Quinoxaline 2- acetate

Proceed as in (A), using 50 ml. of ethanol, with boiling for 20 minutes. The quinoxaline (III) crystallises readily during the boiling. Cool the mixture, filter off the quinoxaline, and wash it with ethanol. The dry product, of m.p. 220 225", weighs 1 3 g. Recrystallise the quinoxaline from chloroform or acetic acid pale yellow crystals, m.p. 226°. Yield, 0 9-ro g. 

Formation of a Quinoxaline. Heat together for 5 minutes under reflux 0 2 g. of phenanthraquinone dissolved in i ml. of glacial acetic acid and 0-2 g. of O -phenylene diamine also dissolved in i ml, of glacial acetic acid. The yellow substituted quinoxaline (p. 305) separates rapidly. Cool, filter and recrystallise from benzene m.p. 225 . 

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Other reactions with their counterparts in the pyridine series are also well known. Thus, 2,3-dimethylpyrazine 1,4-dioxide reacts with acetic anhydride to yield 2,3-bis(acetoxy-methyl)pyrazine (S3) in good yield (72KGS1275). Pyrazine 1-oxide also reacts directly with acetic anhydride to yield 2(ljH)-pyrazinone by way of the intermediate acetate (Scheme 22). The corresponding reaction in the quinoxaline series is not so well defined and at least three products result (Scheme 23) (67YZ942). 

As might be expected from a consideration of electronic effects, an amino substituent activates pyrazines, quinoxalines and phenazines to electrophilic attack, usually at positions ortho and para to the amino group thus, bromination of 2-aminopyrazine with bromine in acetic acid yields 2-amino-3,5-dibromopyrazine (Scheme 29). 

The bromination of 5,8-dimethoxyquinoxaline in methanol gives a mixture of 6-bromo and 6,7-dibromo compounds/ Treatment of 2-methylquinoxaline with bromine in acetic acid yields a mixture of 27% of 2 bromomethyl- and 37% of 2-dibromomethyl-quinoxaline." Thus in the absence of powerfully activating groups, side-chain rather than nuclear substitution takes place. 

Oxidation of 4-methylquinoxalin-3-one 2-carboxy-fV -methylamlide (45) with hydrogen peroxide and acetic acid furnishes the 1-oxide but, on removal of either or both of the fV-raethyl groups (giving 46, 47, or 48), oxidation with hydrogen peroxide or with peracetic or perbenzoic acid results in the removal of the carboxyamide groups and the formation of a quinoxaline-2,3-dione. ... 

Quinoxalin-2-ones, unlike quinoxaline itself, may be nitrated under mild conditions. Nitration of quinoxalin-2-one in acetic acid gives mainly the 7-nitro derivative in sulfuric acid, the 6-nitro compound is formed (Scheme 6). ... 

Quinoxalin-2-one is a very weak base (pK — 1.37) and so the different orientation of substitution in acetic and sulfuric acids may mean that in acetic acid the principal species undergoing nitration is the neutral molecule, and in sulfuric acid, the mono-cation. Treatment of quinoxaline-2,3-dione, or its iViV -dimethyl derivative in sulfuric acid, with 1 equivalent of potassium nitrate, results in nitration at position 6 with 2 equivalents of potassium nitrate, 6,7-dinitro compounds are formed. When quinoxaline is boiled with aqueous nitric acid, 6-... 

Methylthioquinoxaline is oxidized by hydrogen peroxide in acetic acid at room temperature mainly to 2-methylsulfonylquinoxa-line (88) at 55°C, 2-methylsulfonylquinoxaline 4-oxide (89) and quinoxaline-2,3-dione are formed. 

Benzocyclobutene-l,2-dione (11) can be condensed with benzene-1.2-diamine to provide an annulated quinoxaline (cf. Houben-Weyl, Vol. E9b/Part 2, p203), which on oxidation with hydrogen peroxide in acetic acid leads to the 1,4-diazocine derivative 12.34... 

Benzoxadiazole 1-oxide (481) with 3-acetyltetrahydro-2-furanone (2-acetyl-butyrolactone 482) gave 2-(2-hydroxyethyl)-3-methylquinoxaline 1,4-diox-ide (483) (KOH, MeOH-HaO, 20°C, 24 h 50%) but with 2-acetylacetaldehyde dimethyl acetal (484), in the presence of morpholine as base, it gave 2-(2-morpholinovinyl)quinoxaline 1,4-dioxide (485) (PhH, reflux, water separation, 9 h 47%) ... 

Dimethylquinoxaline (147) gave 2-ethoxycarbonyl-2-hydroxy -methyl-2,3-dihydro-[l/ ]-pyrrolo[l,2-u]quinoxalin-10-ium bromide (148) (BrCH2CO-C02Et, AcEt, reflux, 3h, then 20°C, 12 h 72%) and thence successively ethyl 4-methylpyrrolo[l,2-fl]quinoxaline-2-carboxylate (149) (EtONa, EtOH, 20°C, 4h 93% note oxidation by loss of H2O), the uncharacterized quaternary salt (150) (as the first step but 6h 50%), and diethyl dipyr-rolo[l,2-fl 2, l -c]quinoxaline-2,ll-dicarboxylate (151) (KOH, H2O, reflux, 1 h 56%). ° " - ... 

Chloro-3-methylquinoxaline 4-oxide gave 3-chloro-2-quinoxalinecarbalde-hyde 1-oxide (172) (SeOi, PhH, reflux, h 72%) dioxane may be used as solvent for such oxidations yielding, for example, 3-amino-2-quinoxaline-carbaldehyde ethyl acetate may also be so used. 

Quinoxalinamine (177) and chloroketene diethyl acetal (178) gave 2-(quinox-alin-2-ylamino)imidazo[ 1,2-u]quinoxaline (180), probably via the intermediate (179) [reactants, TsOH, MeCN, 20°C, 6 h then more (177)], reflux, 4 h ... 

Nearly all (extranuclear) hydrazonoquinoxalines are made by treatment of quinoxaline aldehydes, ketones, or their acetals with hydrazine or substituted hydrazine, but a few are produced by diazo coupling. These reactions are illustrated by the following examples. 

Quinoxalinecarbaldehyde 1,4-dioxide diethyl acetal (23) gave 2-quinoxaline-carboxylic acid 4-oxide (24) (NaOH, EtOH, 22°C, 24 h 96% mechanism... 

Quinoxaline (161) with 1,3,6-trioxanegavethecyclic acetal, 2-(l,3,5-trioxan-2-yl)-quinoxaline (162) (Bu 02H, FeS04, MeCN, reflux, 5 h crude), and thence 2-quinoxalinecarbaldehyde (163) [5% H2SO4, reflux, briefly 35% overall, by gas-liquid chromatography (glc)] 1,4-dioxane has been used in a some-... 

Quinoxalinecarbaldehyde 1,4-dioxide (178) gave its acetal, 2-(diethoxy-methyl)quinoxaline 1,4-dioxide (179) (HCl gas/EtOH, reflux, 1 h 47%) and thence the corresponding hydrate 2-(dihydroxymethyl)qumoxalme... 

Chloro-2-quinoxalinecarbaldehyde (182) gave its cyclic acetal, 2-chloro-3-(l,3-dioxolan-2-yl)quinoxaline (183) (HOCH2CH2OH, PhMe, trace TsOH, reflux, 3 h 78%).64... 

Reactions of 2,3-dioxo-l,2,3,5,6,7-hexahydropyrido[l,2,3-carboxylic acids and the homologous acetic and propionic acids, prepared by basic hydrolysis of the corresponding ester, with amines, 28% NH4OH, and hydroxylamine derivatives in the presence of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and hydroxybenztria-zole <1995BML1527>, 1995BML1533>, and in the presence of NEt3 and A, A -bis(2-oxo-3-oxazolidinyl)phosphinic... 

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