Isoindoles Isoindoline

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. 

Elimination from A -oxides of substituted isoindolines provides an exceptionally facile synthesis of the isoindole sy.stem. Kreher and Seubert found that treatment of the oxides of both 2-alkyl- and 2-arylisoindolines with acetic anhydride at 0° to —10° afforded... 

Pyrolytic elimination from isoindoline A -oxides also affords iso-indoles, but yields were found to be generally lower than those obtained by Kreher and Seubert s procedure. The considerable amount of polymeric material formed in the pyrolytic reaction makes isolation of the isoindole difficult, but a convenient method for separation of the product was found utilizing complex formation with 1,3,5 -trin i tro benzene. 

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 perhydroisoindole system can be prepared by high-pressure hydrogenation of the isoindole over nickel on alumina at elevated temperatures. The use of Raney nickel with dioxane in the reduction of l,3-diphenyl-2-methylisoindole (47) gives the perhydro product (96), accompanied by the isoindoline (97). An alternative route to partially hydrogenated isoindoles has been described in Section III, D. 

Electrolytic reduction of phthalimide and of phthalimidines which are at an oxidation level above that of isoindole, proceeds through the isoindole to the isoindoline stage, which is then stable to further... 

Note, Added in Proof-. In their study of the autoxidation of 2-butyl-isoindoline, Kochi and Singleton showed that 2-butylisoindole is formed and is converted by further oxidation to 2-butylphthalimide and 2-butylphthalimidine. The rate of oxidation of 2-butylisoindoline to the isoindole was found to be markedly dependent on hydrogen donor ability of the solvent and was shoivn to involve a free radical chain process. Autoxidation of 2-butylisoindole also appears to be a radical process since it can initiate autoxidation of 2-butylisoindoline. 

Activation of the carboxylic acid function of 2-(l//-pyrrol-l-yl)isoindolin-l-one 253 yielded 5,5a-dihydropyrro-lo[l, 2 2,3]pyridazino[6,l- ]isoindole-4,10-dione 254 (Equation 64) <1995H(41)689>. 

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. 

Isoindoline li/-Isoindole, 2,3-dihydro- Orotic acid 4-Pyrimidinecarboxylicacid,l,2,3,6-tetrahydro-2,6-... 

Bisbromomethyl derivatives are cyclized by reaction with liquid methylamine at - 80 C [2061]. Hydrazine and its simple derivatives sometimes behave as mono-functional compounds, for example, in a reaction with the dibromoarylacetic ester (81.1) [2658, 2687]. Under these conditions, phenylhydrazine ves a mixture of the isoindole and isoindoline. An unconventional synthesis of a fused pyrrole is that in which a dihalide is heated with ethyl chloroacetate and pyridine in DMF. The pyridine reacts and becomes an integral part of the product [2985]. 

Isoindoles can be produced by eliminations from A-substituted isoindolines (1,3-dihydro-isoindoles), themselves readily produced by the reaction of a nitrogen nucleophile and a l,2-bis(bromomethyl)-benzene examples are the pyrolytic eUmination of acetic acid from the cyclic hydroxylamine acetate,or, at a much lower temperature, of benzyl alcohol from an A-hydroxy-isoindoline benzyl ether, or of methanesulfonic acid from a corresponding mesylate. A-substituted isoindoles, too, have generally been made from an isoindoline by elimination processes, thus A-oxides can be made to lose water by pyrolysis," or better, by treatment with acetic anhydride. ... 

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