Isoindolines Phthalimidines

In this approach the heterocycle is built on to an existing benzenoid ring. Of course, some of the reactants—isoindolines, phthalimidines, and phthal-imides—considered in some of the previous sections may have had o-disubstituted benzenes as precursors. Here we consider reactions that lead directly to isoindoles. 

Electrolytic reduction of phthalimide and of phthalimidines which are at an oxidation level above that of isoindole, proceeds through the isoindole to the isoindoline stage, which is then stable to further... 

Phthalimide was hydrogenated catalytically at 60-80° over palladium on barium sulfate in acetic acid containing an equimolar quantity of sulfuric or perchloric acid to phthalimidine [7729]. The same compound was produced in 76-80% yield by hydrogenation over nickel at 200° and 200-250 atm [43 and in 75% yield over copper chromite at 250° and 190 atm [7730]. Reduction with lithium aluminum hydride, on the other hand, reduced both carbonyls and gave isoindoline (yield 5%) [7730], also obtained by electroreduction on a lead cathode in sulfuric acid (yield 72%) [7730]. 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

In strongly acid solution 213 is dehydrated to the easily reducible 3-oxoisoindole (214) which is reduced to phthalimidine (215) a further reduction to isoindoline (216) may take place under conditions similar to those used for the reduction of benzamides.223-225... 

The general utility of this reaction remains in doubt, however. Reduction of JV-(pent-4-enyl)phthalimide gives a mixture containing about equal amounts of the isoindole and isoindoline, with a smaller amount of the phthalimidine.55... 

Phthalaldehyde has also been employed as a precursor. 2-Arylisoindoles are formed when phthalaldehyde is reacted with primary aromatic amines in the presence of potassium tetracarbonylhydridoferrate. In some examples, reduction to the isoindoline level also occurs, and this is the main pathway when aliphatic amines are employed.62 The reactions of phthalaldehyde with ammonia and with amines in the absence of a reducing agent give complex mixtures. With ammonia, the major products are phthalimidine and 3-(2-cyanophenyl)isoquinoline.6 3... 

Chlorthalidone (pKa = 9.4) is an example of a diuretic in this class of compounds that bears a structural analogy to the quinazolinones (Table 27.4). This compound may be named as a 1-oxo-isoindoline or a phthalimidine. Although the molecule exists primarily in the phthalimidine form, the ring may be opened to form a benzophenone derivative. 

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