Isoindoles electrophilic substitution

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 7r-electron excessive character of pyrrole and indole renders both systems extremely susceptible to electrophilic attack and the fused benzene rings of carbazole also undergo electrophilic substitution more readily than does an unsubstituted benzene ring. In contrast, the 2/7-isoindole system only survives intact during electrophilic substitution reactions under the mildest of conditions and the system is more susceptible to [ 4 + 2] cycloaddition reactions than is pyrrole. 1,1-Disubstituted IH-isoindoles generally undergo nucleophilic addition-elimination reactions across the 2,3-bond or yield products derived from an initial electrophilic attack at the 2-position. 

Isoindoles protonate to generate only one cation this electrophilic addition of protons sets the pattern for substitution in these systems, but there are relatively few clear cut examples, no doubt partly because of the instability of less substituted isoindoles, isobenzofurans and benzo[c]thiophenes. Detritiation studies showed the intrinsic reactivity of 2-methylisoindole in this electrophilic substitution to be 10" greater than that of 1-methyhndole. ... 

An interesting example of electrophilic substitution is the conversion of phthalimidine (2,3-dihydro-l/f-isoindol-l-one) into l-bromo-3-formyhsoindole under Vilsmeier conditions (formation of 1-bromo-2//-isoindole may be the first step)." Mannich substitution of 2-methyl-l-phenylisoindole is another straightforward example. ... 

Isoindole reacts with ethanolic 1,3,5-trinitrobenzene to give a deep red color attributed to a 7t-complex. With Ehrlich s reagent a red-purple color, which slowly turns blue, is observed. This reaction presumably involves electrophilic substitution at C-l (Section V,D) to give charge resonance systems of the types shown in 17 and 18 (cf. Section V,F,2). 

If aromatic electrophilic substitution is dependent on ground-state n-electron densities in the isoindole system (Section IV,A Table II) then reaction would be expected to occur preferentially at C-l (C-3), followed by... 

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). 

Annelation of 2,5-disubstituted pyrroles provides a useful route to isoindoles as shown in reactions (140)-(142). These reactions can be formulated as electrophilic aromatic substitutions of the pyrrole ring and proceed under the influence of acid catalysts (66T2481, 68JCS(C)3036, 72JCS(P1)904). 

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. 

ButylisoindoIe is much more stable than the unsubstituted heterocycle or other 2-substituted isoindoles, thus its reactions can be used as a measure of intrinsic reactivity, set aside from instability even weak electrophiles such as aryldiazonium ions attack it and it undergoes alkylation, in each case at the hetero ring 1-position. ... 

---