Quinoxaline N-oxides Research Articles

One-Pot Synthesis of Quinoxaline N-Oxides via Radical-Mediated Cyclization of Ketene N,S-Acetals

AbstractA facile and efficient one-pot synthesis of bench-stable quinoxaline N-oxides has been realized using α-oxoketene N,S-acetals and tert-butyl nitrite (TBN) in open air via cascade annulation. The double functionalization of N,S-acetals proceeds through an unanticipated (Csp2)–H nitrosation by NO radical (generated in situ by TBN) and subsequent intramolecular N-arylation leading to quinoxaline, which undergoes oxidation to quinoxaline N-oxides harboring three variegated substituents on their framework. Notably, two new C–N bonds are formed with the same N-oxide nitrogen. This protocol features short reaction time, good functional group tolerance and mild conditions, and does not require the use of either catalyst or external additive.

Synthesis of quinoxaline derivatives via aromatic nucleophilic substitution of hydrogen.

The electrophilic nature of quinoxaline has been explored in the vicarious nucleophilic substitution (VNS) of hydrogen with various carbanions as nucleophiles in an attempt to develop a general method for functionalizing the heterocyclic ring. Only poorly stabilized nitrile carbanions were found to give the VNS products. 2-Chloroquinoxaline gave products of SNAr of chlorine preferentially. A variety of quinoxaline derivatives containing cyanoalkyl, sulfonylalkyl, benzyl or ester substituents, including fluorinated ones, have been prepared in the VNS reactions with quinoxaline N-oxide.

Dichotomy of platinum(II) and gold(III) carbene intermediates switching from N- to O-selectivity

Pt(II) and Au(III)-mediated intermolecular divergent annulations of benzofurazans and ynamides highlighted the N- to O-selectivity of tunable metal carbene intermediates. PtCl2 with a bulky phosphite ligand resulted in the specific synthesis of six-membered quinoxaline N-oxides and successfully suppressed the in-situ deoxygenation of N-oxides. On the other hand, an unique gold(III) catalyst (2,6-di-MeO-PyrAuCl3) led to the five-membered ring products, benzimidazoles. A broad scope of functional groups was well compatible, delivering better yields and selectivities in contrast to conventional gold(I) catalysts. The different behavior of presumed platinum(II) and gold(III) carbenes with respect to chemoselectivity was intensively examined by experiments and DFT calculations. A detailed mechanistic study, based on DFT calculations, revealed that the highly electrophilic carbocation-like gold(III) carbene triggers an oxophilic cyclization, followed by a cascade ring contraction and acyl migration. On the contrary, the Pt carbene species is less cationic, favoring the formation of the six-membered ring via N-attack.

Organocatalyzed Synthesis of Fully Substituted Furans from Ynamides and Quinoxaline N-Oxides

Organocatalyzed Synthesis of Fully Substituted Furans from Ynamides and Quinoxaline N-Oxides

Benzofurazan N-Oxides as Mild Reagents for the Generation of α-Imino Gold Carbenes: Synthesis of Functionalized 7-Nitroindoles.

An efficient gold-catalyzed [3 + 2] annulation of benzofurazan N-oxides with ynamides has been developed, which provides a concise and regioselective access to highly functionalized 7-nitroindoles. Although N-oxides are often considered as oxygen transfer reagents in gold catalysis, benzofurazan N-oxide was found to act as a facile precursor for an α-imino gold carbene intermediate. Benzofurazan can also react with ynamides to afford quinoxaline N-oxides via a [4 + 2] annulation process.

Palladium-catalyzed C–H alkenylation of quinoxaline N-oxide enabled by a mono-N-protected amino acid

The efficient alkenylation of quinoxaline N-oxide was achieved via Pd-catalyzed C–H activation, using the assistance of a mono-N-protected amino acid. Further deoxygenation of the 2-styrylquinoxaline-N-oxides yielded the corresponding styrylquinoxaline derivatives.

Quinoxaline N-Oxides by Dehydrogenative N-Incorporation of Imines

Key words imines - quinoxaline N-oxides - dehydrogenative coupling - C–N bond formation - aromatization

Dehydrogenative N-incorporation: a direct approach to quinoxaline N-oxides under mild conditions.

An efficient method for the synthesis of quinoxaline N-oxides proceeds by the dehydrogenative N-incorporation of simple imines by C(sp(2))-H and C(sp(3))-H bond functionalization. The overall transformation involves the cleavage of three C-H bonds. The reaction is easily handled and proceeds under mild conditions. Simple and readily available tert-butyl nitrite (TBN) was employed as the NO source.

Fragmentation of the quinoxaline N-oxide bond to the ˙OH radical upon one-electron bioreduction

The ˙OH radical is released from 3-trifluoromethyl-quinoxaline 1,4-dioxides upon one-electron reduction by cytochrome P450 oxidoreductase. This process effectively competes with back oxidation of the intermediate radical anion by oxygen and underlies the increased aerobic cytotoxicity of such compounds compared to that seen for the related clinical bioreductive benzotriazine drug, tirapazamine.

Reaction of 2-pyridyllithium with azine N-oxides. Simple and convenient method for the synthesis of 2,2′-bipyridine 1-oxide and 2,2′:6′,2″:6″2′″-tetrapyridine 1′-oxide

In the reaction of 2-pyridyllithium with quinoline 1-oxide and isoquinoline 2-oxide a nucleophilic substitution of hydrogen occurs to form the corresponding pyridin-2-ylquinolines. A dimerization of the substrate occurs with pyridine 1-oxide, 2,2′-bipyridine 1-oxide or quinoxaline N-oxide. A similar dimerization in good yield occurs when treating azine N-oxides with tert-butyllithium and this serves as a simple and convenient method for preparing bi- and tetrapyridines.

Synthesis and Biological Evaluation of New 2-Arylcarbonyl-3-trifluoromethylquinoxaline 1,4-Di-N-oxide Derivatives and Their Reduced Analogues

As a continuation of our research in the quinoxaline 1,4-di-N-oxide new series of 2-arylcarbonyl-3-trifluoromethylquinoxaline, 1,4-di-N-oxide derivatives have been synthesized and evaluated in a full panel of 60 human tumor cell lines. Selective reductions were carried out on two compounds which allowed us to determine the compound structures by comparison of the 1H NMR spectra. In general, all the di-N-oxidized compounds showed good cytotoxic parameters. The best activity was observed in derivatives with electron-withdrawing groups in position 6 or 7 on the quinoxaline ring and in the unsubstituted analogues, whereas loss of one or two oxygens reduced the cytotoxicity. The best five compounds were selected for evaluation for the in vivo hollow fiber assays. In vitro studies reveal that compound 5h efficiently generates reactive oxygen species via redox cycling in the presence of the NADPH/cytochrome P450 enzyme system, providing a plausible molecular mechanism for the observed aerobic cytotoxicity of these quinoxaline N-oxides.

An Improved Understanding of the Reaction of Bis(bromomethyl)quinoxaline 1-N-Oxides with Amines Using Substituent Effects

The reaction of bis(bromomethyl)quinoxaline N-oxides with amines is interesting from a reaction mechanism perspective and due to the reported biological activity of compounds in this general class. The complex mechanism of this reaction (particularly in the case of primary amines) is complicated further when C6 or C7 substituted mono-N-oxides are considered. In this study, the synthesis and subsequent characterization of a series of 2,3-bis(bromomethyl)quinoxaline 1-N-oxides is reported. Experimental and computational evidence is used to show that the observed product ratios from the reaction with diethylamine reflect the influence of both the C6/C7 substituent and the N-oxide functional group on the initial nucleophilic substitution reaction.

Reaction Kinetics and Transformation of Carbadox and Structurally Related Compounds with Aqueous Chlorine

The potential release of carbadox (CDX), a commonly used antibacterial agent in swine husbandry, into water systems is of a concern due to its carcinogenic and genotoxic effects. Until this study, the reactivity of carbadox (possessing quinoxaline N,N'-dioxide and hydrazone moieties) toward aqueous chlorine has yetto be investigated in depth. Chemical reactivity, reaction kinetics, and transformation pathways of carbadox and structurally related compounds with free chlorine under typical water treatment conditions were determined. This study found that only CDX and desoxycarbadox (DCDX), a main metabolite of CDX with no ring N-oxide groups, react rapidly with free chlorine while other structurally related compounds including olaquindox, quindoxin, quinoxaline N-oxide, quinoxaline, and quinoline N-oxide do not. The reaction kinetics of CDX and DCDX with chlorine are highly pH dependent (e.g., the apparent second-order rate constant, kapp, for CDX ranges from 51.8 to 3.15 x 10(4) M(-1)s(-1) at pH 4-11). The high reactivity of CDX and DCDX to chlorine involves deprotonation of their hydrazone N-H moieties where initial chlorine attack results in a reactive intermediate that is further attacked by nucleophiles in the matrix to yield non-chlorinated, hydroxylated, and larger molecular weight byproducts. All of the CDX's byproducts retain their biologically active N-oxide groups, suggesting that they may remain as active antibacterial agents.

Qinolone Analogues 4. Synthesis ofÅ@1-Methyl-3-trifluoromethylpyridazino[3,4-b]quinoxalin-4(1H)-ones

The reaction of the quinoxaline N-oxides (7a, b) with 4,4,4-trifluoroacetoacetate gave the 1,5-dihydro-3-trifluoromethylpyridazino[3,4-b]quinoxaline-4-carboxylates (15a, b), whose oxidation with nitrous acid afforded the 1,4-dihydro-4-hydroxy-3-trifluoromethylpyridazino[3,4-b]quinoxaline-4-carboxylates (16a,b), respectively. The reaction of compounds (16a, b) with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) provided the 1,5-dihydro-3-trifluoromethylpyridazino[3,4-b]quinoxalin-4-ols (17a, b), whose oxidation with sodium bromate produced the 1-methyl-3-trifluoromethylpyridazino[3,4-b]quinoxalin-4(1H)-ones (6a,b), respectively.

Quinolone Analogues 5. Synthesis of 1-Methylpyridazino[3,4-b]quinoxalin-4(1H)-ones

The reaction of the quinoxaline N-oxide (8a) with diethyl ethoxymethylenemalonate gave the 1,4-dihydropyridazino[3,4-b]quinoxaline-4,4-dicarboxylate (10c), whose reaction with a base afforded the 1,5-di-hydropyridazino[3,4-b]quinoxaline-4-carboxylate (6a). The oxidation of compound (6a) with nitrous acid provided the 1,4-dihydro-4-hydroxypyridazino[3,4-b]quinoxaline-4-carboxylate (7), whose reaction with potassium hydroxide gave 7-chloro-1-methylpyridazino[3,4-b]quinoxalin-4(1H)-one (5a). On the other hand, the reaction of the quinoxaline N-oxide (8b) with acetylacctaldehyde dimethyl acetal afforded 4-acetyl-1,5-dihydro-1-methylpyridazino[3,4-b]quinoxaline (6b), whose oxidation with selenium dioxide provided 1-methylpyridazino[3,4-b]quinoxalin-4(1H)-one (5b).

Synthesiss of novel 3-(2-thienyl)-1,2-diazepino[3,4-b]quinoxalines with algicidal activity

The reaction of the quinoxaline N-oxide 1 with thiophene-2-carbaldehyde gave 6-chloro-2-[1-methyl-2-(2-thienylmethylene)hydrazino]quinoxaline 4-oxide 5, whose reaction with 2-chloroacrylonitrile afforded 8-chloro-2,3-dihydro-4-hydroxy-1-methyl-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6. The reaction of compound 6 with various alcohols in the presence of a base effected alcoholysis to provide the 5-alkoxy-8-chloro-2,3,4,6-tetrahydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]-quinoxalines 7a-d. The reaction of compounds 7a and 7b with diethyl azodicarboxylate effected dehydrogenation to give the 5-alkoxy-8-chloro-4,6-dihydro-1-methyl-4-oxo-3-(2-thienyl)-1H-1,2-diazepino[3,4-b]-quinoxalines 8a and 8b, respectively. Compounds 8a and 8b were found to show good algicidal activities against Selenastrum capricornutum and Nitzchia closterium.

Desulfurization of 4-Nitro-N,2-diphenyl-3-(phenylamino)isothiazol- 5(2H)-imine: Formation of a 3-Imino-2-nitroprop-2-enamidine

The course of the desulfurization reaction of 4-nitro-N,2-diphenyl-3-(phenylamino)isothiazol-5(2H)-imine (3) is investigated and the formation of the unstable 3-imino-2-nitroprop-2-enamidine (A) as intermediate is discussed. Addition of amines and thiophenol to the reaction mixture yielded the amidine derivatives 5 and the thioimidate 6, respectively, via nucleophilic addition of the respective reagent to A (Scheme 2). Benzoic acid and thiobenzoic acid afforded the amide 7 and the thioamide 8, respectively, as secondary products of the expected adducts 7a and 8a (Schemes 3 and 4). The presence of (benzylidene)(methyl)amine in the reaction mixture of the desulfurization of 3 led to the 1,2,4-oxadiazole derivative 10, together with the quinoxaline N-oxide 4 as a minor product. Reaction mechanisms involving an intermediate ketene imine and participation of the NO2 group in the reaction leading to 1,2,4-oxadiazole 10 are proposed. Ab initio calculations of model structures for the nitroketene imine were performed and the results correlated with the experimental results. The structures of 8 and 10 were established by X-ray crystal-structure analysis.

Free Radical Intermediates in the Reduction of Quinoxaline N-Oxide Antitumor Drugs: Redox and Prototropic Reactions

The free radical intermediates formed on one-electron reduction of imidazo[1,2-a]quinoxaline N-oxides RB91724 (I), RB90740 (II), and RB93918 (III) were investigated by pulse radiolysis. Reaction with radiolytically-generated CO2•- radical anions produced the N-oxide radicals. The radicals decayed by second-order kinetics, but the lifetimes of the radicals of I increased with increasing pH, whereas the lifetimes of the radicals of II and III were not significantly affected by pH (pH 4−11). The pKa values of the protonated radicals were measured as 7.4, 6.2, and 5.5 for I, II, and III, respectively. The radicals reacted with oxygen, with rate constants of 1.6, 3.2, and 1.8 × 108 dm3 mol-1 s-1 for I, II, and III, respectively, at pH 7.4. From redox equilibria with viologens and 1-methylnicotinamide, the one-electron reduction potential of I was estimated to be −0.70 V, and those for II and III were estimated as ∼−0.80 V vs NHE, i.e., much lower than the corresponding value for the benzotriazine dioxide tirap...

Structure of Reaction Products of Some Substituted Quinoxaline N-Oxides with Carbanions

1,2,3-Triazolo[1,5-a]- (II) and 1,2,4-triazolo[4,3-a]quinoxaline 5-oxide (III) react with the carbanions of β-diketones and β-keto esters to give enaminones in the same way as their tetrazolo analogue. The difference in mechanism of reactions of these N-oxides with carbanions of 3-alkylpentane-2,4-dione and ethyl methyl acetoacetate giving aziridinopolyazoloquinoxalines and ethyl 2-(polyazoloquinoxalin-4-yl)propanoates, respectively, is discussed. It was shown that the reaction with carbanion including the aziridine ring closure proceeds with 3,4-dihydro-3-oxoquinoxaline-1-oxide as well.

Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships.

A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.