Isoindoles oxidation

The crude isoindole is dissolved in diethyl ether (2 L) under nitrogen. The solution is filtered and reduced in volume to 300 mL. It is then left under nitrogen for several hours until crystallization is complete. The fluffy white precipitate is collected by filtration, washed with a little diethyl ether, and dried under vacuum to give pure 1,3,4,7-tetramethylisoindole (mp,2 144° in vacuo). Yield 60 g (33%). This product is used for the preparation of metalloporphines. (Pink coloration due to isoindole oxidation does not reduce yields in subsequent steps). 

Although phthalimidine (27, R = H) is formally at the isoindole oxidation level, its chemical properties are those of an amide. The corresponding cyclic imidate (28), which is formed from the amide using Meerwein s reagent in the normal way, is an isoindolenine derivative, however. Moreover, when the starting phthalimidine is 2-substituted, the product after basification is a 1-alkoxyisoindole (29).48,49... 

The syntheses described above in which a benzenoid ortho-dicarbonyl derivative reacts with an amine require two reducing equivalents to proceed smoothly to the isoindole oxidation level. The synthesis described by White and Mann5,68 accommodates this feature by employing a 1,4-dihydro-benzene derivative (Eq. 11). 

Ci2H,5N203]- H3C CH3 1 [Tn-0 H3C CH3 6.7.8 Isoindol Oxidation of corresp. amine with pertungstic acid/ CH2CI2 inyl-2-ox EPR/ 300 yls N 1.40 79Gril )... 

A general method for the preparation of 2JT-isoindol-4,7-diones, eg (97) [72726-02-4] involves 1,3-dipolar addition of oxa2ohum-5-oxides (sydnones) (98) to 2-meth5l-l,4-ben2oquinone (96). Yield of (97) is 37%. 

Phthalazine-1,4-diones reactions, 3, 39 Phthalazines applications, 3, 56 isoindoles from, 4, 152 mass spectra, 2, 21 metabolism, 1, 233 N-oxidation, 3, 20 nitration, 3, 22 nucleophilic attack, 3, 25 oxidation, 3, 31... 

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. 

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... 

Isoindoles are reactive toward oxidizing agents, and precautions usually advocated in the preparation of these compounds to prevent their oxidation merit careful consideration. The end products of oxidation are most often colored, resinous materials of indeterminate structure. The oxidative reactions appear to be accelerated by light and occur much more rapidly in solution than in the solid state. In a separate but possibly related process, certain isoindoles undergo polymerization in the solid state to give resins which, according to... 

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. 

A study of the electrochemical oxidation and reduction of certain isoindoles (and isobenzofurans) has been made, using cyclic voltammetry. The reduction wave was found to be twice the height of the oxidation wave, and conventional polarography confirmed that reduction involved a two-electron transfer. Peak potential measurements and electrochemiluminescence intensities (see Section IV, E) are consistent vidth cation radicals as intermediates. The relatively long lifetime of these intermediates is attributed to steric shielding by the phenyl groups rather than electron delocalization (Table VIII). 

Mercury-sensitized irradiation of 1,2,3-triphenylisoindole (65) in the presence of oxygen gives a peroxide (103). This peroxide is relatively stable compared with the peroxide (104) derived from similar oxidation of 1,3-diphenylisobenzofuran and can be reconverted to the isoindole (65) by pyrolysis or by treatment with zinc and acetic acid. Reduction of 103 under mild conditions affords o-dibenzoylbenzene (46) and aniline. Aerial oxidation of 47 gives 46 and methylamine, presumably via a peroxide intermediate similar to 103. °... 

Isoindoles which have a free hlH group can undergo himolecular, oxidative coupling. Thus, 1-phenylisoindole (38), when refluxed in benzene in the presence of air, gives a 4,5% yield of the dehydrobisiso-indolenine (39), a product identical with that obtained by catalytic hydrogenation of o-cyanobenzophenone (37). ... 

Mendoza and Torres and later Torres alone carried out systematic studies of the consequences of replacing an isoindole ring by a 1,2,4-triazole one. A first attempt to introduce two triazole subunits gave the dihydro 20-77 ring 86 instead of the I8-77 system 87 [89JCS(P2)797]. All attempts to oxidize 86 into 87 failed. Compound 87 was calculated to be less stable than... 

Reduced isoindoles are formed when acetylenes are cooligomerized with N-phenyl- or N-methylmaleimide but the synthetic value of these processes is limited by competing secondary reactions of product cycloaddition (Scheme 51) and oxidation.87... 

Similar treatment of 5-nitrobenzothiadiazole 97 with ethyl isocyanoacetate and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the thiadiazolo[3,4-< ]isoindole 93 (21%), but when a phosphazene base was employed the major isolated product was the pyrimidine fV-oxide 98 (46%) (Equation 13) <1996J(P1)1403, 1996TL8391>. 

Use has been made of the C-N cleavage in the conversion of the bicyclic tertiary amines, derived from the 4tc + 2tc cycloaddition of pyrroles and isoindoles with benzynes, into aromatic systems, e.g. naphthalen-l,4-imines and anthracen-9,10-imines yield naphthalenes and anthracenes with the extrusion of the nitrogen bridge [24] in yields which are higher than those obtained by standard oxidation procedures. 

Introduction of the nitrogen atom in 89 was achieved84 by reaction of the 1,4-dichloro derivative 87 with a primary amine in acetonitrile to give initially the nonaromatic system 88. Aromatization was effected through dehydration of the TV-oxide by a method due to Kreher and Seubert,85 used originally for the preparation of N-substituted isoindoles. 

Owing to the susceptibility of indole, isoindole and pyrrole rings to oxidation (see Section 3.05.1.4) and acid-catalyzed dimerization and polymerization (see Section 3.05.1.2.2), the products of the reactions with nitrating and nitrosating agents are subject to the reaction conditions. 

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). 

The aromatic pyrrole, indole, isoindole and carbazole rings can in general be obtained by oxidative aromatization of more highly reduced nonaromatic derivatives. In practice this method has been of most synthetic significance for indoles and carbazoles, where the corresponding 2,3-dihydroindoles (indolines) and 1,2,3,4-tetrahydrocarbazoles are accessible by a variety of synthetic pathways. 

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