2- Methylquinoxaline preparations

The structure of this compound is confirmed by the preparation of the 1-acetyl derivative, acid degradation to 4-methylquinoxalin-3-one-2-carboxylic acid (12), and alternative synthesis from the acid chloride of (12) and AW -dimethyluread A most unusual cyclization occurs when AW-dimethyl-o-phenylenediamine (15) is treated with alloxan in ethanolic solution this apparently involves an A-methyl group and leads to the formation of the spirobarbituric acid (16). The struc-... 

Crude 5-dibromomethylquinoxaline (259) (prepared by bromination of 5-methylquinoxaline) gave 5-quinoxalinecarbaldehyde (261) via the hydrate (260) (CaCOs, H20-Et0H, reflux, 3h 71%)/ ... 

Methylquinoxaline may be prepared in 88-92% yields from o-phenylenediamine and pyruvic aldehyde-sodium bisulfite by this same procedure. 

Methyl-5,6-pyrazinedicarboxylic acid may be prepared in 70-75% yields from 2-methylquinoxaline by this same procedure. The crude acid (m.p. 155-160°, dec.) is somewhat unstable at elevated temperatures. It should not be heated above 100° for long periods of time. In order to obtain pure 2-methyl-5,6-pyrazinedicarboxylic acid (m.p. 175°, dec.) the crude product is best recrystaUized from acetone. 

Quinoxaline has been prepared by the reaction of glyoxal with o-phenylenediamine, and 2-methylquinoxaline by the reaction of pyruvic aldehyde or isonitrosoacetone with < -phenylenedi-amine. 2,3-Pyrazinedicarboxylic acid has been prepared only by the permanganate oxidation of quinoxaline. 2-Methyl-5,6-pyrazinedicarboxylic acid has been prepared from 2-methyl-quinoxaline in the same way. - ... 

During the last few years, numerous quaternary salts of quinoxalines have been prepared, and their reactions studied. 2-Methylquinoxaline and some of its 6,7-substituted derivatives (101) form 4-methyl-quinoxalinium methosulfates and perchlorates (102).116 On hydrolysis of these salts, the quinoxalinones (103) are formed. Similarly 2,3-dimethyl-... 

Quinoxalin-2-ylmethyllithium (8), prepared by lithiation of 2-methylquinoxaline with lithium diisopropylamide, undergoes an alkylation reaction with bis(trimcthylsilyl)peroxide to yield 2-ethylquinoxaline (9) as an oil. ... 

Metalation of 3-methylquinoxalin-2(l//)-one with lithium diisopropylamide prepared in situ affords the dianion in good yield. 

C and addition of excess of potassium iodide to the product, gives only a small yield of methiodide, but 2-acetamidoquinoxaline 4-methiodide (67) is readily prepared by this method. Proof that quaternization occurs at position 4 is obtained by degradation of (67) by boiling alkali to l-methylquinoxaline-2,3-dione and 1 equivalent of ammonia. Similar treatment of the 1-methiodide would yield l-methylquinoxalin-2-one, and under these conditions this compound is not converted into the dione.9... 

Following an 80 min reaction, ribose/phosphate buffer mixtures were rapidly cooled to 25 C, treated with o-phenylenediamine and incubated at 50 C for 30 min. Quinoxalines and unreacted OPD were extracted and concentrated for GC/MS analysis or separation by preparative TLC. Volatile quinoxaline and methylquinoxalines were identified by Rt and MS of available standards. 2-Ethylquinoxaline was tentatively identified by its MS alone. Non-volatile quinoxalines were isolated by preparative TLC and tentatively identified through literature Rf, NMR and UV data. Addition of OPD at die start of ribose/phosphate buffer reactions produced somewhat higher yields of the same quinoxalines in a similar ratio. No evidence for quinoxaline products was found in control experiments run in bis-tris buffer. 

Recently, Chan prepared Ir PQ Phos complex and applied it to the catalytic enantioselective hydrogenation of 2 methylquinoxaline [8], and up to 80% ee was obtained in THF with full conversion in the presence of I2. 

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). 

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. 

A successful preparation of 3-methylquinoxaline-2-carboxaldehyde (9) by the selective reduction of the ester 8 is reported. ... 

The IR spectrum of 2-acetyl-3-methylquinoxaline shows carbonyl stretching absorption at 1695 cm in Nujol and therefore in the region to be expected of an aryl methyl ketone. A range of standard derivatives have been prepared from quinoxalinyl ketones (see Table 1) but cycliza-tion occurs on treatment of various 2-benzoylquinoxalines (10) with... 

Methylquinoxalines are converted into the corresponding carboxylic acids by condensation with an aromatic aldehyde and oxidation of the resulting styryl derivative with potassium permanganate. Quinoxaline-2-carboxylic acids are also conveniently prepared by oxidation of the readily available D-arabinotetrahydroxybutylquinoxalines with sodium peroxide in water or in a heterogeneous benzene-water system. ... 

Chloroquinoxalines have also been prepared from quinoxaline mono-N-oxides. For example, treatment of 5-methylquinoxaline 1-oxide with phosphoryl chloride gives 2-chloro-5-methylquinoxaline, and reaction of... 

Alkylquinoxalines have also been prepared by various transformations of preformed quinoxalines. Thus 2-carboxy groups are usually readily decarboxylated and 2-chloro groups removed by catalytic hydrogenation. Illustrative of this approach is the reduction of 2-chloro-3-methylquinoxaline to 2-methylquinoxaline. " ... 

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. ... 

Benzofuroxan (150) on reaction with ethyl acetoacetate provides the methylquinoxaline 151, which on bromination gives the bromomethyl derivative 152. Treatment of this compound with amines gives the monooxopyrrolo compound 154. The 2-methyl derivative 154 (R = Me) was also prepared directly from benzofuroxan by reaction with the JV-methylpyrrolinone 153. The products 154 are claimed to be antibacterials and animal growth promotants. ... 

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