Isoindolenines

According to a molecular orbital calculation of Veber and Lwowski, isoindole should be favored over its tautomer, isoindolenine, by about 8 kcal/mole. However, the calculated electronic distribution is markedly different in the two oases, particularly at position 1, and it is to be expected that the nature and pattern of substituents will play an important role in determining the position of tautomeric equilibrium between these two species. 

Syntheses of phthalimidines (e.g., 30) do not in themselves constitute syntheses of isoindoles or isoindolenines, since the lactam from shows no tendency to tautomerize, as discerned from spectroscopic evidence, to lactim forms (31 and 32). However, phthalimidines are... 

Attempts to prepare isoindolenine (4) by pyrolytie or acid-eatalyzed elimination from the aminoacetal (36). proved fruitless, the only... 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

Tetramethylisoindolenine (50) is obtained as an unstable, crystalline solid from the reaction of 2,5-hexanedione with 2,5-dimethylpyrrole in the presence of sulfuric acid. Treatment of the same diketone with ammonium sulfate also affords this isoindolenine. NMR measurements in deuteriochloroform indicate that a small amount of 1,3,4,7-tetramethylisoindole (51) is present in equilibrium with the isoindolenine. This same isoindole was postulated as an intermediate in the reductive self-condensation of 2,5-dimethyl-pyrrole (52) which affords a mixture of cis- and lwMs-l,3,4,7-tetra-methylisoindolines (53 and 54). Hydrolytic opening of the... 

An early claim by Gabriel and Neumann to have synthesized 1-methylisoindolenine (59) from the diazanaphthalene (60) has been shown to he in error, the actual product being 1-methylisoindoline (61). Several synthetic routes to 1,3,3-trisubstituted isoindolenines... 

Two independent molecular orbital calculations (HMO method) of delocalization energies for isoindole and isoindolenine tautomers agree that the isoindole form should possess the more resonance stabilization. The actual difference calculated for isoindole-isoindolenine is about 8 kcal/mole, but increases in favor of the isoindole with phenyl substitution at position 1 (Table VI).Since isoindole and isoindolenine tautomers have roughly comparable thermodynamic stabilities, the tautomeric proce.ss is readily obser-... 

The isoindole-isoindolenine equilibrium has been studied quantitatively only in the case of certain 1-arylisoindoles. Although two structurally different isoindolenines are possible, only that with the carbon-nitrogen double bond conjugated with both aromatic rings was observed. Investigation of the isoindole-isoindolenine ratios for three compounds by NMR and ultraviolet spectroscopy indicated a... 

Photochemical oxidation of a mixture of 1,3,4,7-tctramethyliso-indole (51) and its tautomer (50) has been found to give the isoindolenine hydroperoxide (105). Conceivably, this hydroperoxide could disproportionate to give a hydroxyisoindolenine, since 106 is a major by-product when the condensation between 2,5-hexanedione and... 

As was pointed out earlier (76AHCS1, p. 217), tautomeric equilibria for substituted isoindole-isoindolenine systems depend critically upon the substituents. Isoindole exists in the o-quinoid form 6. Computational results for the parent systems are given in Table III (99UP1). The results indicate that within the B3LYP functional only large basis sets provide reliable energy differences. 

Electron-releasing substituents stabilize the isoindolenine tautomer 7, whereas eleetron-withdrawing groups have the opposite effect. In Table IV some data are given. 

Tautomeric interconversions of 1,3-diimino-isoindolenine and its nitro and amino derivatives have been studied theoretically by the AMI method (97MI9). 

Among the variety of nitrogen-containing fulvalenes emerging from types 7-14, X-ray structural determinations have been performed on about 20 representative examples. Tire first crystal structure determination was carried out by application of the folding-molecule method on 3,3 -diphenyl-l,l -bi-isoindolylidene 64 (R = FI) (71CB3108). Tire dimeric isoindolenine system... 

Although isoindole itself exists preferentially as such (73JCS(Pl)1432, 72TL4295, 77TL1095), in accord with predictions of MO calculations (77JA8248 and refs, therein), the low resonance energy of isoindoles often results in the isoindolenine tautomer being favored in substituted derivatives. 1H NMR spectroscopy has been especially useful in the study of this tautomeric... 

Addition of DMAD to the carbonyl-stabilized nitrogen ylid 329 gave the furan 330 and the isoindolenine 331. This and similar reactions201 could involve either a symmetry allowed concerted cycloaddition or a nonconcerted reaction followed by elimination of the tertiary amine. 

Vollmann found that the reaction between Timino-3-amino isoindolenine (124) and 2-amino-4-methylthiazole is catalyzed by ammonium chloride and involves the exocyclic nitrogen (285). This reaction (Scheme 82) was later used to prepare dyes (286). 

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