Quinoxalines reduction

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

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). 

An early synthesis of pyrido[3,4-6]quinoxalines involved cyclization by strong heating of o-aminoanilinopyridinamine derivatives, e.g. (418) to give (419) (49JCS2540). In a related reaction, o-nitroanilinopyridines (420) were cyclized to pyrido-[2,3-6]- or -[3,4-6]-quinoxa-lines (421) by reduction with iron(II) oxalate, probably via a nitrene intermediate (74JCS(P1)1965). 

This method is widely applicable to the unambiguous synthesis of quinoxalin-2-ones." It involves the intermediate preparation of a l,2,3,4-tetrahydro-2-oxoquinoxaline by the reductive ring closure of the o-nitrophenyl derivative of an a-aminoacid. These derivatives are formed readily from the aminoacid and an o-nitrohalogenobenzene. The final step of oxidation of the tetrahydro- to the dihydro-quinoxa-line is carried out with potassium permanganate or hydrogen peroxide. The preparation of 7-nitroquinoxalin-2-one illustrates the application of this synthesis ... 

The nitration of 6-methoxyquinoxaline in concentrated sulfuric acid at 0°C gives 6-methoxy-5-nitroquinoxaline. The position of the nitro group is confirmed by reduction of the product to 5-amino-6-methoxy-quinoxaline identical with a sample prepared from 2,3,4-triamino-anisole and glyoxal ... 

Catalytic reduction of 2-acetyl-3-methylquinoxaline (29) in ethanol with 1 mole of hydrogen, gives a deep crimson solution, from which red-brown needles of 2-acetyl-l,4-dihydro-3-methylquinoxaline (30) are obtained. Ethanolic solutions of (30) reoxidize on exposure to air to 2-acetyl-3-methylquinoxaline, but the solid dye is stable in air for several days. Similar results are obtained with 2-acetyl-3-phenyl-quinoxaline (31), from the reduction of which a purple-red dye (32) is obtained. ... 

Attempts to isolate 1,4-dihydroquinoxalinc itself were not successful, but the polarographic behavior of quinoxaline and 6-substituted quin-oxalines in buffered aqueous media suggests that in all cases reduction stops at the 1,4-dihydro stage/ - 2,3-Dimethylquinoxaline and 2-d-araho-tetrahydroxybutylquinoxaline show similar polarographic be-havior, ... 

Tetrahydro derivatives are formed when either quinoxaline or 6-chloroquinoxaline is reduced with lithium aluminum hydride in ethereal solution. Similar reduction of 2,3-dimethylquinoxaline gives the meso-(cts)-1,2,3,4-tetrahydro derivative. This is shown to be a stereospecific reduction since lithium aluminum hydride does not isomerize the dl-(trans)-compound. Low temperature, platinum catalyzed, hydrogenation of 2,3-dimethylquinoxaline in benzene also gives meso (cis) -l,2,3,4-tetrahydro-2,3-dimethylquinoxaline. ... 

Catalytic hydrogenation or chemical reduction with concomitant cyclization has been used to convert several types of such nitro substrates into a variety of quinoxalines. The following examples, classified according to type of substrate, illustrate the possibilities available. 

Acetamido-5-methoxy-1,2-benzenediamine (prepared in situ by reduction of 1 -acetamido-2-methoxy-4,5-dinotrobenzene) gave 6-acetamido-7-methoxy-quinoxaline (104) (OHCCHO-2NaHS03 H20, 70°C, 2 h 96%). 4-Acetamido-2,3-diaminophenol (105) (prepared in situ by reduction of the 2,3-dinitro analog) gave 8-acetamido-5(l//)-quinoxalinone (106) (OHCCHO-2NaHS03-H20, reflux, Nji, 2 h 79%). °... 

Reduction of unsubstituted benzo[3,4]cyclobuta[l,2-/7]quinoxaline (526) with Raney nickel in refluxing ethanol during 30 min gave 2-phenylquinoxaline (527) in... 

Reduction of 7,8-diphenyl[l,2,5]oxadiazolo[3,4-/ quinoxaline (574) with sodium bis(2-methoxyethoxy) aluminum hydride in refluxing toluene for 1 h gave 2,3-diphenyl-5,6-quinoxalinediamine (575) in 64% yield. ... 

Pyrazolo[3,4-/>]quinoxalines can undergo ring fission under reductive or hydrolytic conditions to give different types of quinoxalme. The following examples illustrate these possibilities. 

Note The C-alkylation of quinoxaline has been done by addition (with or without subsequent aromatization see also preceding subsection), by reductive alkylation, or by homolytic alkylation. 

Quinoxaline gave l,4-diethyl-l,2,3,4-tetrahydroquinoxaline by indirect reductive alkylation (AcOH, KBHai, <15°C, 1 h, then reflux, 6h 87% presumably by nuclear reduction, A-acylation, and further reduction of the acetyl groups ). ... 

Although A-aUcyl- and A-arylpiperazines abound in the pyrazine literature, ° the corresponding reduced quinoxalines are rarely encountered. However, reductive alkylation of quinoxaline gave products such as l,4-diethyl-l,2,3,4-tetrahydroqui-noxaline (see Section 2.1.3), and several other typical preparative routes are illustrated in the following examples. 

Whether activated or not, halogeno substituents may be removed in favor of hydrogen by chemical reduction or by catalytic hydrogenation (usually in the presence of a base and often accompanied by nuclear reduction). Such dechlorination may also be achieved by loss of hydrogen halide from a nucleus-reduced quinoxaline. The following examples illustrate these procedures. 

However, at least two other minor routes have been used. Thus reduction of 2-hydroxyaminoquinoxaline (209) gave A, A -di(quinoxalin-2-yl)hydrazine (210) (CoCl2 -6H20, THF, reflux, 1 h % LiAlHa, THF, 20°C, 10 min 62%) and reduction of 2,2 -azoquinoxaline (211) gave the same product (210) (NiCl2 -6H20, MeOH, NaBH4 slowly, 20°C, 30 min 76% 1,2,3,4-tetrahydronaphthalene, reflux. 

Two reactions of quinoxalinecarboxylic esters have been covered already reduction to hydroxyalkylquinoxalines (Section 4.3.2) and hydrolysis to quinoxaline carboxylic acids (Section 7.1.1). Other reactions are illustrated in the following classified examples. 

The redox behavior of aminonaphthoquinones has been investigated by Matsuoka and co-workers.11 Reduction of quinoxaline quinone (40) by sodium dithionite in aqueous sodium hydroxide gives the corresponding leuco dye (41) which absorbs at 445nm. Compound 40 shows quinone-... 

Acetamido-5-methoxy-1,2-benzenediamine (prepared in situ by reduction of 1 -acetamido-2-methoxy-4,5-dinotrobenzene) gave 6-acetamido-7-methoxy-quinoxaline (104) (OHCCHO-2NaHS03H20, 70°C, 2 h 96%).282... 

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