Reduced Quinoxalines

This chapter updates the earlier review in Simpson s monograph except that consideration of l,2-dihydro-2-oxoquinoxalines and 1,2,3,4-tetrahydro-2,3-dioxoquinoxalines has been transferred to Chapter V, which deals with quinoxalin-2-ones and quinoxaline-2,3-diones.  

Reduction of quinoxaline with sodium in tetrahydrofuran, or elec-trochemically in an alkaline medium, gives 1,4-dihydroquinoxaline. This is described as a white, insoluble compound of m.p. 158-159°, and it is thought to be a 1,4- rather than a 1,2-dihydro compound because reaction with methyl magnesium iodide shows that it contains approximately 1.8 atoms of active hydrogen per molecule. 

A systematic study of the electrochemical reduction of 2-methyl-, 2,3-dimethyl-, 2-phenyl-, 2,3-diphenyl-, and 2-methyl-3-phenylquinoxaline in alkaline or neutral media has been made. For example, reduction of 2-methylquinoxaline in either an alkaline or neutral medium gives 1,2-dihydro-3-methylquinoxaline at pH 9 and a higher reduction potential, 

4- dihydro derivatives. The driving force for rearrangement is the formation of a more conjugated system. Further reduction then gives a 

2-Dihydroquinoxalines are formed in the photochemical reactions of quinoxalines with diethyl ether, tetrahydrofuran, and dioxan in the presence of benzophenone. Thus reaction of 2,3-dimethylquinoxaline and tetrahydrofuran yields the product 1 of 1,2-addition. With 2-t-butyl-quinoxaline a mixture of the diastereoisomers resulting from addition to the 3,4-bond is formed but with quinoxaline itself, 2-substituted quinoxalines are produced. These are thought to arise from autoxidation of the intermediate 1,2-adducts.  

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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). 

This is by far the most used type of primary synthesis for quinoxalines. It usually involves the cyclocondensation of an o-phenylenediamine (or closely related substrate) with a synthon containing an oxalyl [—C(=0)—C(=0)—] or equivalent [e.g., HC(=0)—C=N] grouping. For convenience, discussion of this synthesis is subdivided according to the type of synthon used to produce formally aromatic quinoxalines the formation of similar ring-reduced quinoxalines (mostly from related synthons at a lower oxidation state) is included in each such category. 

Although useful, this synthesis of reduced quinoxalines has not been fully developed yet. 7-Azabicyclo[4.1.0]heptane (423, R = H) and glycine (424, Q = H) in refluxing aqueous ammonium chloride for 90 min gave octahydro-2(l//)-quinoxalinone (425, Q = R = H) in 40% yield." Similar treatment of 7-methyl-7-azabicyclo[4.1.0]heptane (423, R = Me) gave l-methyloctahydro-2(l//)-quinox-alinone (425, Q = H, R = Me) in 62% yield and 7-methyl-7-azabicyclo[4.1.0] heptane (423, R = Me) with L-alanine (424, R = Me) in refluxing aqueous ammonium chloride for 16 h gave two separable diastereoisomers of 1,3-dimethylocta-hydro-2(l//)-quinoxalinone (425, Q = R = Me), isolated as hydrochlorides in 26%... 

Recently reported physical data for quinoxaline and its salts etc are collected under quinoxaline in the Appendix (Table of Simple Quinoxalines), at the end of this book. More notable studies on the properties of quinoxaline or reduced quinoxaline are briefly indicated here with references. 

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. 

The M-acylation of primary or secondary amino groups attached to quinoxaline or the ring NH group(s) of reduced quinoxalines can be done for several reasons, one of which is subsequent intramolecular cyclization (see Section 6.3.2.5). The following examples illustrate such acylations and related processes. 

The foregoing processes are illustrated in the following examples, not including the 1/4-alkylation of reduced quinoxalines that has been discussed in Section 2.2.2. 

It should be noted that, as all carbon positions in pyrazine are identical, the locant 2- in a monosubstituted derivative is unnecessary. All possible reduced derivatives of pyrazine 1, and several of those of its benzo analogues quinoxaline 2 and phenazine 3, are known. There are four dihydropyrazines, the 1,2-, 2,3-, 1,4-, and 2,5-isomers, two tetrahydropyrazines, the 1,2,3,4- and 1,2,3,6-, and hexahydropyrazine or piperazine, the last of which is omitted in this chapter. The reduced quinoxalines are the 1,2- and 1,4-dihydro compounds and 1,2,3,4-tetrahydroquinoxaline. The only known reduced phenazine is 1,4-dihydrophenazine. Hydroxypyrazine 4 and hydroxyquinoxaline 6 have been shown to exist in the tautomeric amide form by spectral studies, and therefore they are formulated as 2(1//)-pyrazinone 5 and 2(l//)-quinoxalinone, respectively. In contrast, aminopyrazine and aminoquinoxaline exist as described in the amino rather than the imino forms (Figure 1). 

The 1,5-benzodiazepine 40 on irradiation in benzene under oxygen undergoes oxidative ring contraction to 2-benzoyl-3-methyl-quinoxaline.42 Similarly, photolysis of 7-chloro-2-methylamino-5-phenyl-3//-l,4-benzodiazepine-4-oxide (41) in benzene yields the N-benzoylquinoxaline 42. Related ring contractions of diazepines to reduced quinoxalines have also been observed.43... 

Bovine superoxide dismutase and catalase were purchased from Sigma Chemical Co., glutathione peroxidase from Boehringer Mannheim and quinoxaline from Fluka AG. The synthesis of 6,7-dimethylperin and its 7,8-dihydro derivative has been described before. 6,7-Dimethyl-5,6,7,8-tetra-hydropterin was prepared by controlled potential electrolysis a 0.1 M phosphate buffer pH 7.0 at a glassy carbon or a mercury pool cathode. After complete electrolysis the tetrahydropterin was used in situ. 1,2,3,4-Tetrahydroquinoxaline was prepared by reducing quinoxaline in dry ether with lithium aluminium hydride or in ethanol with solid sodium. ... 

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