Quinoxaline 1,4-dioxide preparation

A further variation on this general method for preparing quinoxaline dioxides is the use of o-quinone dioximes (54) rather than benzofurazan 1-oxides. The dioxime undergoes cycloaddition with cr-dicarbonyl and a-hydroxycarbonyl compounds, and hydroxamic acids of type 55 are particularly easily prepared by this method.56... 

There are many patents on the Beirut reaction thus 2-carbamoyl,57 2-amino-3-amidino-,58 2-methyl-3-carbamoyl-,59 2-amino-3-carbamoyl-,60 2-halomethyl-3-carboxy,61 2-mercapto-,62 and 2-trifluoromethyl63 quinoxaline 1,4-dioxides are just a few examples among the many quinoxaline derivatives prepared by this method. In a... 

The X-ray crystal structures of pyrazine V.JV -dioxide (134) <02AX(E)1253>, the P-polymorph of phenazine (135) <02AX(C)181>, cobalt(III) complexes of pyrazine-2,6- and pyridine-2,6-dicarboxylic acids <02JIC458>, and bis-urea-substituted phenazines <02ZN(B)937> were reported. Fluorescent pyrido[l,2-a]quinoxalines 136 prepared as pH indicators were examined by X-ray crystallography <02JCS(P2)181>, as were macrocyclic quinoxaline-bridged porphyrinoids obtained from the condensation of dipyrrolylquinoxalines 137 and 1,8-diaminoanthracene... 

A further variation on this general method for preparing quinoxaline dioxides is the use of o-quinone dioximes (54) rather than benzofurazan... 

Quinoxaline 1,4-dioxides have also been prepared by condensation reactions carried out on the surface of solid catalysts such as silica gel, " molecular sieves, " or alumina. " As a representative example, " BFO 1 and the P-dicarbonyl compound 16 were combined with silica gel in methanol. The excess methanol was removed by evaporation and the silica gel with adsorbed reagents was allowed to stand for two weeks without drying. The quinoxaline 1,4-dioxide 17 was obtained in 90% yield after elution from a silica gel column. 

The authentic quinoxaline AT -oxide (108) is prepared from quinoxaline 1,4-dioxide by the following route ... 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

The pyrazine ring is stable toward permanganate oxidation, and this explains a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines or benzo-fused quinoxalines. In contrast, alkyl side chains on pyrazines are effectively oxidized by permanganate, selenious acid, selenium dioxide, or dichromate to afford the corresponding carboxylic acids (Section 8.03.7.1). Oxidation of pyrazines with hydrogen peroxide or percarboxylic acids gives pyrazine A -oxides and/or A, A -dioxides (Section 8.03.5.2). 

Many quinoxaline 1,4-dioxides have been prepared by the Beirut reaction (Section 8.03.10). Phenazine 5,10-dioxides are prepared by the Beirut reaction using hydroquinone (Section 8.03.10), and they can be also synthesized by treatment of o-nitroanilines with dihydroxybenzenes (Equation 32) <1995M1217>. 

Quinoxalines are, in general, comparatively easy to prepare, and numerous derivatives have been prepared in work designed to produce biologically active materials. Quinoxaline W-oxides continue to be a focal point of study. Their reactions, as well as their pharmacological actions, continue to stimulate many investigations. Thus 2-methyl-quinoxaline (V,(V -dioxides substituted in the 3-position (e.g., with amide,2 amidino,3 hydrazinocarbonyl,4 and ester5 groups) are potent bacteriocides. 

The preparation of quinoxaline derivatives carrying a substituent in the benzene ring requires suitably substituted o-phenylenediamines. These have been prepared by reductive cleavage (SnCl2) of appropriately substituted 2,1,3-benzoselenadiazoles (I9).21 Benzo-selenadiazoles, readily prepared from 1,2-diaminobenzenes and selenium dioxide, undergo halogenation at positions 4 and 7 and sulfonation at C-4. 5,6-Dichloro- 2,3-diphenylquinoxaline has been synthesized from benzil and l,2-diamino-3,4-dichlorobenzene, the diamine in turn was obtained from 4,5-dichloro-2,l,3-benzoselenadiazole.22... 

Pyrazinecarboxylic acid has been obtained by selenious acid oxidation in pyridine of methylpyrazine or aqueous permanganate oxidation of ethylpyrazine, in yields of 64 and 48%, respectively.171,218 It has also been obtained in 70% yield by partial decarboxylation of pyrazine-2,3-dicarboxylic acid on heating in vacuo at 210°.219 Aqueous permanganate oxidation of 2,5-distyrylpyrazine gives the 2,5-dicarboxylic acid.220 Pyrazine-2,5-dicarboxylic acid has also been prepared in 45% yield by direct carboxylation of pyrazine with carbon dioxide at 50 atm pressure at 250° for 3 hours in the presence of a potassium carbonate and calcium fluoride catalyst.221 Pyrazine-tricarboxylic acid (57), obtainable in only very poor yields by oxidation of 2,5-dimethyl-3-ethylpyrazine, is prepared in 87% yield by alkaline permanganate oxidation of 2-(D-arabo)tetrahydroxybutyl-quinoxaline (56).222 Decarboxylation of the tricarboxylic acid by... 

The main search for biologically active quinoxalines has centered around the preparation of quinoxaline iV-oxides. 3-Substituted 2-methylquinoxaline 1,4-dioxides with high antibacterial activity have been prepared (Chapter IV). Quinoxaline 2-sulfonamide has had sustained use as a coccidiostat for poultry (Chapter XI). A series of naturally occurring quinoxaline antibiotics, the quinomycins and triostins, are known, but their therapeutic index is low (Chapter IX). 

The results of oxidizing other 2,3-disubstituted quinoxalines are broadly predictable from what is known about the oxidation of the monosubstituted compounds. Thus 1,4-dioxides can be prepared from 2-methyl- and 2-ethyl-3-phenylquinoxalines, but a considerable amount of... 

Quinoxaline mono-iV-oxides result from the partial reduction of the di-N-oxides. Among reagents that have been used for this purpose are hydrogen and a metal catalyst, phosphorus trichloride, and sodium dithionite. Thus 2-methylquinoxaline 1-oxide has been prepared by partial hydrogenation of the di-JV-oxide quinoxaline-2-carboxyanilide 1-oxide has been prepared from the partial deoxygenation of the 1,4-dioxide with phosphorus trichloride and quinoxaline-2-carboxylic acid... 

Quinoxaline-2-carboxaldehydes are conveniently prepared either from the corresponding methyl- or polyhydroxyalkylquinoxalines. The oxidation of methylquinoxalines to quinoxalinecarboxaldehydes is usually carried out with selenium dioxide, and sodium metaperiodate (NaI04) is the reagent recommended for the oxidation of tetrahydroxybutyl-quinoxalines. An indirect method for the conversion of methylquinoxalines into quinoxalinecarboxaldehydes is illustrated in Scheme 1. 

Dimethylsulfoxide oxidation of a-bromomethylquinoxalines yields quinoxalinecarboxaldehydes, and 2,3-bis(bromomethyl)quinoxaline (2) is oxidized by this reagent to the 2,3-dicarboxaldehyde 4. This preparation yields 60% of the cyclic monohydrate 3, which is converted into the dialdehyde by vacuum sublimation. The cyclic monohydrate is also formed by treatment of 2,3-bis(hydroxymethyl)quinoxaline 1,4-dioxide... 

Selenium dioxide oxidation of 2-methylquinoxaline yields quinoxaline-2-carboxaldehyde, and 3-methylquinoxaline-2-carboxaldehyde has been similarly prepared from 2,3-dimethylquinoxaline. Dimethylsulfoxide oxidation of 2,3-bis(bromomethyl)quinoxaline yields the furoquinoxaline 45, and this on sublimation gives quinoxaline-2,3-dicarboxaldehyde. 3-Dibromomethylquinoxaline-2-carboxaldehyde (46) is a by-product of the oxidation reaction. Direct selenium dioxide oxidation of 2,3-dimethylquinoxaline appears to be a less satisfactory method of preparing the dialdehyde. ... 

Routes via o-aminophenylpyrroles present the most convenient syntheses of a wide variety of pyrrolo[l,2-a]quinoxalines. Thus reaction of the amino compound 6 with acetic anhydride in acetic acid gave the acetamido derivative which was cyclized with phosphoryl chloride to give the 4-methyl compound 7 (R = Me) in 56% yield. The 4-phenyl compound 7 (R = Ph) has been prepared similarly. An even more convenient synthesis of 4-aryl compounds is achieved by reaction of compound 6 with aromatic aldehydes to give the 4,5-dihydro derivatives These are readily oxidized to 4-arylpyrrolo[l,2-a]quinoxalines 9 with manganese dioxide. This approach may be carried out in one step by reaction of compound 6 with aromatic aldehydes (e.g., benzaldehyde) in the presence of cupric acetate. Reaction of the aminophenylpyrrole 6 with 90% formic acid gave pyrrolo[l,2-a]quinoxaline (7, R = H) directly in 98% yield. Pyrrolo[l,2-a]quinoxalines substituted in the l-position and the 7-position have also been prepared from appropriately substituted... 

In basic medium and under mild conditions, phenazine-5,10-dioxides 35 are formed. However, from 1,2,3-benzoxadiazol-l-oxide and enolates or enamines quinoxaline-1,4-dioxides arise. The Beirut reaction possesses considerable preparative scope, but its mechanism has not yet been fully elucidated. 

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