Isoindoles 1-aryl

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. 

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... 

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. ... 

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). 

For example, McNab and coworkers have discovered that flash-vacuum pyrolysis (FVP) (1000 °C, 0.01 Torr) of pyrrole 10-114 led to the formation of pyrrolo[2,l-a]isoindol-5-one 10-117 in 79% (Scheme 10.29) [44]. The transformation is proposed to proceed via an initial 1,5-aryl shift to give intermediate 10-115, which then undergoes an elimination of methanol. Finally, electrocydization of the ketene 10-116 results in the formation of 10-117. 

Wu and co-workers developed a synthesis of benzannulated nitrogen heterocycles 120 and 121 based on the addition of sodium methoxide to 2-alkynylbenzo-nitriles 118 in methanol, followed by the Pd(PPh3)4-catalyzed heteroannulation of ketimine intermediate 119 with aryl iodides [104]. The 5-exo versus 6-endo mode of cyclization leading to isoindoles 120 or isoquinolines 121, respectively, proved to be dependent on the nature of the substituent on the terminal alkyne carbon. 2-(2-Phenylethynyl) benzonitrile 118a underwent exclusive 5-exo cyclization whereas 2-(l-hexynyl)benzonitrile 118b led to mixtures of isomers with a marked preference for the 6-endo mode of cyclization. This endo/exo balance was attributed to steric interactions between the entering group and the substituent on the terminal alkyne carbon (Scheme 8.49). 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

The other type of carbamoyllithiums IIIc can also be prepared by reaction of CO with (V-lithioketimines, resulting from the addition of rert-butyllithium to aryl cyanides 10477,102. These intermediates 105 underwent selective cyclization to give 177-isoindole derivatives 10677 and six- (107)102 or seven-membered (108)102 cyclic products (Scheme 27). Compounds 107 result either by insertion of the carbene structure into the benzylic carbon-hydrogen bond, as in the case of carbamoyllithiums96, or by intramolecular protonation. 

FVP of l-(2-methoxycarbonylphenyl)pyrrole 19 at925°C (0.001 Torr) gives the unusual 5//-pyrrolo[2,l- 7]isoindol-5-one system 21 (79%) by a novel three-step cascade process involving rate-determining [l,5]-aryl migration. 

An alternate strategy to identify the upstream kinase responsible for phosphorylating a particular phosphoserine protein also was reported (22). In this scheme, a bis aryl aldehyde ATP analog was designed to form an imine with the lysine (Lys 72 in PKA) essential for orienting the a/fi phosphates of ATP. The substrate of interest, with its target serine mutated to cysteine, provides a nucleophile to attack the imine, which then cyclizes with a second aldehyde to form a stable isoindole adduct that links kinase and substrate (Fig. 8b). 

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