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Scheme 9. Reactions of thiols with NPQ [78].

Figure 13 Reactions of thiols with NPQ [78].

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Figure 3. Some subgroups of quinoneimine dyes. Celestine blue dye is used with iron-aluminium complexes as a substitute for haema- toxylin in H-E (haematoxylin-eosin) staining because of its resistance to low-pH solutions. It has been used as a new electroactive indicator in DNA biosensors and is also applicable to HOC] detection in living cells and to assaying the chlorinating activity of myeloperoxidase [40].
Figure 3. Some subgroups of quinoneimine dyes. Celestine blue dye is used with iron-aluminium complexes as a substitute for haema- toxylin in H-E (haematoxylin-eosin) staining because of its resistance to low-pH solutions. It has been used as a new electroactive indicator in DNA biosensors and is also applicable to HOC] detection in living cells and to assaying the chlorinating activity of myeloperoxidase [40].
Table 1. Naturally occurring quinoneimines and their biological activities.
Table 1. Naturally occurring quinoneimines and their biological activities.
Figure 4. Some of the common quinoneimine dyes.
Figure 4. Some of the common quinoneimine dyes.
Some chemicals and drugs have been reported to form reactive q metabolites [56]. Quinoneimines are found as highly redox-ac trophiles, with both properties being crucial for their reactivity in are highly reactive organic chemicals and comprise a class of uinone and quinoneimine ive molecules and elec- biological systems. They oxicological intermedi- ates [57,58] that interact alone by generating reactive oxygen species (ROS) in biological systems to promote inflammatory reactions and reactive immune cells, oxidise DNA, and induce toxicity. They can be responsible for effects in vivo, inc cytotoxicity, and carcinogenesis [57]. Quinoneimines reduce the uding immunotoxicity, oxygen to reactive oxy- gen species, acting as prooxidants, and, as electrophiles, they form covalent bonds with tissue nucleophiles. — The actinomycins are a family of chromopeptide antitumor antibiotics isolated from various Streptomyces strains [50]. Actinomycins C3 and D have found clinical application as anticancer drugs, particularly in therapy for Wilm’s tumor [52] and soft tissue sarcomas [53] in children, and are still of interest in molecular biology [50].
Some chemicals and drugs have been reported to form reactive q metabolites [56]. Quinoneimines are found as highly redox-ac trophiles, with both properties being crucial for their reactivity in are highly reactive organic chemicals and comprise a class of uinone and quinoneimine ive molecules and elec- biological systems. They oxicological intermedi- ates [57,58] that interact alone by generating reactive oxygen species (ROS) in biological systems to promote inflammatory reactions and reactive immune cells, oxidise DNA, and induce toxicity. They can be responsible for effects in vivo, inc cytotoxicity, and carcinogenesis [57]. Quinoneimines reduce the uding immunotoxicity, oxygen to reactive oxy- gen species, acting as prooxidants, and, as electrophiles, they form covalent bonds with tissue nucleophiles. — The actinomycins are a family of chromopeptide antitumor antibiotics isolated from various Streptomyces strains [50]. Actinomycins C3 and D have found clinical application as anticancer drugs, particularly in therapy for Wilm’s tumor [52] and soft tissue sarcomas [53] in children, and are still of interest in molecular biology [50].
Table 2. Various oxidising agents used in the preparation of quinoneimines.
Table 2. Various oxidising agents used in the preparation of quinoneimines.
metabolising agent) and cytochrome P450 3A4 (CYP3A4) metabolism. NAPQI is then conjugated by glutathione (GSH) to form a nontoxic metabolite for excretion (Scheme 1) [56].
metabolising agent) and cytochrome P450 3A4 (CYP3A4) metabolism. NAPQI is then conjugated by glutathione (GSH) to form a nontoxic metabolite for excretion (Scheme 1) [56].
Scheme 1. Paracetamol bioactivation to reactive species (quinoneimine) [56] Figure 6. Some drugs that form quinoneimine reactive metabolites [56]. 1.5. Synthesis of Quinoneimines
Scheme 1. Paracetamol bioactivation to reactive species (quinoneimine) [56] Figure 6. Some drugs that form quinoneimine reactive metabolites [56]. 1.5. Synthesis of Quinoneimines
Table 2. Cont.
Table 2. Cont.
Scheme 2. Preparation of N-phenylquinoneimine 1 [60]. Other oxid ising agents used include iodoxybenzene and iodosylbenzene [68,69]. The use of AgoCO3 on Celite for the oxidation of 4-hydroxydiphenylamine 6 is shown in Scheme 2. The AgyCO3 adsorbed onto Celite, also known as Fétizon’s reagent, is a solid- supported oxid iminoquinones ising agent (and so is easily removed after the reaction); it provides the in an excellent yield and is preferred to other methods [60,70]. The method uses two equivalents of AgyCO3 and, at room temperature, 99% conversion to product 1 is observed in 24 n.
Scheme 2. Preparation of N-phenylquinoneimine 1 [60]. Other oxid ising agents used include iodoxybenzene and iodosylbenzene [68,69]. The use of AgoCO3 on Celite for the oxidation of 4-hydroxydiphenylamine 6 is shown in Scheme 2. The AgyCO3 adsorbed onto Celite, also known as Fétizon’s reagent, is a solid- supported oxid iminoquinones ising agent (and so is easily removed after the reaction); it provides the in an excellent yield and is preferred to other methods [60,70]. The method uses two equivalents of AgyCO3 and, at room temperature, 99% conversion to product 1 is observed in 24 n.
Scheme 3. Reactions of N-Phenylquinoneimine leading to structural complexity [21]. Scheme 3 [21] shows some reactions of N-Phenylquinoneimine that can lead to struc- tural complexity and molecular diversity.
Scheme 3. Reactions of N-Phenylquinoneimine leading to structural complexity [21]. Scheme 3 [21] shows some reactions of N-Phenylquinoneimine that can lead to struc- tural complexity and molecular diversity.
NPQ 1 can react with nucleophiles via 1,2-addition or 1,4-addition. NPQ has two unique sites susceptible to 1,2-addition: the ketone and the imine. If the nucleophile is an amine, for example, RNH)z, then attack at the carbonyl carbon followed by reduction gives 1A-diaminoarenes 8, whilst attack at the imino carbon converts the N-phenyl group to a new group 7 (Scheme 4). Scheme 4. Nucleophilic attack via 1,2-addition to the ketone or the imine.
NPQ 1 can react with nucleophiles via 1,2-addition or 1,4-addition. NPQ has two unique sites susceptible to 1,2-addition: the ketone and the imine. If the nucleophile is an amine, for example, RNH)z, then attack at the carbonyl carbon followed by reduction gives 1A-diaminoarenes 8, whilst attack at the imino carbon converts the N-phenyl group to a new group 7 (Scheme 4). Scheme 4. Nucleophilic attack via 1,2-addition to the ketone or the imine.
Scheme 7. The reaction mechanism of the 1,4-conjugate addition of aromatic amines to the «,B- unsaturated ketone and «,B-unsaturated imine of NPQ [21,76].
Scheme 7. The reaction mechanism of the 1,4-conjugate addition of aromatic amines to the «,B- unsaturated ketone and «,B-unsaturated imine of NPQ [21,76].
Scheme 8. Reaction of aromatic amines with NPQ and subsequent oxidation to phenazinones [76].
Scheme 8. Reaction of aromatic amines with NPQ and subsequent oxidation to phenazinones [76].
With a change in the reaction conditions (0 °C in benzene), the 6-monosubstitute: derivatives 29 was formed (Scheme 10). Scheme 10. Alternative mode of addition of thiols to NPQ.
With a change in the reaction conditions (0 °C in benzene), the 6-monosubstitute: derivatives 29 was formed (Scheme 10). Scheme 10. Alternative mode of addition of thiols to NPQ.
Scheme 11. Addition of sodium arenesulfinates to NPQ derivatives [80]. Some polymers containing sulfone groups are useful engineering plastics, as they exhibit high strength and resistance to oxidation, corrosion, high temperatures, and creep under stress; for example, some are valuable as replacements for copper in domestic hot- water plumbing [82]. Precursors to such polymers are the sulfones bisphenol 5 33 and 4,A’-dichlorodipheny] sulfone 34 (Figure 7). Examples of sulfones in pharmacology include dapsone 35, a drug formerly used as an antibiotic to treat leprosy. Several of its derivatives, such as promin, have similarly been studied or applied in medicine [83].
Scheme 11. Addition of sodium arenesulfinates to NPQ derivatives [80]. Some polymers containing sulfone groups are useful engineering plastics, as they exhibit high strength and resistance to oxidation, corrosion, high temperatures, and creep under stress; for example, some are valuable as replacements for copper in domestic hot- water plumbing [82]. Precursors to such polymers are the sulfones bisphenol 5 33 and 4,A’-dichlorodipheny] sulfone 34 (Figure 7). Examples of sulfones in pharmacology include dapsone 35, a drug formerly used as an antibiotic to treat leprosy. Several of its derivatives, such as promin, have similarly been studied or applied in medicine [83].
Scheme 12. Reaction of HBr with NPQ [84]. The reaction of hydrochloric acid with NPQ was conducted in the same manner and reportedly gave the mono-substituted compound 38. However, the chlorination of the phenyl group was not observed (Scheme 13) [85].
Scheme 12. Reaction of HBr with NPQ [84]. The reaction of hydrochloric acid with NPQ was conducted in the same manner and reportedly gave the mono-substituted compound 38. However, the chlorination of the phenyl group was not observed (Scheme 13) [85].
Scheme 15. The reaction of NPQ with organometallic reagents [87]. The reaction of NPQ with dimedone 39 has been reported by Novikov V. P. et al. [86]. The condensation reaction was carried out by boiling the quinoneimine, dimedone, and anhydrous zinc chloride in propanol for 10 min. The reaction mixture was worked up with water after cooling for 12 h at room temperature. The resulting product was filtered and washed, giving a yield of 58% of compound 40 (Scheme 14).
Scheme 15. The reaction of NPQ with organometallic reagents [87]. The reaction of NPQ with dimedone 39 has been reported by Novikov V. P. et al. [86]. The condensation reaction was carried out by boiling the quinoneimine, dimedone, and anhydrous zinc chloride in propanol for 10 min. The reaction mixture was worked up with water after cooling for 12 h at room temperature. The resulting product was filtered and washed, giving a yield of 58% of compound 40 (Scheme 14).
' Tetrahydrofuran; > a solution of methyllithium was added to the mixture of the substrate and CuCl (1:2) at 25 °C while stirring; © 5 mol% of Cul (referred to the reagent) was added to the solution of the Grignard reagent at —15 °C, and the solution was stirred for 30 min at this temperature, then cooled to —60 °C, and the reaction was effected. Table 3. Reaction of NPQ with organometallic compounds at —60 °C.
' Tetrahydrofuran; > a solution of methyllithium was added to the mixture of the substrate and CuCl (1:2) at 25 °C while stirring; © 5 mol% of Cul (referred to the reagent) was added to the solution of the Grignard reagent at —15 °C, and the solution was stirred for 30 min at this temperature, then cooled to —60 °C, and the reaction was effected. Table 3. Reaction of NPQ with organometallic compounds at —60 °C.
The presence of an electron-withdrawing group should cause a change in the chemical shifts in the 'H NMR spectrum of NPQ N-oxide when compared to NPQ. The largest differences will be for protons closest to the nitrogen, as expected when considering their proximity to the N-oxide. A relatively smaller downshift in the peaks for the other protons, which are farther away from the oxygen of the N-oxide, should, therefore, be expected.
The presence of an electron-withdrawing group should cause a change in the chemical shifts in the 'H NMR spectrum of NPQ N-oxide when compared to NPQ. The largest differences will be for protons closest to the nitrogen, as expected when considering their proximity to the N-oxide. A relatively smaller downshift in the peaks for the other protons, which are farther away from the oxygen of the N-oxide, should, therefore, be expected.
Scheme 17. Cycloaddition reaction of NPQ with diphenylketene. The addition of diphenylketene 45 to NPQ in ether, as reported by Bird C. W. [89], resulted in the formation of a cycloaddition product, $-lactam 46, which rearranged to give the oxindole 47 (Scheme 17). The oxindole can be readily converted into the methyl ether via dimethyl sulphate and methanolic sodium hydroxide.
Scheme 17. Cycloaddition reaction of NPQ with diphenylketene. The addition of diphenylketene 45 to NPQ in ether, as reported by Bird C. W. [89], resulted in the formation of a cycloaddition product, $-lactam 46, which rearranged to give the oxindole 47 (Scheme 17). The oxindole can be readily converted into the methyl ether via dimethyl sulphate and methanolic sodium hydroxide.
The reaction of 3-bromo NPQ 36 with a range of arylboronic acids gave the coupled products 49 in average-to-good yields, with the biaryl products 50 obtained as by-products resulting from the homocoupling of the arylboronic acid (Scheme 18) [21]. A much lower yield was observed when electron-deficient boronic acids were used, and the equivalent of arylboronic acid used was found to be insignificant to the yield of the coupled product. Scheme 18. Suzuki reaction of compound 36 with arylboronic acids.
The reaction of 3-bromo NPQ 36 with a range of arylboronic acids gave the coupled products 49 in average-to-good yields, with the biaryl products 50 obtained as by-products resulting from the homocoupling of the arylboronic acid (Scheme 18) [21]. A much lower yield was observed when electron-deficient boronic acids were used, and the equivalent of arylboronic acid used was found to be insignificant to the yield of the coupled product. Scheme 18. Suzuki reaction of compound 36 with arylboronic acids.
Scheme 19. Stille reaction of compound 36 with arylstannanes [21,92]. The reaction of 3-bromo NPQ 36 with tributyl(phenyl)stannane 51a was carried out using one equivalent of the arylstannane in THF, with LiCl as the base, and heated at 100 °C for 24 h [92]; both the coupled product and biaryl product were obtained in low yields. The reaction was repeated with the base changed to AgzCO3 and the solvent to dioxane, and an increase in yield was observed for the coupled product 52, while the biaryl product was not formed (Scheme 19). This demonstrates that the solvent/base combination is critical in the optimisation of the palladium-catalysed Stille reaction. The reaction with tributyl(thiophen-2-yl)stannane 51b was, therefore, only carried out using AgyCO3 in dioxane, and the coupled product was obtained at a good yield, while the biaryl product was not formed. This selectivity could also result from the use of one equivalent of the arylstannane, since the reaction of a Pd(II) precatalyst with two equivalents of the arylstannane mostly accounts for the homocoupling side-products [93].
Scheme 19. Stille reaction of compound 36 with arylstannanes [21,92]. The reaction of 3-bromo NPQ 36 with tributyl(phenyl)stannane 51a was carried out using one equivalent of the arylstannane in THF, with LiCl as the base, and heated at 100 °C for 24 h [92]; both the coupled product and biaryl product were obtained in low yields. The reaction was repeated with the base changed to AgzCO3 and the solvent to dioxane, and an increase in yield was observed for the coupled product 52, while the biaryl product was not formed (Scheme 19). This demonstrates that the solvent/base combination is critical in the optimisation of the palladium-catalysed Stille reaction. The reaction with tributyl(thiophen-2-yl)stannane 51b was, therefore, only carried out using AgyCO3 in dioxane, and the coupled product was obtained at a good yield, while the biaryl product was not formed. This selectivity could also result from the use of one equivalent of the arylstannane, since the reaction of a Pd(II) precatalyst with two equivalents of the arylstannane mostly accounts for the homocoupling side-products [93].
Scheme 21. Reaction of 3-bromoNPQ with aniline derivatives [21]. Scheme 20. Reaction of 3-bromo NPQ with isopropylmagnesium chloride [21,91].
Scheme 21. Reaction of 3-bromoNPQ with aniline derivatives [21]. Scheme 20. Reaction of 3-bromo NPQ with isopropylmagnesium chloride [21,91].
nd = not detected, t = trace amount. Table 4. Reaction of 3-bromo NPQ with aniline derivatives.
nd = not detected, t = trace amount. Table 4. Reaction of 3-bromo NPQ with aniline derivatives.
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