Isoindoles intermediates

Sommelet rearrangement, intermediate temperatures favor Stevens rearrangement,- and high temperatures promote elimination to form isoindoles. Treatment of 2-methyl-2-o-tolylmethylisoindolinium... 

The intermediate alkylation product (33) undergoes facile elimination. In one instance a hydroxyisoindoline (34) was isolated and subsequently dehydrated to the corresponding isoindole.The phthal-imidine route has been used to prepare mainly 1,2-disubstitutcd... 

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... 

Treatment of dimethyl sulfoxide (DMSO) is reported to lead to 2-phenylisoindole (17) in yields up to 40%. An interesting possibility in this case is involvement of the isoindole valence tautomer (67) as an intermediate. P. A. Barrelt, R. P. LinsteacI, G. A. P. Tuey, and J. M. Robertson, J. Chem. Soc. p. 1809 (1939). 

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. ... 

It is apparent from simple valence bond considerations as well as from calculations of rr-electron density, " that isoindoles should be most susceptible to electrophilic attack at carbon 1. This preference is most clearly evident when the intermediate cations (85-87) from electrophilic attack (by A+) at positions 1, 4, and 5 are considered. The benzenoid resonance of 85 is the decisive factor in favoring this intermediate over its competitors. 

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. °... 

Emission spectra have been recorded for four aryl-substituted isoindoles rmder conditions of electrochemical stimulation. Electrochemiluminescence, which was easily visible in daylight, was measured at a concentration of 2-10 mM of emitter in V jV-dimethylformamide with platinum electrodes. Emission spectra due to electrochemi-luminescence and to fluorescence were found to be identical, and quantum yields for fluorescence were obtained by irradiation with a calibrated Hght source. Values are given in Table X. As with peak potentials determined by cyclic voltammetry, the results of luminescence studies are interpreted in terms of radical ion intermediates. ... 

Chlorthalidone (49) is another thiazide-like diuretic agent that formally contains an isoindole ring. Transformation of the amine in benzophenone, 47, to a sulfonamide group by essentially the same process as was outlined for chlorexolone (46) affords Intermediate 43. This product cyclizes to the desired pseudoacid 1-ketoisoindole (49) on successive treatments with thionyl... 

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

For example, McNab and coworkers have discovered that flash-vacuum pyrolysis (FVP) (1000 °C, 0.01 Torr) of pyrrole 10-114 led to the formation of pyrrolo[2,l-a]isoindol-5-one 10-117 in 79% (Scheme 10.29) [44]. The transformation is proposed to proceed via an initial 1,5-aryl shift to give intermediate 10-115, which then undergoes an elimination of methanol. Finally, electrocydization of the ketene 10-116 results in the formation of 10-117. 

A synthesis of highly-substituted tetracenes was developed starting from isoindole (benzo[c]pyrrole) <06OL273>. For example, treatment of dibromonaphthalene 87 with phenyllithium in the presence of isoindole 86 followed by deamination of the intermediate cycloadduct provided tetracene 88. Separately, the synthesis and cycloaddition chemistry of oxadisilole-fused isoindoles was investigated <06SL2510>. 

A possible mechanism for the observed transformation includes the sequence outlined in Scheme 2.327 (i) propargyl (A) - allene (B) tautomerization, (ii) 8jt-cyclization (C), (iii) N-0 cleavage (diradical D), (iv) diradical recombination (cyclopropanone derivative E), and (v) one or two step cyclizations of the azadienyl cyclopropanone into azepinone F. The occurrence of cyclopropanones (type E), as intermediates, is supported by the formation, in some cases, of isoindoles (type I) (789) as minor products (Scheme 2.327) (139, 850, 851). 

The formation of anthracene in reactions of 185 and 186 with benzyne, which was unexplained by Wittig et aZ., possibly is due to an alternative reaction of the intermediate zwitterion (202) with another molecule of benzjme or with a benzyne precursor. Benzyne reacted with the isoindole (206) to give the tetramethyltriptycene (208) and, in a separate run using excess of the benzyne precursor, W-benzylcarbazole. The latter product would appear to be made up of the iV-benzyl group from an intermediate anthracen-9,10-imine (207) and two molecules of benzyne. Mass spectral evidence also implicated the adduct 207, and the formation of 208 was attributed to benzyne-induced deamination of 207 to 1,4,9,10-tetramethylanthracene, which was trapped by further addition of benzyne across the 9- and 10-positions. 

The synthetic viability of this protocol was demonstrated by the efficient synthesis of an isoindole alkaloid from the Mexican sponge Reniera. a-Cyanosi-lylamine (9) was treated with AgF, in the presence of dipolarophile 10 to furnish the requisite cycloadduct in 68%. An advanced intermediate in the synthesis of nicotine was also prepared by cycloaddition of 11 with phenylvinylsulfone giving the requisite adduct 12 in a 3 1 diastereomic mixture (Schem 3.3). 

On pyrolysis, 1-arylimidazoles rearrange to 2-arylimidazoles. In other systems pyrolysis causes more deep-seated changes. 1-Arylbenzotriazoles on pyrolysis or photolysis give carbazoles via intermediate nitrenes (see Section 3.4.1.2.1). 1-Phenyl-1,2,4-triazole (714) is pyrolyzed to isoindole... 

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). 

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). 

For the synthesis of isoindoles (benzo[c]pyrroles) by type la cyclization the required intermediate is an o -acylbenzylamine. The only viable route to these substances which has been developed starts with a -bromo-o -toluic acid which is converted first to a phthalimide and then to the acid chloride. The acid chloride is then elaborated to the requisite ketone by Friedel-Crafts acylation. Condensation to the isoindole occurs on liberation of the primary amino group using hydrazine (equation 18) (64JA4152). 

A route based on a benzyne intermediate can afford the isoindole ring via a category lb process. iV-Cyanomethyl-Af-methyl-0-chlorobenzylamine cyclizes to 1-methylisoindole under the influence of potassium amide in liquid ammonia (equation 36) (77T581). The cyano group plays two important roles. First, it provides stabilization of the carbanion... 

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. 

Wu and co-workers developed a synthesis of benzannulated nitrogen heterocycles 120 and 121 based on the addition of sodium methoxide to 2-alkynylbenzo-nitriles 118 in methanol, followed by the Pd(PPh3)4-catalyzed heteroannulation of ketimine intermediate 119 with aryl iodides [104]. The 5-exo versus 6-endo mode of cyclization leading to isoindoles 120 or isoquinolines 121, respectively, proved to be dependent on the nature of the substituent on the terminal alkyne carbon. 2-(2-Phenylethynyl) benzonitrile 118a underwent exclusive 5-exo cyclization whereas 2-(l-hexynyl)benzonitrile 118b led to mixtures of isomers with a marked preference for the 6-endo mode of cyclization. This endo/exo balance was attributed to steric interactions between the entering group and the substituent on the terminal alkyne carbon (Scheme 8.49). 

The Michael adduct can be the precursor of several cyclizations giving rise to new tandem sequences. This has been mainly due to the mechanistic aspects of the process itself and to the synthetic potential of the resultant products. A new stereoselective synthesis of pyrrolo[2,l-c/]isoindol-5-ones has been described. It consisted of a sequential Michael addition to the in situ generated anion of methyl IV-phthaloylalaninate 289, onto a series of conjugate acceptors. Cyclization of the resultant anion intermediate by condensation with one of the carbonyl imido groups gave the desired products 291 in good yields as single isomers in only one step (Scheme 89). 

The reaction of aromatic orf/zo-substituted imidoyllithiums 56 with carbon monoxide and methyl iodide afforded li/-isoindole derivatives 61 in moderate yields (Scheme 16)77. In this process the formation of an acyllithium 57 was proposed to occur which, after formation of intermediate 58, cyclized to give the compound 59. The rearrangement of the alkyl group giving the aromatic product 60, followed by quenching with methyl iodide at — 78 °C, gave indolines 61. 

The other type of carbamoyllithiums IIIc can also be prepared by reaction of CO with (V-lithioketimines, resulting from the addition of rert-butyllithium to aryl cyanides 10477,102. These intermediates 105 underwent selective cyclization to give 177-isoindole derivatives 10677 and six- (107)102 or seven-membered (108)102 cyclic products (Scheme 27). Compounds 107 result either by insertion of the carbene structure into the benzylic carbon-hydrogen bond, as in the case of carbamoyllithiums96, or by intramolecular protonation. 

Dihydro-17/-pyrrolo[l,2-< ][l,3,5]oxadiazocin-6(5/7)-one ring system 78 can be obtained from 2,3-dihydro-3-hydroxy-2-(pyrrol-l-ylmethyl)-17/-isoindol-l-one 76. No intermediate acyl chloride was observed during the cyclization of 77a, and product 78 (X = O) was isolated in low 15% yield. Yields were not improved after addition of Lewis acids or use of polyphosphoric acid as a condensation reagent (Scheme 16 <1998JHC9>). Similarly, 2,3-dihydro-l/7-pyrrolo[l,2-< ][l,3,5]thiadiazocin-6(577)-one ring system 19 (X = S) was obtained in low yield. Key intermediate 77b was prepared from 76 in one step under acidic catalysis. 

The thermolysis of isoindole 50 in diphenyl ether under similar conditions gave the unusual benzotriazole migration products 53 (benzotriazol-l-yl) and 54 (benzotriazol-2-yl) in the ratio of 1 2, which is postulated to proceed through intermediate 51, along with minor tricyclic lactam product 52 (Scheme 14) <2000ARK471>. 

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