Quinoxaline A -oxides

Quinoxaline A-oxides have marked biological effects for example, N-(2-hydroxyethyl)-3-methyl-2-quinoxalinecarboxamide 1,4-dioxide (Olaquindox BA-YO-N-OX) is marketed as a growth-promoting feed additive for stock 315,948,cf 931 

However, they are of greater interest as intermediates not only do they undergo a variety of reactions, but the N-oxide entity decreases the aromaticity index149 and substantially affects reactivities at other positions. 

Some such iV-oxides have been made by primary synthesis (see Chapter 1, especially Sections 1.1.2.2, 1.2.4, 1.6.7, and 1.7.16) virtually all others have been made by direct oxidation, as illustrated in the following examples, which are classified according to the oxidant used. 

2-Phenyl-6-trifluoromethylquinoxaline (229) gave 2-phenyl-6-trifluoromethyl-quinoxaline 4-oxide (230) (HC02H, 30% H202, 50°C, 12 h 85% homologs similarly) 840 6-methoxy- (231, R = OMe) and 6-nitro-3-phenylquinoxaline 1-oxide (231, R = N02), as well as other analogs, were made similarly in 

6-Methoxy-5-nitro-3-phenylquinoxaline gave only 6-methoxy-5-nitro-3-phenyl-quinoxaline 1-oxide (232) (AcOH, 30% H202, 80°C, 3 h 81%) 35 1,3-dimethyl-2(l//(-quinoxalinone 4-oxide (233) was made similarly but in only 

3-Methoxycarbonylmethyl-l-methyl-2(177)-quinoxalinone (223, X = O) gave 3-methoxycarbonylmethyl-l-methyl-2(177)-quinoxalinethione (223, X = S) (P2S5, PbCl, 125°C 

3-Methyl-l-phenyl-2(17/)-quinoxalinone (226) and methyl methacrylate (227) gave the photoadduct, methyl l,2a-dimethyl-3-oxo-4-phenyl-2,2a,3,4-tetra-hydro-l//-azeto[l,2-fl]quinoxaline-l-carboxylate (228) as a separable mixture of two stereoisomers (CH2CI2, MeOH, hv, N2, 15 h 40% each) analogs likewise.  

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Quinoxaline A-oxides undergo rearrangement under a variety of conditions. Thus on treatment of 2-ethoxy- and 2-methoxy-quinoxa-line 4-oxide with hydrochloric acid, rearrangement and hydrolysis occurs to give quinoxaline-2,3-dione. A possible intramolecular mechanism of rearrangement is shown in Scheme 7. Reaction of 2,3-... 

Protonation of pyrazine A-oxides takes place at the unsubstituted ring nitrogen as revealed by examination of their UV spectra and ionization constants in water. The same holds for unsubstituted quinoxaline A-oxide and the 3-amino derivative. Pyrazine and quinoxaline di-A-oxides are protonated at one A-oxide oxygen atom (74KGS1554). 

Such direct cyclizations usually occur in basic media to afford quinoxaline A-oxides. For success, C2 in the ethyl group needs to be a carbonyl entity or to be suitably activated. The following examples illustrate this valuable route to such A-oxides (and thence to quinoxalines see Section 4.6.2.1). 

Several recent general papers on the properties of quinoxaline A -oxides have... 

Some aspects of the deoxidative C-substitution of quinoxaline N-oxides (see Section 4.6.2.2 for cross-references) and the photoinduced rearrangement of quinoxaline dioxides into quinoxalinediones (see Section 4.5.1) have been discussed already. The remaining reactions of quinoxaline A -oxides are covered in the following subsections. 

Some minor reactions of quinoxaline A -oxides are illustrated in the following classified examples. 

The only publication on the angularly condensed benzologues, pyrimido[2,l-tf]quinoxalines, describes the synthesis of 161 by formation of both the pyrimido and the pyrazino ring from [6+0] atom fragments. Compound 160, the targeted cyclocondensation product of the propanediamine derivative 159, spontaneously cyclized to the pyri-mido[2,l- ]quinoxaline A-oxide 161 (Equation 17) <2002S2687>. 

Deoxygenation of quinoxaline A -oxides or A, A -dioxides has been realized with sodium dithionite <199681477, 2005AF754>. 

A particular class of quinoxaline A-oxides can be synthesized by a reaction sequence starting from condensation of anilines with a-oximino ketones (Scheme 50) <1998S1769>. The key step is oxidation of the oxime to an a-acetoxy nitroso group, which behaves as an electrophile leading to the formation of the quinoxaline ring. 

Catalytic hydrogenation of iV-(o-nitrophenyl)aminoacetonitriles 192 with palladium(ll) oxide hydrate gives high yields of quinoxaline A -oxides 193 through condensing the reduced hydroxylamine intermediate with nitrile (Equation 31) <2001EJ0987>. 

Cyclization of cr-aryl-o-nitroacetanilides 56 to quinoxaline A-oxides has been reported independently by three groups.66-68 Thus treatment with ethanolic sodium ethoxide of 56 (R=R =H R2=Ph), synthesized from o-nitroaniline and PhCH2COCl, gives l,2-dihydro-2-oxo-3-phenyl-quinoxaline 4-oxide (57 R=R =H, R =Ph). 

The synthesis of quinoxaline A-oxides from benzofurazan 1-oxides, and by N-oxidation of the corresponding substituted quinoxaline derivatives, has already been discussed (Sections II,D and III,C, respectively). 

There are several reports of the deoxygenative halogenation of quinoxaline A-oxides. Thus, 3-(o-hydroxyphenyl)quinoxaline 1-oxide with sulfuryl chloride furnishes 2-chloro-3-(o-hydroxyphenyl) quinoxaline,51 and 2,3-diphenylquinoxaline 1-oxide with phosphoryl... 

The UV spectra of substituted quinoxaline A-oxides 250 have been calculated and also observed experimentally,249 and the effect of solvent... 

A nitrogen common to two rings was obtained by cycloaddition of phenyl isocyanate to 3-picoline TV-oxide.126 Isomeric products 37 and 38 were obtained, the first predominating. Phosgene, acting on an amino-quinoxaline A-oxide, gave a comparable fused ring system.127 Hamana... 

Related 1,3-oxazepines have been obtained from irradiation of many other heterocyclic A-oxides including pyridine A-oxides, isoquinoline A-oxides, quinoxaline A-oxides, quinazoline A-oxides, phenanthridine A-oxides, benzophenazine A-oxides, and acridine A-oxides.4 However, the reported yields are variable and have generally been higher for phenyl and other aryl-substituted derivatives. 

In quinoxaline A -oxides, ring substituents show enhanced reactivity towards nucleophilic substitution relative to the unoxidized compounds, in particular in the position a to the 7V-oxide moiety. 

The synthesis of quinoxaline A-oxides by intramolecular cyclization was first reported by Tennant. ... 

From Benzofuroxan to Quinoxaline A -Oxides or Quinoxaline Di-A -Oxides (the Beirut Reaction)... 

Quinoxaline A -oxide is resistant to nitration with concentrated sulfuric acid and fuming nitric acid at 100... 

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