2- quinoxaline 4-oxide cyclization

Benzylidenehydrazino-3-methoxyquinoxaline (273) underwent oxidative cyclization to 4-methoxy-l-phenyl[l,2,4]triazolo[4,3-fl]quinoxaline (274) [Cu(OAc)2, AcOH, reflux, 1 h 80% " tetrachlorobenzoquinone, CICH2CH2 Cl, reflux, 90 min 92% " analogs by both procedures]... 

Thus, the substituted tetrazoles 113 upon oxidation with lead tetraacetate gave rise to the fused tetrazoles 114, in most cases in high yields. Tetrazole derivatives 115, bearing an anisidine side chain, also underwent oxidative cyclization and afforded 10-methoxycarbonylmethyltetrazolo[l,5- ]quinoxaline 116 in good yield. This compound was obtained as a mixture of tautomers (with participation of the methylene hydrogen atoms) and the depicted tautomeric form 116 proved to be dominant. 

Less common methods of synthesis include nitrosation of suitable alkenes in acetonitrile solution (see Section 3.02.8.1.3(ii)) <84TLI319>, cyclization of iV-alkoxy ureas <87S1058>, and specific approaches to benzimidazole oxides from quinoxaline oxides, and to imidazole oxides from oxa-diazine and pyrazine oxides <93CHE127>. 

The diamine 34 (R = H) on heating as its dihydrochloride gave a 58% yield of the 5,10-dihydro derivative 35 (R = H), which was oxidized to the aromatic parent heterocycle using hydrogen peroxide. Although the methyl compound 34 (R = Me) could also be converted into the corresponding pyrido[3,4-h]quinoxaline, attempted cyclizations of the methoxy analogue 34 (R = OMe) were unsuccessful. 

Keywords o-Phenylenediamines, aldehydes, MnFe204-NP, methanol, room temperature, oxidative-cyclization, chemoseletivity, 2-substituted benzimidazoles, quinoxalines... 

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). 

Reaction of commercially available 3-chlorotetronic acid 762, obtained by pyrolysis of methyl 2,4-dichloroacetoacetate at 140 °C in vacuo [235], with o-phenylene-diamine affords, after cyclization-oxidation with AgOAc, the quinoxaline lactone 763 in 69% yield [234] (Scheme 5.83). 

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>. 

The iV-( -nitrophcnyl)pipcrazinc-2-carbonitrilc 251 (Y = NBOC) was reductively cyclized to the tricyclic /V-oxides 252 (Y = NBOC) either by catalytic hydrogenation, or by electrochemical reduction. Electrochemical reduction gave lower yield. Compounds 251 were prepared by electrochemical cyanation of the iV-(o-nitrophenyl)piperazine 250. The jV-oxides 252 were further hydrogenated to the 2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2- ]quinoxaline 253 (Y = NBOC) (Scheme 46) <2001EJ0987>. 

In a different type of cyclization, the pyrazolo[3, 4 5,6]pyridazino[3,4-A]quinoxalin-3-one 83 results from the oxidation of the n-hydroxyhydrazide 82 (Scheme 26) <2005JHC551>. 

Scheme 3) <05TL2189>. However, in this case the reaction did not afford the expected DA adduct, the product being the porphyrin derivative 10 resulting from the tetradehydrogenation of the corresponding adduct. The porphyrin derivative 11 was also obtained although in minor amount this product must result from a cyclization reaction between the beta-fused quinoxaline ring and the adjacent maso-aryl group. Also, bisadducts 12 and 13 were isolated these are the result of site specific bisaddition to opposite pyrrolic rings followed by oxidative processes.

The synthesis of an interesting mesoionic [l,2,4]triazolo[4,3- ]quinoxaline derivative shown in Scheme 53 is noteworthy. A Korean-Japanese team described the treatment of an iV-methylhydrazinoqionoxaline-A7-oxide 425 by isocyanates to give a semithiocarbazide 426 which upon heating underwent cyclization to the thiolate 427 in medium to good yields <1997JHC1539>. 

Intramolecular deoxidative nucleophilic substitution of 2-(Tmethylhydrazino)quinoxaline 4-oxides 62 to tricyclic heteroaromatics has been extensively researched by Kurasawa e( al. <1995JHC1085, 2000JHC1257, 2002H(56)291, 2002H(58)359, 2003JHC837>. The cyclization consists of initial formation of hydrazone followed by nucleophilic... 

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). 

Quinoxaline 1-oxide (209) reacts with phenyl isocyanate to give 2-anilinoquinoxaline (210) together with 1,3-diphenyl-l-(2-quinoxalinyl)-urea (211) and cyclized oxidation product of the urea 212.215 2-Quinoxalinone 4-oxide (205) and its 1-methyl derivative undergo addition reactions, e.g., with phenyl isocyanate and benzyne to give compounds 214 and 216, respectively.216 These reactions are formulated as proceeding via the intermediate cycloadducts 213 and 215. Compound 216 has also been obtained by photolysis of 3-(o-hydroxy-phenyl)quinoxaline 1-oxide.51 1,3-Dipolar cycloaddition of quinoxaline... 

Since oximes are more stable to oxidation and often more available than the corresponding carbonyl compounds they also can be used as starting material for the cyclizations. For instance, quinoxaline-2-aldehyde oxime 49a as well as ketoxime 49b are converted by hydrazine in acidic medium into flavazoles 50 (Scheme 14) (01JHC829). Hydroxylamine, which is liberated in the first step, may act as a hydride ion acceptor. This minimizes using a large excess of arylhydrazine or any another oxidant. 

Imines 73, generated in situ from 2-aminoquinoxalines 72 and ketones in acetic acid, are transformed spontaneously into pyrrolo[2,3-Zt]quinoxalines 76 (Scheme 22) (02RCR707). The SNH cyclization seems to proceed by equilibrium amounts of enamine 74. Adducts 75 are oxidized, apparently, with air oxygen or cation 72H7... 

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