted to the isocoumarin, but not to the five-membered lactone [72,73]. 

Interestingly, electrochemical reductions of alkylidenephthalides (14), which might conceivably give radicals isomeric in the heterocyclic moiety with 13, resulted either in the addition of two electrons or in ring scission, although phthalide radicals such as 15, which is not heteroaromatic, may be prepared. ... 

The general methods, indicated above, can be extended to the synthesis of benzo-phthalides and other heterocyclic analogues of phthalides. These are given below. 

Phthalides have an extremely high oxidative potential (2.86 V) (03GC512). Selective fluorination also takes place in the case of carbonyl-containing heterocyclic compounds. Thus mono- and difluoro derivatives of 4-(metho-xyphenyl)acetone and ethyl 4-(methoxyphenyl)acetate (87TL2359, 98JFC(87)215) and fluoroindanes (90TL3137) are produced by anodic fluorination of hydrocarbon substrates in the... 

Finally, the Hammett equation has been applied in a few instances to heterocycles of the indole-benzofuran type. The double p method of q. (3) was first designed for this type of system and was here applied. When this approach was originally proposed, the only truly heterocyclic system to which it was applied was the substituted phthalids 14, and pertinent data on the hydrolysis of these compounds are included in Table IX. 

Phthalides are an important class of oxygen-containing heterocycles found in natural products and exhibit a broad spectrum of biological activities [7]. 

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