1.4- Dihydroquinoxaline

Benzene-1,2-diamine undergoes reaction with halomethyl phenyl ketones to give 3-aryl-l,2-di-hydroquinoxalines 1, ° or after oxidation 2-arylquinoxalines 2. ° 1,2-Dihydroquinoxalines can be readily oxidized with different reagents. 

The fusion of a benzene ring to pyrazine results in a considerable increase in the resistance to reduction and it is usually difficult to reduce quinoxalines beyond the tetrahydroquinoxa-line state (91). Two possible dihydroquinoxalines, viz. the 1,2- (92) and the 1,4- (93), are known, and 1,4-dihydroquinoxaline appears to be appreciably more stable than 1,4-dihydropyrazine (63JOC2488). Electrochemical reduction appears to follow a course anzdogous to the reduction of pyrazine, giving the 1,4-dihydro derivative which isomerizes to the 1,2- or 3,4-dihydroquinoxaline before subsequent reduction to 1,2,3,4-tetra-hydroquinoxaline (91). Quinoxaline itself is reduced directly to (91) with LiAlH4 and direct synthesis of (91) is also possible. Tetrahydroquinoxalines in which the benzenoid ring is reduced are well known but these are usually prepared from cyclohexane derivatives (Scheme 30). 

In spite of the usefulness of the Beirut reaction, mechanistically it is not well understood. It has been suggested that the first step involves the nucleophilic attack by the enolate or the enamine at N-3 of the benzofuroxan to yield an intermediate iV-oxide (Scheme 50) which subsequently undergoes tautomerism to an hydroxylamino derivative. This intermediate then cyclizes to the dihydroquinoxaline 1,4-dioxide. This suggestion has not been proven, and indeed there is evidence that benzofuroxan is in equilibrium with 1,2-dinitrosobenzene... 

Treatment of bis-lactim ether 420 with BuLi, then with cw-l,4-dichloro-2-butene in the presence of Nal afforded 3,4,9,9n-tetrahydro-6//-pyrido[l,2-fl]pyrazin-4-one (421) with 96% diastereomeric excess (97TA1855). Reaction of l,2-diphenyl-6-methyl-quinoxaline with 1,4-dichlorobutane in THF in the presence of Na at —78°C afforded a 3 1 mixture of 4a,5-diphenyl-9-methyl-l,2,3,4-tetrahydro-4a//-pyrido[l,2-n]quinoxaline and 4-(4-chlorobutyl)-2,3-diphenyl-6-methyl-1,4-dihydroquinoxaline (98JHC1349). 

Note These synthons will usually give hydroquinoxalines, but some such products may undergo aerial aromatization during the reaction or workup. 1,2-Benzenediamine (129) gave 2-phenyl-3,4-dihydroquinoxaline (130) (AcONa, MeOH, reflux, CH4I, 2 h 55% with unsymmetric analogs of substrate (129), two isomers resulted in each case and the kinetics of such... 

Benzenediamine (185) and benzoin (186) gave a separable mixture of 2,3-diphenyl-1,2-dihydroquinoxaline (187, R = Ph) and 2,3-diphenylquinoxaline (188, R = Ph) (dry mixture, microwave irradiation under reflux, 4 min 21% and 67%, respectively) in contrast, similar treatment with m,m -dichloro-benzoin gave only the aromatized product, 2,3-bis(m-chlorophenyl)quinoxa-line (188, R = C6H4Cl-m) (94%). ... 

Recent examples of this synthesis are of two types. The first involves condensation of the activated phenol, 2-amino-4,6-dinitrophenol (346a) with 2-dimethyl-amino-3,3-dimethyl-3//-azirine (346b) (in MeCN, 0°C- 20°C, A, 24 h) to afford a separable mixture of four products, one of which was 2-dimethylamino-3,3-dimethyl-5,7-dinitro-3,4-dihydroquinoxaline (346c) ( 20% yield) and another its hydrolysis product, 3,3-dimethyl-5,7-dinitro-3,4-dihydro-2(l//)-quinoxalinone (346d) ( 8%) the mechanism of such condensations has been discussed. ... 

Methyl- 3 -, 4 -dihydrospiro[pyrimidine-5(2//),2 (1 7/)-quinoxaline] -2,4,6( 1 //,3//)-trione (605) gave l-methyl-3-ureidocarbonyl-l,2-dihydroquinoxaline (606) (2M Na2C03, 15% H2O2, then AcOHj 74% two homologs similarly mechanism discussed). ... 

Methylquinoxaline with phenyUithium gave a separable mixture of 2-methyl-3-phenylquinoxaline (45), 2-methyl-3-phenyl-3,4-dihydroquinoxaline (46), and 2-methyl-2,3-diphenyl-1,2,3,4-tetrahydroquinoxaline (47) [PhLi (made in situ), Et20, <20°C, 90 min 20%, 45%, and 35%, respectively). 

Diiodoquinoxaline (53) and malononitrile gave the expected product (54) that was characterized as its oxidized counterpart, 5,8-bis(dicyanomethy-lene)-5,8-dihydroquinoxaline (55), confirmed in stmcture by X-ray analysis... 

A mixture of 2-methyl-3-methylene-7-nitro-4-phenyl-3,4-dihydroquinoxaline (97) and its quaternary perchlorate, 2,3-dimethyl-6-nitro-l-phenylquinoxali-nium perchlorate (98), underwent oxidative coupling to give l,2-bis(3-methyl-6-nitro-1 -phenyl-1,2-dihydroquinoxalin-2-ylidene)ethane (99) [Cu-(OAc)2, AcOH-MeCN, 95°C, 20 min 60%] many such condensations... 

Dimethyl-6-nitro-l-phenylquinoxalinium perchlorate (103) gave 2-methyl-3-methylene-7-nitro-l-phenyl-3,4-dihydroquinoxaline (104) (EtsN, AcMe,... 

Diphenylquinoxaline gave 2,3-diphenyl-l,2-dihydroquinoxaline (205) (TiCls, EtOH, 20°C, N2, 18 h 70%) and thence 2,3-diphenyl-l,2,3,4-tetra-hydroquinoxaline (206) (similar treatment 64%, as a mixture of cis- and frani-isomers) 1-benzyl-3-phenylquinoxalinium bromide (207) gave 1-benzyl-3-phenyl-l,2-dihydroquinoxaline (208) (TiCls, H2O, 20°C, 1 h 92%). ... 

Among the recently (as of 2003) described reactions of such quaternary salts, reduction to dihydroquinoxalines has been exemplified toward the end of Section 2.2.4 treatment of the diquaternary compound, 1,4,6,7-tetramethylquinox-alinediium bis(tetrafluoroborate) (215), with sodium iodide gave a well-characterized product that appears in X-ray studies to have the cation radical structure (216) ""° and a fundamental spectrophotometric study on the addition of hydroxyl and methoxyl ions to the 1-methylquinoxalinium cation has been reported. ... 

Methylquinoxalinium iodide (217) with diethylamine gave 2-diethylamino-1-methyl-1,2-dihydroquinoxaline (218) (EtaO, 20°C, 5 min 91%) and thence either 5-methyl-l,2,3,4,4a,5,10,10a-octahydropyrazino[2,3-/7]qui-... 

Note Such deoxygenation is usually accompanied by partial nuclear reduction. 3-phenyl-2(177)-quinoxalinone (90) gave 2-phenyl-3,4-dihydroquinoxaline (91) (LiAlH4, THF, N2, 0°C reflux, 24 h 65%). ... 

Methylthio-3,4-dihydroquinoxaline (44) and 2-benzimidazolamine (45) gave 2-(benzimidazol-2-ylamino)-3,4-dihydroquinoxaline (46) (Me2NCHO, reflux, 4 h 57% several analogs likewise)." ... 

Chloroquinoxaline and hydroxylamine hydrochloride (0.5 equiv) gave 2-(quinoxalin-2-yloxyimino)-l,2-dihydroquinoxaline (169) (Me2SO, Na2C03, 20°C, 24 h >80%, in two polymorphic forms, checked by X-ray analysis the mechanism clearly involved rapid aminolysis followed by (9-arylation). " ... 

Phenacyl-3-phenyl-l,2-dihydroquinoxaline (208) gave 2-phenylquinoxalme (HCl, MeOH, H2O, reflux, 15 min 53% acetophenone also isolated as its dinitrophenylhydrazone. Note that this is a passenger deacylation in the... 

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