Quinone-imine system

The total synthesis of (+)-dynemicin A was achieved by S.J. Danishefsky et al. As part of the synthetic studies, highly sensitive enediyne containing quinone imine systems were prepared, and their biological properties were evaluated. The first step in the sequence leading to one such quinone imine began with the oxidation of the nitrogen of the phenanthridine substrate, and the resulting A/-oxide was heated in neat acetic anhydride to induce the Polonovski reaction. 

The drug resembles very similar to chloroquine mechanistieally and it does not possess any added advantages over the other 4-aminoquinoline drugs. It has been demonstrated amply that the hydroquinone (phenol) amine system rapidly gets oxidized to a eorresponding quinone-imine system, either accomplished via antioxidatively and/or metabolically and the resulting product may be solely responsible for the ensuing amodiaquine toxicity. 

The processes of oxidation of cyclohexadiene, 1,2-substituted ethenes, and aliphatic amines are decelerated by quinones, hydroquinones, and quinone imines by a similar mechanism. The values of stoichiometric inhibition coefficients / and the rate constants k for the corresponding reactions involving peroxyl radicals (H02 and >C(0H)00 ) are presented in Table 16.3. The/coefficients in these reactions are relatively high, varying from 8 to 70. Evidently, the irreversible consumption of quinone in these systems is due to the addition of peroxyl radicals to the double bond of quinone and alkyl radicals to the carbonyl group of quinone. 

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in... 

Similar types of nucleophilic substitutions have also been carried out when PIFA is activated by two equivalents of Lewis acids such as trimethylsilyl triflu-oromethanesulfonate (TMSOTf) and BF3 Et20 or heteropolyacid in standard solvents such as CH2C12 and MeCN. These reactions were applied to intramolecular reactions by the same authors leading to biaryls (49) [54-57], quinone imine derivatives (50) [58], and dihydrobenzothiophens (51) [59], which are important structures of bioactive natural products [Eqs. (7)-(9)]. Dominguez and co-workers have expanded the above biaryl coupling reaction to the syntheses of benzo[c]phenanthridine system (52) [60] and heterobiaryl compounds (53) [61] [Eqs. (10,11)]. 

Iodylbenzene in hot nitrobenzene effected some oxidations mimicking its isoelec-tronic ozone. Among them, the most interesting was with pyrene which was converted into a mixture of three isomeric pyrenequinones this method was advantageous for the preparation of the 4,5-isomer, despite its low yield (14%) [7]. The system iodylbenzene and catalytic amounts of vanadyl acetylacetonide was used for the synthesis of some quinone-imines from phenothiazines and related heterocycles also iV-phenyl-phenylsulphonamide was converted into N-(phenylsulphonyl)-1,4-benzoquinone-imine. 

The mechanism of action of a number of new analogs of e lipticine has been the subject of several papers. Activation of (9-OH-NME ) 17 by a peroxidase-HgO, system gives the quinone imine (R=H) and eventually... 

A third pathway leads via the quinone imine intermediates 38 to 3-hydro-xycarbazoles 41 (mode C in Scheme 12) [97, 98, 108, 109]. Oxidation of the complexes 36 with manganese dioxide afforded the quinone imines 38, which on treatment with very active manganese dioxide undergo oxidative cyclization to the tricarbonyl(ri" -4b,8a-dihydrocarbazol-3-one)iron complexes 39. Demetalation of 39 with trimethylamine iV-oxide and subsequent aromatization lead to the 3-hydro-xycarbazoles 41. The isomerization providing the aromatic carbazole system is a... 

A new route to quinone imines has been introduced based on this oxidizing system. The oxidation of the tricyclic scaffold 820 gives quinone imines 821 in moderate yields (Scheme 3.324) [1117]. 

Recently an analogous mechanism for cyclic chain termination has been established for quinones [47], Quinones, which can act as acceptors of alkyl radicals, do not practically retard the oxidation of hydrocarbons at concentrations of up to 5 x 10 3 mol L 1, because the alkyl radicals react very rapidly with dioxygen. However, the ternary system, /V-phenylquinonc imine (Q) + H202 + acid (HA), efficiently retards the initiated oxidation of methyl oleate and ethylbenzene [47]. This is indicated by the following results obtained for the oxidation of ethylbenzene (343 K, p02 = 98 kPa, Vi = 5.21 x 10-7 mol L 1 s 1). 

Photoreduction of benzophenone by primary and secondary amines leads to the formation of benzpinacol and imines [145]. Quantum yields greater than unity for reduction of benzophenone indicated that the a-aminoalkyl radical could further reduce the ground state of benzophenone. Bhattacharyya and Das confirmed this in a laser-flash photolysis study of the benzophenone-triethylamine system, which showed that ketyl radical anion formation occurs by a fast and a slow process wherein the slow process corresponds to the reaction of a-aminoalkyl radical in the ground state of benzophenone [148]. Direct evidence for similar secondary reduction of benzil [149] and naphthalimides [150] by the a-aminoalkyl radical have also been reported. The secondary dark reaction of a-aminoalkyl radicals in photo-induced electron-transfer reactions with a variety of quinones, dyes, and metal complexes has been studied by Whitten and coworkers [151]. 

An even more direct route would evolve from the connection of the two reagents shown below. Interestingly, the photochemically mediated reaction of a quinone with an imine has never been reported. If we can identify suitable reaction conditions for this transformation, we will have secured an exceptionally direct route to the benzodiazepine ring system. The imine required for this reaction has been previously synthesized and can readily be generated in multigram quantities by the condensation of benzaldehyde with the N-methyl amide of glycine. Even though the... 

Enol imine-enaminone and phenol—quinone tautomerism in (arylazo) naphthols and in analogous Schiff bases were studied by Fabian et al. [92, 93]. In all these molecules there is a favorable N- -H- -O intramolecular hydrogen bond. Depending on the X-H sigma bond (X = N, O), there are two possible tautomers in solution. The solvent effect was calculated on the equilibrium [92], and a combined effect of the solvent and the benzene substituent was studied in [93]. While the FEP/MC simulations provided consistent organic solvent effects in accord with the experimental results [92], the wide spectrum of the solvent-effect calculation methods could predict rather diverse results for several groups of systems in [93]. 

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