Isoindoline synthesis

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... 

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. 

In contrast to phthalocyanines (tetra- or octasubstituted) in which the isoindoline units carry all the same substituents, reports of phthalocyanines with lower symmetry, which have been prepared by using two different phthalonitriles, have rarely appeared. This is due to the problems which are associated with their preparation and separation. For the preparation of unsymmetrical phthalocyanines with two different isoindoline units four methods are known the polymer support route,300 " 303 via enlargement of subphthalocyanines,304 " 308 via reaction ofl,3,3-trichloroisoindoline and isoindolinediimine309,310 and the statistical condensation followed by a separation of the products.111,311 319 Using the first two methods, only one product, formed by three identical and one other isoindoline unit, should be produced. The third method can be used to prepare a linear product with D2h symmetry formed by two identical isoindoline units. For the synthesis of the other type of unsymmetrical phthalocyanine the method of statistical condensation must be chosen. In such a condensation of two phthalonitriles the formation of six different phthalocyanines320 is possible. 

Recently, the use of flash vacuum pyrolysis, at 420°C and at pressure less than 0.5 mm Hg has been described for the synthesis of isoindolyl nitrone 1,1,3-tri-methylisoindole A-oxide (TMINO) from isoindoline nitroxide 1,1,3,3-tetra-methylisoindolin-2-yloxy (TMIO), with yields up to 73% (Scheme 2.71) (354). 

This paper traces in some detail the path which led to the discovery of a new class of herbicides, the 2-(5-oxo-2-imidazolin-2-yl)arylcarboxylates. The journey started when it was found that a phthalimide, a-isopropyl-a-methyl-l,3-dioxo-2-isoindoline-acetamide, had sufficient herbicidal activity to warrant further synthesis effort. This work led to a series of analogs essentially devoid of herbicidal activity yet possessing interesting plant growth regulating effects. Further chemical modifications resulted in the synthesis of two new groups of compounds, imidazoisoindolediones and dihydro-imidazoisoindolediones, and the return of herbicidal activity. The imidazoisoindolediones were in turn transformed into o-(5-oxo-imidazo-lin-2-yl)benzoates, the first members of a very interesting new class of herbicides. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

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. 

Synthesis of 4-(l//-tetrazol-l-yl)butylamine 453 from 2-[4-(l//-tetrazol-l-yl)butyl]isoindoline-l,3-dione 452 has been reported <2006S1504>. In a subsequent reaction, butylamine 453 was converted in low yield into 1 -[4 (4//-l,2,4-triazol-4-yl)butyl]-l //-tctrazole 454 (Scheme 56) <2006S1504>. 

Lamblin M, Couture A, Deniau E, Grandclaudon P (2008) Alternative and complementary approaches to the asymmetric synthesis of C3 substituted NH free or N-substituted isoindolin-1-ones. Tetrahedron Asymmetry 19 111-123... 

Figure 7.9 Validation in solution for the synthetic scheme to the isoindoline SP pool library L2 synthesis of 7.7.

Although the precise mechanism of formation of phthalocyanines is unknown, it is generally thought that isoindoline intermediates are involved. A notional cyclization process could be that shown in equation (43). Template synthesis of phthalocyanines can also be achieved starting with 1,3-diiminoisoindoline and various analogs can be obtained from combinations of starting materials. Ligands such as (96) and (97) can be synthesized in this manner. 

The most common synthetic method for the synthesis of metal-containing Pcs involves the cyclotetramerization of phthalic acid, phthalic anhydride, 2-cyanobenzamide, phthalimide, diimino-isoindoline, or phthalonitrile at elevated temperatures (>200 °C) in the presence of a metal or metal salt. These reactions can be carried out either in a suitable solvent or in the melt. It should be noted that the use of a metal halide in the melt often leads to a monohalogenated Pc. Except for phthalonitrile and diiminoisoindoline cyclotetramerizations, a nitrogen source is required,... 

Design, synthesis, and assessment of anticholinesterase activity of 2-(2-(4-Renzylpiperazin-l-yl)ethyl)isoindoline-l,3-dione derivatives showed that some of these compounds can function as potential acetylcholinesterase inhibitors with a potency comparable to that of donepezil [170]. 

Mohammadi-Farani A, Ahmadi A, Nadri H, Aliabadi A (2013) Synthesis, docking and acetylcholinesterase inhibitory assessment of 2- (2 - (4-Benzylpiperazin -1 -yl) ethyl) isoindoline-l,3-dione derivatives with potential anti-Alzheimer effects. Darn 21 47... 

Scheme 3.20 One pot synthesis of enantioenriched isoindolines based on chiral Bronsted acid catalyzed F C reaction/base catalyzed aza Michael addition reaction sequence.

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]. 

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