Phthalaldehydes phthalimidines

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. 

Quite interestingly, the hydrazido(2-) Hgands derived from the ligating N2 in complexes 1 and 2 are transformed into N-hetero cyclic compounds by application of the condensation and related methods (Scheme 6). Thus, their reactions with 2,5-dimethoxytetrahydrofuran, pyrylium salts, and phthalaldehyde, followed by workup of the complexes containing N-heterocyclic ligands with LiAlH4 or KOH/alcohol, result in the formation of pyrroles [29], pyridines [30], and phthalimidines [31], respectively. 

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... 

For this purpose detectable levels in the range of 1 pg per ml of plasma are needed. In order to achieve this sensitivity it is necessary to make a fluorescent derivative of sulfisoxazole. One such derivative is the highly fluorescent "Dansylsulfonamlde" which is formed by the reaction shown in Figure 9. The fluorescence yield of this compound is sufficient to measure about 1 yg of sulfisoxazole per ml of plasma. An even more sensitive derivative is formed when sulfisoxazole is reacted with 4,5-methylene-dioxy-phthalaldehyde to form a phthalimidine derivative (Figure 9). The sensitivity limit for this derivative is from 1 X 10 to 1 X 10 10 mole/ml (22). 

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