Synthesis of Isoindoles

Isoindolines comprise a group of well-characterized and easily synthesized substances, and being at the next stable reduction state below that of isoindoles, they constitute suitable precursors for synthesis of the latter. In principle, either oxidation or elimination from isoindolines should lead to isoindoles however, in view of the susceptibility of isoindoles to further oxidation, elimination has been preferred, and in all cases reported the leaving group has been placed on nitrogen rather than 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. 

Di-o-xylyleneammonium bromide (7) gave only an 8% yield of 2-o-tolylisoindole (8) with phenyllithium, although the yield was 

Wheland, Resonance in Organic Chemistry, p. 99. Wiley, New York, 

In the case of elimination from (9), isoindole formation competes with 1,2-migration of the benzyl group (Stevens rearrtingement ), whichgives l-benzyl-2-m6thylisoindoline (10), and also with migration 

The first clearly authenticated preparation of an isoindole was reported by Wittigei 1951. It was found that elimination from 

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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. 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Sato, R. Ohmori, M. Kaitani, E Kurosawa, A. Senzaki, T Goto, T Saito, M. Synthesis of isoindoles. Acid- or base-induced cyclization of 2-cyanoben-zaldehyde with alcohols. Bull. Chem. Soc. Jpn. 1988, 61, 2481-2485. 

The [,4 + 2] cycloaddition of dienophiles with 1-substituted pyrroles is also a reversible reaction, which has been utilized in the synthesis of 3,4-disubstituted pyrroles (b-77MI305oq) and, via the initial reaction of the pyrrole with benzyne, for the synthesis of isoindoles (81 AHC(29>341). The retro-reaction can be controlled and aided by a 1,3-dipolar cycloaddition of the intermediate adduct with benzonitrile oxide (74TL2163, 76RTC67) (Scheme 61). 

For the synthesis of isoindoles (benzo[c]pyrroles) by type la cyclization the required intermediate is an o -acylbenzylamine. The only viable route to these substances which has been developed starts with a -bromo-o -toluic acid which is converted first to a phthalimide and then to the acid chloride. The acid chloride is then elaborated to the requisite ketone by Friedel-Crafts acylation. Condensation to the isoindole occurs on liberation of the primary amino group using hydrazine (equation 18) (64JA4152). 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

The methodology for synthesis of isoindoles is not as thoroughly explored as that of pyrroles and indoles and there is less information about the generality of specific methods. Nevertheless, reaction patterns for cyclizative condensation are similar to those for pyrroles and indoles. Generation of o-acylbenzylamines generates isoindoles. Several l-arylisoindoles were prepared in two steps from (7) by a Friedel-Crafts reaction followed by release of the amino group from the phthalimide by hydrazinolysis (Scheme 24) <64JA4152>. 

Category Ilae cyclizations play a prominent role in the synthesis of isoindoles. Simple 2-alkyl-2/f-isoindoles can be prepared from l,2-bis-(bromomethyl)benzene via dihydroisoindole-A(-oxides. The oxides undergo Polonovsky elimination in acetic anhydride/triethylamine <88CZ85>. A similar reaction sequence can be applied to the synthesis of 2-aryl analogs (Scheme 72) <87CZI55>. 

The use of oxazole-alkene Diels-Alder cycloadditions to form biologically relevant molecules has recently been applied to the synthesis of isoindoles, useful intermediates for the preparation of substance P antagonists. Thus 5-ethoxy-4-methyloxazole 8 reacted with 4,4-dimethyl-2-cyclopentenone 78 in refluxing benzene in the presence of catalytic zinc bromide to give the (l//)-cyclopenta(c)-pyrrole 80 as a separable 3 1 mixture of cis and trans isomers in 53% yield (Fig. 3.22). The reaction is presumed to proceed via the intermediacy of cycloadduct 79. When cyclohexenone 81 was used as the dienophile, the product was the hydro-(l//)-isoindole 82, obtained via dehydroformylation of the cycloadduct, in 85% yield after only 30 min in refluxing benzene. 

Scheme 44 Attempted synthesis of isoindoles from mononitro-substituted aromatic compounds...

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