Isoindoles substituted

Isoindoles substituted in the pyrrole ring are thermally more stable. They can be prepared on several routes [209],... 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104], In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(tntIuoromethyl)benzyne were shown to react in moderate yields with A7-(trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

Several calculations of the electronic structure of isoindoles have Ijeen published, and the distribution of charge density around the isoindole nucleus calculated by these methods is summarized in X able I. A common prediction of the calculations, which are based on tlie LCAO-MO method or the frontier electron concept, is the relatively high electron density to bo found at position 1, and the expectation, thei efore, i.s that electrophilic substitution on carbon... 

The first clearly authenticated preparation of an isoindole was reported by Wittig et in 1951. It was found that elimination from isoindolinium bromides and iodides with bases such as aryl- and alkyllithium afforded 2-substituted isoindoles in variable yields. For instance, 2,2-dimethylisoindolinium bromide (5) on treatment with one equivalent of phenyllithium in ether under nitrogen, evolved methane and gave 2-mcthylisoindole (6) in 74% yield. With methyl-lithium as base, a slightly lower yield was obtained. 

Elimination from A -oxides of substituted isoindolines provides an exceptionally facile synthesis of the isoindole sy.stem. Kreher and Seubert found that treatment of the oxides of both 2-alkyl- and 2-arylisoindolines with acetic anhydride at 0° to —10° afforded... 

In contrast to isoindoliiiium salts and A-oxides of isoindolines, successful elimination from simple 2-substituted isoindolines has been realized in only two cases. One of these, however, was the synthesis of isoindole itself, and it seems likely that this method is particularly well suited to the preparation of other sensitive isoindoles. 

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-... 

Benz[/]isoindole (125), recently prepared from the p-toluene-sulfonyl derivative (124), proved to be too unstable for isolation, but eould be trapped in solution as the Diels-Alder adduct (127). The corresponding 1-phenyl derivative (126) was also prepared and, aecording to spectral measurements, reacts with maleic anhydride to give the product (128) derived by additive substitution. This subsequently rearranged to the adduct (129). The same behavior is observed in the reaction of (126) with V-phenylmaleimide. This provides the first clear indication that substitution products from isoindole derivatives and dienophiles can be converted into the normal addition products. 

Accurate, quantitative spectroscopic data for the simple alkyl-substituted derivatives of isoindole are not available, cither because of their inherent instability or tendency to tautomerize to isoindole-nines. However, the presence of an isoindole in a tautomeric mixture can be readily discerned by means of ultraviolet spectroscopy. ... 

Emission spectra have been recorded for four aryl-substituted isoindoles rmder conditions of electrochemical stimulation. Electrochemiluminescence, which was easily visible in daylight, was measured at a concentration of 2-10 mM of emitter in V jV-dimethylformamide with platinum electrodes. Emission spectra due to electrochemi-luminescence and to fluorescence were found to be identical, and quantum yields for fluorescence were obtained by irradiation with a calibrated Hght source. Values are given in Table X. As with peak potentials determined by cyclic voltammetry, the results of luminescence studies are interpreted in terms of radical ion intermediates. ... 

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. 

Efficiencies ( p) of 1-Cyano-W-substituted Benz[f]isoindoles (CBI) in Aqueous Acetonitrile... 

A synthesis of highly-substituted tetracenes was developed starting from isoindole (benzo[c]pyrrole) <06OL273>. For example, treatment of dibromonaphthalene 87 with phenyllithium in the presence of isoindole 86 followed by deamination of the intermediate cycloadduct provided tetracene 88. Separately, the synthesis and cycloaddition chemistry of oxadisilole-fused isoindoles was investigated <06SL2510>. 

Indolizines, aromatic heterocycles with 12-jr-elec-tron system salts, isomeric with indole and isoindole, are prepared in good yields from pyrylium salts with active a-methylene groups.215 216 Aromatics derived from pyrylium salts by substitution of one or two fi-CW group(s) with a heteroatom are also possible. 

NDA derivatization has also been automated for analysis of amino acids in brain tissue and microdialysates (Shah et al, 1999). NDA reacts with primary amines in the presence of cyanide to form a highly stable N-substituted l-cyanobenz[/] isoindole (GBI) derivative. Addition of a nucleophile, such as cyanide, hydrogen sulphite, isothiocyanate, or 2-mercaptoethanol, is essential for the formation of the derivative. 

Changes in R, and X had very similar effects whether these changes were in the imidazoisoindoles, the dihydroimidazo-isoindoles or the benzoates. Optimum activity was associated with = CH and R = CHCCH ) There was nevertheless still considerable activity in compounds in which R,, R2 were methyl, methyl or methyl, ethyl or methyl, cyclopropyl. Other combinations of Rj and R2 usually resulted in compounds with lower levels of activity. Substitution in the aromatic ring also reduced biological activity. 

The cyano-substituted nitrile ylides 123 have been generated via 1,1-elimination reactions. For example, the benzyhdene derivative 122 (R=Ph) eliminated benzene on vapor phase pyrolysis to give 123 (R=Ph), which reacted via 1,5-electrocycli-zation [see also (66)] to give the isoindole 124 (41%) (67). In a similar way, 122 [R=(CH2)3CH=CH2] gave the corresponding nitrile yhde that reacted via intramolecular cycloaddition to give the pyrroline derivative 126. 

In an attempt to investigate this theory further, the analogous alkoxy-substituted nitrile ylides 171 were investigated. Species of this type were previously unknown but were successfully generated for this work by the thermolysis of the 4-alkoxy substituted l,3-oxazol-5-ones 170 (89). In the absence of a dipolarophile, the nitrile ylides reacted via 1,5-electrocyclization to give the isoindoles 173 [see also... 

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