Of isoquinoline quinone

The transformation of isoquinoline has been studied both under photochemical conditions with hydrogen peroxide, and in the dark with hydroxyl radicals (Beitz et al. 1998). The former resulted in fission of the pyridine ring with the formation of phthalic dialdehyde and phthalimide, whereas the major product from the latter reaction involved oxidation of the benzene ring with formation of the isoquinoline-5,8-quinone and a hydroxylated quinone. 

This quinone synthesis was used to obtain the isoquinoline quinone 2, a unit of some saframycin antibiotics (equation I). 

To all rules, there are always exceptions. These have been made to allow unexpected natural isoquinolines that just happen to present unexpected substituents that nature for some reason chose to contribute to this collection. Mention has been made of an occasional carbonyl group disrupting the aromaticity of the benzene ring (this is the basis of the quinonic isoquinolines). The nitrogen atom (position 2) occasionally displays an amide group (these have been entered at the fourth letter of the structural alphabet). Several natural compounds demand a hydroxyl or methoxyl function at the isoquinoline 3- or 4-positions. When this occurs, the compound is listed as a footnote under the parent structure. 

Diels-Alder addition of azadienes to quinones has been used to prepare analogues of the antibiotic diazaquinomycin (26). Quinoline-5,6-quinone yields both regioisomers (Equation (8)) while the isoquinoline quinone gives only the pyrido[3,4- ]quinoline (79) (Equation (9)) <91TL1307>. 

C-NMR spectra of several isoquinoline-5,8- and -7,8-diones were recorded (85CPB823). A comparative study of electrochemical reduction of isoquinoline-5,8-dione and other heterocyclic quinones revealed that all compounds show two well-defined reduction peaks and that these reductions are reversible (72MI2). 

Most of the isoquinoline quinones described above have antibacterial activity (Table 3) and moderate levels of cytotoxicity (Table 1) have been reported. Other bioactivity reported for mimosamycin and 7-amino-7-demethoxymimosamycin (89) are aldose reductase inhibition, 34.6% at 10 pmol dm 3, and cAMP phosphodiesterase inhibition, 26.3% at 100 pmol dm 3, respectively (71). 

Catalyzed cyclization reactions for the synthesis of isoquinolines were the focus of various reports. 4-Aryl-l,2,3,4-tetrahydroquionlines were synthesized in good yield via a quinone methide mediated cyclization in the presence of zinc chloride <04TL7487>. The intramolecular radical cyclization of a, 3-unsaturated amides 85 was reported for the synthesis of isoquinoline analogs 86. In this study a-unsubstiuted acrylamides afforded 6-exo products exclusively. On the other hand, substrates bearing an a-chlorine (X = Cl) substituent provided the 1-endo benzazepine derivatives <04TL2335>. 

Pyridine is present in many metabolites of haplosderid sponges, but few examples have been found in Halichon-drida, such as pyraxinine (pyridylguanidine), isolated from Cymbastela cantharella from New Caledonia (Al Mourabit et al, 1997) and related to girolline (Al Mourabit and Potier, 2001). Mimosamydn, an isoquinoline quinone of bacterial origin (Streptomyces lavandulae), has been isolated... 

Parker, K.A. and Casteel, D.A. (1988) Isoquinoline quinones. Preparation of saframydn intermediates and a total synthesis of mimosamycin. J. Org. Chem., 53, 2847-2850. 

Park, A. and Schmitz, F.J. (1993) Synthesis of perfragilin B, a cytotoxic isoquinoline quinone isolated from the bryozoan Membranipora peifragilis. Tetrahedron Lett., 34, 3983-3984. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Advantage has been taken of the propensity for equilibrium lithiation demonstrated for diethyl nicotinamide (447a) which has been induced under a double self-condensation to form the 2,7-diazaanthraquinone (452) (Scheme 136) (88S388). The quinone 452 was transformed by a reduction-aromatization sequence into the pyrido[3,4-g]isoquinoline (453) in high overall yield. 

Figure 3. Four parameter, simplex-optimized SFC separation of a 12-component mixture. Chromatographic conditions as in Vertex 13 of Table II. Sample components isoquinoline, n-octadecane (n-CigH3g), naphthalene, quinoline, acetophenone, undecylbenzene, benzophenone, 2 -acetonaphthone, diphenylamine, o-dioctylphthalate, unidentified impurity, N-phenyl-1-naphthylamine, phenanthrene quinone. Other conditions as described in the experimental section.

In an unusual example of electrophilic cyclization in neutral aprotic medium, the 2-allyl quinones (77), on heating in benzene, yield the 2//-pyrano[2,3-/]isoquinolines (78) <90JOC6140>. 

There is some question about the mechanism involved in an extensive series of nucleophilic reactions discovered by Umezawa and Hoshino and their co-workers.58,77 78 In these reactions, the 4,7-diacetoxy compound (30) was treated, in base, with alcohols (to yield 31), amines (to yield 32), mercaptans (to yield 33), KCN (to yield 34), nitromethane (to yield 35), malononitrile (to yield 36), malonic ester (to yield 37), cyclohexanone (to yield 38), acetophenone (to yield 39), and dimethyl sulfoxide (to yield 40). The reaction with cyclopentanone was anomalous in that a dimer of the ketone reacted with the isoquinoline. Since the acetoxy group on C-7 was almost always lost and the reaction failed when a 7-methoxy group was present, a quinone methide intermediate (41) was proposed. Some of the reactions were done in aqueous or alcoholic base and some were done under anhydrous conditions with NaH. 

Electrochemical oxidation of racemic salsolinol (SAL) was investigated in aqueous solution at physiological pH (29/) (Fig. 42). The initial step was a reversible two-electron oxidation of SAL to the short-lived ortho-quinone E, isolated as the more stable quinone methide C. Further reaction of E, probably via quinone methide F and addition of water, yielded c/5-alcohol A and fra/i5-alcohol B, which are shown in an arbitrarily chosen configuration. Another product which was isolated is the fully aromatic isoquinoline D. Alcohols A and B are chemically related to the condensation product obtained from epinephrine and acetaldehyde (165). 

A three-component one-pot synthesis of highly substituted spiro[l,3]oxazino[2,3-a]isoquinolines has been demonstrated <03TL729>. The starting materials are quinoline, DMAD, and either 1,2- or 1,4-quinones. An example is shown. 

JA6181). Thermal rearrangement of diazidoquinones to 2-aza-3-cyano-quinones opened a new, general route to azaquinones and the reaction was elaborated also in the naphthoquinone series to give isoquinoline-1,4-diones (75JA6181). 

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