Oxidative radical, isoquinoline

Alkyl Isoquinolines. Coal tar contains small amounts of l-methylisoquinoline [1721-93-3] 3-methylisoquinoline [1125-80-0] and 1,3-dimetliylisoquinoline [1721-94-4J. The 1- and 3-methyl groups are more reactive than others in the isoquinoline nucleus and readily oxidize with selenium dioxide to form the corresponding isoquinoline aldehydes (174). These compounds can also be obtained by the hydrolysis of the dihalomethyl group. The 1- and 3-methyhsoquinolines condense with benzaldehyde in the presence of zinc chloride or acetic anhydride to produce 1- and 3-styryhsoquinolines. Radicals formed by decarboxylation of carboxyUc acids react to produce 1-aIkyhsoquinolines. 

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. 

Moreover, one should mention that in spite of similar electronic structures, PBN and the isoquinoline nitrone (278) react in a different way. Under no circumstances does PBN give an oxidative methoxylation product, whereas nitrone (278) reacts readily to form a,a-dialkoxy-substituted nitroxyl radical (280) (517). Perhaps this difference might be due to the ability to form a complex with methanol in aldo-nitrones with -configuration. This seems favorable for a fast nucleophilic addition of methanol to the radical cation (RC), formed in the oxidation step. The a-methoxy nitrone (279), obtained in the initial methoxylation, has a lower oxidation potential than the initial aldo-nitrone (see Section 2.4). Its oxidation to the radical cation and subsequent reaction with methanol results in the formation of the a,a-dimethoxy-substituted nitroxyl radical (280) (Scheme 2.105). 

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 ). " ... 

For pyridine N- oxides, direct oxygen loss may occur, but for quinoline and isoquinoline N- oxides (118) a 1,2-shift is an alternative, giving the corresponding -one radical cation (119) (68T3139), while -one derivatives themselves readily lose CO, as shown for N-methylquinolin-2-one (120) and acridinone (121) molecular ions (67AJC1179, B-71MS364). 

Radical attack on isoquinoline, as either free base or isoquinolinium cation, always occurs at position 1 and the method is not suitable for the preparation of benzo ring-substituted products. The same can be said of radical attack on the JV-oxides of quinoline and isoquinoline. 

Early publications on [VO(/3-diketonato)2] have been reviewed.355 More recently, complexes with benzoyl m-nitroacetanilide, benzoyl acetanilide545 and l,l -(l,3-phenylene)-bis(butane-1,3-dione546 have been synthesized. Other [VO(/S-dik)2] adducts have been isolated, for example [VO(acac)2] adducts with a series of pyridine N-oxides547 and several pyridine carboxamides, 48 and [VO(bzac)2] adducts with pyridine, methylamine, isoquinoline and 4-picoline.549 Equilibrium constants of 1 1 and 2 1 adducts of pyrazine with [VO(tfacac)2] have been determined (equation 38).550 In the 2 1 complex, the pyrazine bridge between two equatorial sites of adjacent vanadium atoms promotes a weak exchange interaction. The nitroxide radical 2,2,6,6-tetramethylpiperidinyl N-oxide also forms an adduct with [VO(hfacac)2] in which there is a strong interaction between the electrons on the metal and nitroxide.551... 

The radical may attack either the anion-radical or isoquinoline in the latter case, a second electron is transferred from an A7. The reductive rert-butyl-ation of 3-methylisoquinoline gives mainly 162 and 163 together with small amounts of 4-, 5-, or 8-substituted dihydroisoquinolines. Imine 163 was oxidized to 164 during workup40 [Eq. (102)]. 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

Isoquinolines have been prepared on insoluble supports by radical-mediated cycli-zations and by intramolecular Heck reaction (Table 15.25). Entry 1 in Table 15.25 is a rare example of the formation of a biaryl by intramolecular addition of an aryl radical to an arene. Oxidative aromatization was achieved by using a large excess of AIBN. 

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-... 

The first reduction wave for phenanthridine jV-oxide in dimethyl-formamide (at 25°) appears at — 1.774 (vs. s.c.e.) in good agreement with the HMO energy of the lowest vacant orbital277 a mechanism for the reduction has been proposed.278 No esr signal could be detected during controlled-potential electrolysis at the appropriate potential, perhaps because of the relative instability of the anion radical. This behavior, which is paralleled by isoquinoline, contrasts sharply with that of the oxides of other polynuclear N-heteroaromatic systems (e.g., quinoline and acridine).277... 

A more interesting series of alkaloids arises when benzyl isoquinoline alkaloids cyclize by radical reactions. Phenols easily form radicals when treated with oxidizing agents such as Fe(III), and benzyl isoquinoline alkaloids with free phenolic hydroxyl groups undergo radical reactions in an intramolecular fashion through a similar mechanism. Here are the details of some methylations of a class of alkaloids closely related to papaverine. 

Chuang has also described a manganese(III) acetate initiated oxidative free radical reaction between benzoylindoles 126 and dimethyl malonate which provides faeile access to benzo[b]carbazoles 127 <97H(45)347>. Similar reaction of N-benzoylindoles affords the corresponding indolo[ 1,2-b]isoquinolines. 

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