Quinoxalinones, formation

There are numerous references in the literature to the preparation of quinoxalinones as characterizing derivatives for a-keto acids. Paper chromatographic, " gas-liquid chromatographic, and fluorimetric methods have been used for the microestimation of quinoxalinones. Quinoxalinone formation is also the basis of a method for amino acid identification, as shown in Scheme 18. It has found application in... 

Peracetic acid oxidation of 2-carbamoylquinoxaline (94) at 20°-25° gives the monoxides 95 and 96, and at higher temperatures the 1,4-dioxide (97) is isolated in 50% yield, together with a small amount of the 1,4-dioxide of 2-amino-3-quinoxalinone.m However, Hayashi and co-workers report the isolation of only 96 from 94 using monoperphthalic acid in ether <10°.109 In their attempt to correlate the nature of 2-substitution with the formation of 1- versus 4-oxides, they examined the behavior of some 2-alkyl substituted quinoxalines 113,114 2-ethylquin-oxaline gives the 1- and 4-oxides and the 1,4-dioxide, 2-isopropylquin-oxaline yields the 4-oxide and the 1,4-dioxide however, 2-f-butylquin-oxaline only furnishes the 4-oxide because of steric hindrance.114 The N-oxidation of 2-phenyl- and 2-alkyl-3-phenyl-quinoxalines with monoperphthalic acid furnishes the products shown in Table 1.114... 

Direct amination of quinoxalinones with hydroxylamine-O-sulfonic acid produces the 1-amino derivatives (135) in 70-80% yield, and subsequent oxidation with lead tetraacetate gives the 1,2,4-benzotriazines (138). Benzotriazine formation probably involves the formation of an intermediate nitrene (136), ring expansion to a benzo-triazepinone (137) and subsequent loss of carbon monoxide. The nitrene (136 R = Ph) was trapped as the sulfoximide 139 when the oxidation was carried out in the presence of dimethyl sulfoxide.147... 

A similar reaction resulting in the formation of compound 185 is observed when 3-phenyl-2-quinoxalinone 4-oxide (184) is treated with... 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

Oxidations of quinoxalines without ring opening include 7V-oxide formation (see Section 6.3.2.1.4.1.) and synthesis of quinoxalinones (see Section 6.3.2.1.4.4 ). 5- or 5,8-Dihy-droxyquinoxalines are oxidized to quinoxaline-5,8-diones i/ s7.4.s8... 

Ethyl 7-oxopteridine-6-carboxylate is synthesized from the diamine and diethyl mesoxalate [2299]. A substituted 2-quinoxalinone is obtained from A -methylphenylenediamine and DMAD [2678], but under slightly different conditions, two molar amounts of DMAD react with one of diamine [3252]. Stirring a diamine with the oxazolone (76.18) in acetic acid under mild conditions leads to the formation of a pyrazinone ring [3250]. 

The formation of unsubstituted quinoxaline 1,4-dioxide in the Beirut reaction has been observed using a number of substrates benzoylacetalde-hyde and its enamines,395 vinyl acetate (Et2NH),396 acetylene (NEt3)397,398 propargyl alcohol, propiolic acid, and phenylacetylene (various amines).398 Some of these are unexceptional, but the apparent dephenylation in the case of the phenylacetylene is surprising. However, recently the reaction of benzofuroxan with diethylamine was reinvestigated399 (see Section V,E), and quinoxaline dioxide was found to be one of the major products from a complex sequence of oxidation and reduction reactions. It seems probable with phenylacetylene, and possible in other cases too, that the amines play more than a catalytic role in quinoxaline dioxide production. The amino-quinoxalinone 175 was reported, using vinyl acetate and morpholine.396... 

The chemistry of quinoxalin-2-ones and quinoxaline-2,3-diones (2-hydroxy- and 2,3-dihydroxyquinoxalines) has been previously reviewed by Simpson. Quinoxalin-2-ones are very easily prepared from condensation of o-phenylenediamines and a-keto acids and because of their ease of preparation, they have been used as characterizing derivatives for a-keto acids. There are widespread references in the patent literature to the preparation of quinoxalinones for potential pharmaceutical and horticultural applications and also for the formation of polymers. 

The quinoxalinone 26 is obtained in 34% yield when the diazetidone 25 is heated in boiling methanol. Rearrangement is accompanied by aerial oxidation of the intermediate 3,4-dihydroquinoxalinone and the formation of the ring-opened product 27. Irradiation of the ben-... 

Treatment of the dihydroimidazo[l,2-a]quinoxaline 19 with sodium hydroxide solution results in opening of the five-membered ring and formation of the quinoxalinone 20. The 4-chloro derivative 21 is susceptible to nucleophilic attack, and displacement of the chlorine has been achieved with sodium methoxide, sodium alkoxides in benzene, and hydrazine. The 4-hydrazino derivative was not isolated but was treated with copper sulfate and sodium hydroxide to give the 4-unsubstituted compound. ... 

Ring closures to three different benzologues of the bicyclic system discussed in the previous section have been published. Thus, reaction of (164) with triphenylphosphine followed by treatment with isocyanate gave [l,2,3]oxadiazolo[3,4-a]quinoxalinium-3-olate (165) (Equation (40)) <91S745>, ring transformation of (166) in the presence of aqueous triethylamine afforded the [ 1,2,4]triazolo[4,5-a]quinoxalinone compound (167) (Equation (41)) <87JHC1013>, and treatment of (168) with sodium alkoxide resulted in formation of the unsubstituted tricyclic compound (25) (Equation (42)) <87JPC101>. 

Quinoxaline is a by-product of cooking some food and can inhibit the growth of some ciliate protozoa and plan-pathogenic fungi. The metabolism of this ring system by Pseudomonas putida can provide the quinoxaline cis-5,6-dihydrodiol, 5-hydroxyquinoxaline, and 2(l//)-quinoxalinone. When quinoxaline is metabolized by Streptomyces badius, two different products were isolated. Both of these two products, 2(l//)-quinoxalinone and 3,4-dihydro-2(l/ )-quinoxalinone, were only isolated from the treatment of Streptomyces badius with quinoxaline. Six other Streptomyces species were tested and only produced 2(l//)-quinoxalinone. The mechanism for the formation of 3,4-dihydro-2(l//)-[Pg.548]

Scheme 2.49 Formation of quinoxalinone 4-oxides 288 starting from anilines 286...

Scheme 2.108 A plausible mechanism for the formation of 3,4-dihydro-2(lff)-quinoxalinone 489 from 3-hydroxyfiiran-2-(5fl)-ones 487 488...

The destmction of spiro-compounds takes place in the case of the A-octyl derivative of spiro-quinoxalinone 166, with the release of ammonia and the formation of corresponding chalcone 167 under the rearrangement conditions (in boiling AcOH) (Scheme 6.75). It seems plausible that for the successful course of the rearrangement one of the necessary conditions is the presence of a hydrogen... 

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