Isoindole ring synthesis

The isoindole ring is present in the phthalocyanines (e.g., 167) and a common method for their synthesis is from 1,3-diiminodihydroisoindole 166 which is prepared by cyclization of 0-phthalonitrile (Scheme 99) <1991JOC82, B-2003MI17-61>. 

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... 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

Singlet oxygen oxidation of 3-substituted indoles in the presence of alcohols followed by treatment with sodium borohydride gives 2-alkoxy-3-hydroxyindolines in high yields. Further reaction with a nucleophile and a Lewis acid forms the basis of a synthesis of 2-substituted indoles (Scheme 70). This represents an alternative approach to CC bond formation at the 2-position of indoles to that involving the reaction of 2-lithioindoles with electrophiles. Isoindoles and indolizines are also preferentially oxidized in the five-membered ring to give phthalic acid and picolinic acid derivatives, e.g., 168, respectively. 

The completion of the synthesis of aspidospeimidine relied on a protocol introduced by Heathcock [72] for annulating the E-ring to the ABCD-framework of 228. Thus, as shown in Scheme 23, acylation of target compound 242 with a-chloroacetyl chloride followed by a Finkelstein reaction afforded the a-iodoacetamide 243 that upon treatment with silver triflate effected an intramolecular alkylation reaction and the formation of the isoindole-based lactam 244. Finally, reduction of this last compound with hthium aluminium hydride gave the racemic modification of aspidospermidine (228) (32%). 

From the data considered above it is clear that the Barton-Zard ccmdensation of nitroarenes is a convenient method for the synthesis of polycyclic compounds of the isoindole family. Formally the reaction involves the process and further cyclization into the pyrrole ring accompanied by elimination of HNOa-... 

In summary, we have succeeded in developing a novel one-step method for the synthesis of isoindoles by annelation of the pyrrole ring to the benzene ring of nitroarenes. 

A number of heterocyclics such as coumarins, flavones, and quino-lones have been prepared from o-subst. co-(methylsulfinyl)aceto-phenones . A simple isoindole synthesis with hydrazines has been published Phenolic coupling with PdCl2 has been used efficiently to produce carpanone whereby five contiguous asym. centers with the correct stereochemistry have been introduced in a single step . A facile synthesis of the tetracyclic skeleton of rheadan alkaloids, whidi have a characteristic azepine ring, has been reported Benzimidazoles and benzoxazoles have been prepared by a novel ring closure of a-amino-/9,7-ethylenenitriles . ... 

Besides their potential applicability as NLO materials noncentrosymmetri-cal phthalocyanines with different substituents on adjacent pairs of isoindole units promise intriguing new aspects in phthalocyanine chemistry polymeric phthalocyanines without crosslinking could lead to linear polymers, controlled binding of the phthalocyanine ring to a substrate could improve the synthesis of novel catalysts [188] and the preparation of highly ordered thin films should be possible [189]. 

This section surveys synthesis of hexadecasubstituted phthalocyanines having at least one fluorine atom directly attached to each of four tetrasubstituted benzene rings. Among them one can distinguish (i) partly fluorinated hexadecasubstituted phthalocyanines [MPcF (R),(j J and two types of perfluorinated phthalocyanines -(ii) hexadecafluorophthalocyanines [MPcFig] and (iii) hexadecasubstituted phthalocyanines combining fluorine atoms and perfluorinated substituents [MPc(R/)i6]. The low synunetry phthalocyanines with only three perfluorinated isoindole units [MPc(R/)i2R] are also considered here. 

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