Reactions with isoindoles

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... 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

An interesting extrapolation of this synthesis deals with the preparation of the bispyridinium salt 62 from 1,2-phthalic dicarboxaldehyde and its subsequent reaction with primary amines (92BSB509).Tlie expected diimines 63 readily cyclize so that 2-aryl-l-arylimino-2,3-dihydro-l//-isoindoles 64 can be isolated in excellent yields (90-95%). Contrary to the reactions performed by employing the dialdehyde and amines directly, the syntheses involving the azinium salts do not produce those typical dark-colored complex mixtures of products (77JOC4217 85JHC449) (Scheme 20). 

The reaction of isoindole 192 with phosphorus pentasulfide in pyridine afforded intermediate 193, which gave with hydrazine hydrate 194 (82S853) (Scheme 40). 

Mopper [265] has described developments in the reverse phase performance liquid chromatographic determination of amino acids in seawater. He describes the development of a simple, highly sensitive procedure based on the conversion of dissolved free amino acids to highly fluorescent, moderately hydrophobic isoindoles by a derivatisation reaction with excess o-phthalaldehyde and a thiol, directly in seawater. Reacted seawater samples were injected without further treatment into a reverse-phase high-performance liquid chromato-... 

Methylisoquinol-l-one behaves as an enamine with dichlorocarbene to produce the dichlorocyclopropane derivative (83%). The corresponding reaction with dibromocarbene produces a thermally labile compound, which is assumed to have an analogous structure. Rearrangement of the dichloro compound under basic conditions leads to the isoindole derivative (96%), whereas controlled thermolysis... 

The reactions of isoindoles with other acetylenic dienophiles have yet to be explored. 

Dichloroacetamide present in chlorinated and chloraminated drinking waters was determined (at detection level of 23 pg L ) through an LC/fluorimetric method and a post-column derivatization reaction with o-phthaldialdehyde in the presence of sulfite at pH 11.5, that leads to the formation of a highly fluorescent isoindole fluorophore [225]. 

Dumitrascu and co-workers (52) transformed 4-halosydnones into 5-halopyr-azoles by cycloaddition with DMAD and methyl propiolate followed by retro-Diels-Alder loss of CO2. Turnbull and co-workers (194) reported that the cycloadditions of 3-phenylsydnone with DMAD and diethyl acetylenedicarboxylate to form pyrazoles can be achieved in supercritical carbon dioxide. Nan ya et al. (195) studied this sydnone in its reaction with 2-methylbenzoquinone to afford the expected isomeric indazole-4,7-diones. Interestingly, Sasaki et al. (196) found that 3-phenylsydnone effects the conversion of l,4-dihydronaphthalene-l,4-imines to isoindoles, presumably by consecutive loss of carbon dioxide and A-phenylpyrazole from the primary cycloadduct. Ranganathan et al. (197-199) studied dipolar cycloadditions with the sydnone 298 derived from A-nitrosoproline (Scheme 10.43). Both acetylenic and olefinic dipolarophiles react with 298. In... 

Owing to the susceptibility of indole, isoindole and pyrrole rings to oxidation (see Section 3.05.1.4) and acid-catalyzed dimerization and polymerization (see Section 3.05.1.2.2), the products of the reactions with nitrating and nitrosating agents are subject to the reaction conditions. 

Pyrroles, indoles, isoindoles and carbazoles having no substituent at the nitrogen atom are weakly acidic and, upon treatment with a strong base, form anions which are capable of subsequent reaction with electrophiles at the nitrogen atom and/or the 1-position of isoindoles, the 2-position of pyrroles and the 3-position of indoles. 1-Substituted pyrroles and indoles also react with butyllithium to give 1-substituted 2-pyrrolyl and 2-indolyl anions (see Section 3.05.1.2.9). 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

Aspartame and its degradation products aspartylphenylalanine, aspartic acid, and phenylalanine can also be separated after reaction with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide (sodium or potassium cyanide) in borate buffer (50 mM, pH 8). This reaction affords highly fluorescent and stable l-cyano-2-substituted-benz[/]isoindole (CBI) derivatives that can be detected at 420 nm excitation and 490 nm emission. The CBI derivatives are separated on a TSK ODS-120T column using a gradient of 30-80% B (acetonitrile water, 9 1 v/v) in A (50 mM acetate buffer, pH 6.0) (75). 

The OPA method is based on the formation of a highly fluorescent isoindole derivative by reaction with o-phthalaldehyde and 2-aminoethanol in mildly basic aqueous solution (331. The advantage of this technique is that a large variety of thiols and other reduced sulfur compounds can be detected at subnanomolar to nanomolar concentrations. Its disadvantage is that the fluorescent derivative, which preserves the thiol in its reduced stage, is unstable and must be formed just prior to injection. These characteristics preclude the delayed analysis (e.g., in the laboratoiy) of large numbers of samples collected in the field. 

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