Isoindoles reactions

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

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... 

The often inaccessible and labile isoindoles can be accessed by the BZ reaction, as can be heteroisoindoles, such as 32. " Novel pyrroles fused to rigid bicyclic skeleta are readily crafted via a BZ reaction. Certain nitroheterocycles undergo the BZ... 

Syntheses from Phthalimidines Syntheses from Ortho-Disubstituted Benzenes Condensation of 1,4-Diketones with Amines and Pyrroles Other Reactions and Rearrangements Leading to Isoindoles IV. Properties of the Isoindole System A. Tautomerism... 

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. 

The reaction between phthalimidine (30) and triethyloxonium fluoroborate is reported to give the fluoroborate salt of 1-ethoxyiso-indolenine, from which the free base (35) can be liberated.The iso-indolenine (35) apparentlj shows no detectable tautomerism with the isoindole form (see Section IV, A). 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

Tetramethylisoindolenine (50) is obtained as an unstable, crystalline solid from the reaction of 2,5-hexanedione with 2,5-dimethylpyrrole in the presence of sulfuric acid. Treatment of the same diketone with ammonium sulfate also affords this isoindolenine. NMR measurements in deuteriochloroform indicate that a small amount of 1,3,4,7-tetramethylisoindole (51) is present in equilibrium with the isoindolenine. This same isoindole was postulated as an intermediate in the reductive self-condensation of 2,5-dimethyl-pyrrole (52) which affords a mixture of cis- and lwMs-l,3,4,7-tetra-methylisoindolines (53 and 54). Hydrolytic opening of the... 

A useful and possibly more general alternative to the Lwowski synthesis- of 1,3-diphenylisoindoles involves condensation of a l,2-dibenzoyl-l,4-cyclohexadiene (e.g., 55) with ammonia or a primary amine. Cyclohexadiene derivatives of this type are easily prepared by Riels-Alder addition of a 1,3-diene to dibenzoylacetylene, 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... 

Several novel reactions and rearrangements giving isoindoles as stable end products have been reported. For certain isoindoles, such processes afford an efficient preparative route to a specific derivative. 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

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... 

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. ... 

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. 

An interesting extrapolation of this synthesis deals with the preparation of the bispyridinium salt 62 from 1,2-phthalic dicarboxaldehyde and its subsequent reaction with primary amines (92BSB509).Tlie expected diimines 63 readily cyclize so that 2-aryl-l-arylimino-2,3-dihydro-l//-isoindoles 64 can be isolated in excellent yields (90-95%). Contrary to the reactions performed by employing the dialdehyde and amines directly, the syntheses involving the azinium salts do not produce those typical dark-colored complex mixtures of products (77JOC4217 85JHC449) (Scheme 20). 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Step 1 1-(p-Chlorophenyl)-3-Ethoxy-1 H-lsoindole - Crystalline triethyloxonium boron-tetrafluoride (21 g) (prepared from 23 g of borontrifluoride etherate and 11 g of epichlorohydrin) is dissolved in 100 ml of absolute methylenechloride. 3-(p-Chlorophenyl) phthalimidine (21 g) is added and the reaction mixture is stirred overnight at room temperature. The resulting solution is poured onto 50 ml of saturated Sodium carbonate, extracted with 500 ml of ether and dried. Upon evaporation of the solvent there is obtained crude material which is recrystallized from methylene chloride/hexane (1 1) to yield l-(p-chlorophenyl)-3-ethoxy-1 H-isoindole MP 102° to 103°C. 

The reaction of ort/io-phthalaldehyde and a thiol compound with an amino acid to form an isoindole derivative can be used to enhance the detection sensitivity for the normally only weakly UV-detectable amino acid compounds, and to introduce an... 

The reaction of isoindole 192 with phosphorus pentasulfide in pyridine afforded intermediate 193, which gave with hydrazine hydrate 194 (82S853) (Scheme 40). 

Chloroalkenes are used as 7i-nucleophiIes in the acid-catalyzcd reaction of phthalimide-derived hydroxylactams. These cyclizations lead to sole formation of the thermodynamically less stable e/ r/(t-l-acetylpyrrolo[2,1-(v isoindole derivatives92. 

Another reagent that readily forms fluorescent derivatives with primary amines is o-phthalaldehyde (trade name "Fluoropa"). The reaction proceeds in aqueous solution in the presence of a mercaptan at a pH of 9-11 producing an isoindole. 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

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