Isoindoles Diels-Alder addition

The o-quinonoid system incorporated within the isoindole nucleus would be expected to be reactive toward dienophiles, and several isoindoles have been found to give Diels-Alder addition products. The products derived from addition to isoindoles, however, depend to a marked degree on the nature of the dienophile and on the substituents in the isoindole component. 

Isoindole itself gives normal Diels-Alder addition products, (107 and 108), with maleic anhydride and A-phcnylmaleimide, these derivatives constituting the main evidence for forma,tion of the parent substance. 2-Alkyl- and 2-arylisoindoles also give normal addition products with these two dienophiles.Although only one product is generally isolated, it seems likely, in view of the known tendency of several Diels-Alder adducts of isoindoles to dissociate to their components (see below), that both exo and endo stereoisomers might be formed in certain cases. The reaction between 2-p-tolyl-isoindole and A-phenylmaleimide has been shown to give both e,xo (109) and endo (110) addition products. ... 

Addition of N-t-butylpyrrole to tetrachlorobenzyne produced 320, which, on thermolysis above 200°, gave the isoindole 321 Diels-Alder addition of DMAD to the latter gave the dihydronaphthalene 322.197... 

More modem methods for the production of isobenzofurans in solution have allowed detailed study of the rates of various substituted derivatives with iV-methyhnaleimide. Diels-Alder additions are also known for benzo[c]thiophene ° and isoindoles." ... 

A useful and possibly more general alternative to the Lwowski synthesis27,37 of 1.3-diphenyl isoindoles involves condensation of a l,2-dibenzoyl-l,4-cyclohexadiene (e.g., 55) with ammonia or a primary amine.43 Cyclohexadiene derivatives of this type are easily prepared by Diels-Alder addition of a 1,3-diene to dibenzoylacetylene,44,45 and these adducts lead directly, and in high yield, to the corresponding isoindoles (56). The reaction is closely related to the well-known synthesis of pyrroles by condensation of 1,4-diketones with ammonia. 4,7-Dihydro- and 4,5,6,7-tetrahydroisoindoles (57 and 58) have been... 

Reactions of 1,3-diphenylisobenzofuran which is much more stable, are typical it undergoes Diels-Alder cycloaddition with diethyl acetylenedicarboxylate " and adds singlet oxygen, indeed this commercially available isobenzofuran is often used as a trapping reagent for transient alkenes and alkynes. Less stable isobenzofurans are traditionally generated and reacted in situ 1-methyl-3-phenylisobenzofuran is typical. More modern methods for the production of isobenzofurans in solution have allowed detailed study of the rates of various substituted derivatives with A-methylmaleimide. Diels-Alder additions are also known for benzo[c]thiophene and isoindoles. ... 

In a neat manipulation of oxidation levels, the reaction of a 1,4-dihydro-1,2-diaroylbenzenes, such as are available from Diels-Alder additions of buta-1,3-dienes with 1,2-diaroylalkynes, with a sulfur source, produces benzo[c]thiophenes note that no reductant is required as would be necessary if a 1,2-aroylbenzene were utilised. These same Diels-Alder adducts react with primary amines to give 2-substituted isoindoles. 

The Diels-Alder addition product (50) from butadiene and 1,2-dibenzoyl-acetylene is a versatile precursor for preparation of isoindoles, isobenzo-furans, and isobenzothiophens. ... 

Benz[/]isoindole (125), recently prepared from the p-toluene-sulfonyl derivative (124), proved to be too unstable for isolation, but eould be trapped in solution as the Diels-Alder adduct (127). The corresponding 1-phenyl derivative (126) was also prepared and, aecording to spectral measurements, reacts with maleic anhydride to give the product (128) derived by additive substitution. This subsequently rearranged to the adduct (129). The same behavior is observed in the reaction of (126) with V-phenylmaleimide. This provides the first clear indication that substitution products from isoindole derivatives and dienophiles can be converted into the normal addition products. 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

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