Isoquinoline hydroxylation

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. 

The oxidoreductase from Pseudomonas diminuta strain 7 that carries out hydroxylation of isoquinoline at C2 is a molybdenum enzyme containing [Fe-S] centers, which is comparable to the aldehyde oxidoreductase from Desulfovibrio gigas (Lehmann et al. 1994). 

Hydroxylation at C-5 or C-l3 has also been successfully achieved by lead tetraacetate oxidation, which was extensively studied in connection with isoquinoline alkaloids by Umezawa s group. (+)-Govanine (96) and (+)-discretine (97) were oxidized with lead tetraacetate in acetic acid to afford 5-acetoxy products 100,101, and 102 via p-quinol acetates (e.g., 99) (Scheme 23)... 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

The oxidative degradations of binuclear azaarenes (quinoline, isoquinoline, and benzodrazines) by hydroxyl and sulfate radicals and halogen radicals have been studied under both photochemical and dark-reaction conditions. A shift from oxidation of the benzene moiety to the pyridine moiety was observed in the quinoline and isoquinoline systems upon changing the reaction from the dark to photochemical conditions. The results were interpreted using frontier-orbital calculations. The reaction of OH with the dye 3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-(l,8)(2//,5//)-acridinedione has been studied, and the transient absorption bands assigned in neutral solution.The redox potential (and also the pA a of the transient species) was determined. Hydroxyl radicals have been found to react with thioanisole via both electron transfer to give radical cations (73%) and OH-adduct formation (23%). The bimolec-ular rate constant was determined (3.5 x lO lmoU s ). " ... 

The intramolecular palladium catalyzed ring closure of the tetrahydro-isoquinoline derivative depicted in 8.41. led to the formation of the aporphine derivative in good yield, which was then converted into racemic aporphine in three steps. In the ring closing step 20 mol% palladium acetate and 40 mol% tricyclohexylphosphine were used as catalyst. The removal of the hydroxyl group was also achieved by palladium catalysis through its conversion to triflate and the subsequent reduction with ammonium formate in the presence of palladium acetate and dppf.53... 

If the starting compound contains a hydroxyl group in the a position, an additional dehydration takes place and the product is an isoquinoline. Higher yields can be obtained if the amide is treated with PC15 to give an imino chloride ArCH2CH2N=CR—Cl, which is isolated... 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

The hydroxyl group of ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l-a]-isoquinoline-3-carboxylate (20) was methylated with methyl iodide in dry boiling acetone for 5 h in the presence of potassium carbonate, with dimethyl sulfate in methylene chloride in methanol in the presence of Triton B at 20°C for 18 h, with methyl fluorosulfonate in 2.5 M sodium hydroxide at 20°C for 5 h, and with diazomethane in a mixture of diethyl ether and methylene chloride at 20°C for 3 h to give the 2-methoxy derivative (89AJC2161). The hydroxy group of 3-hydroxymethyl-4//-pyrimido[2,l-b]-isoquinolin-4-one was alkylated and acylated with 2-(diethylamino)ethyl chloride in dimethylformamide in the presence of sodium hydroxide, and with acetic anhydride in boiling chloroform in the presence of triethylamine and a few drops of 4-dimethylaminopyridine, respectively (86EUP 166439). 

Method of Nys and Rekker The Nys and Rekker method [53,54] has been developed for mono- and di-substituted benzenes. The substituents considered are halogen atoms and hydroxyl, ether, amino, nitro, and carboxyl groups, for which contributions have been calculated by multiple regression analysis (s = 0.106, r = 0.994, F = 1405). Rekker discusses the extension of his approach to other compound classes, such as PAHs, pyridines, quinolines, and isoquinolines. 

The interaction between ammonia and l-R1-3-aryl-substituted ben-zo[c]pyrylium salts 30, as well as 3,4-diaryl-substituted indeno[e l,2-]-benzo[c]pyrylium, and other substituted cations having a similar fragment is more complicated, especially in hydroxyl-containing solvents. In these cases, mixtures in different ratios are obtained that contain isoquinolines 138, 3-hydroxy-3,4-dihydroisoquinolines 137, OR-adducts 109, anhydro-bases 119, diketones 29, a-naphthylamines 140, and a-naphthols 141 (88UP2). 

Interestingly, the recyclization of 146, having hydroxyl groups in the 3-aryl substituent, proceeds readily also without acidic catalysis affording isoquinolines 138 (70KGS1013). Probably, deprotonation of 146 is the primary process in this case, and a quinonoid compound 147 thus formed adds a molecule of ammonia similarly to other quinonoid forms (cf. Section III,E,2) affording 148, which is converted into isoquinoline 138. 

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. 

Phenolic hydroxyl groups were liberated from ferf-butyldimethylsily-loxy groups present in position 7 and a side-chain phenyl group of 1,2,3,4,11,1 la-hexahydro-6H-pyrazino[l, 2-f ]isoquinolin-4-one on the... 

In addition to MPTP, other endogenously produced neurotoxins, namely, the monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-l,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. A-methylated isoquinolines were found to be oxidized by MAO, and hydroxyl radicals were found to be produced by this reaction. In addition, by incubation with the A-methylated isoquinolines, ATP was depleted from a dopaminergic cell model. Pretreatment of the cells with MAO inhibitors such as selegiline could, however, protect against ATP depletion. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1 -methyl-1,2,3,4-tetrahydroisoquinoline and 1 -methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino-... 

These alkaloids are a relatively small group within the isoquinoline family. Ochotensimine (101) was the first to be studied and it and ochotensine are the only compounds of the group that have an exocyclic methylene on the five-membered ring (2, 3, 62). The most common functional groups are carbonyl, hydroxyl, or acetoxy at one or both of C-8 and C-13. The spectra of a series of these alkaloids were reported in 1977 (63) and these data were used recently in the structural elucidation of a new alkaloid (64). The structures and spectral data on the alkaloids discussed in this section may be found in Fig. 19 and Table XVIII, respectively. They are ochotensimine (101), sibiricine (102), corydaine (103), ochrobirine (104), fumaritine (105), and fumaritine A-oxide (106). 

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