Quinoxalines, from benzene derivatives

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). 

The reaction between aromatic 1,2-diamines and 1,2-diketones affords 2,3-disubstituted quinoxaline derivatives (see table below) " however, a number of hindered a-ketones fail to react. " Unsymmetrical diketones give mixtures of isomers whose ratio varies with the acidity of the medium in some examples. A mechanistic study of quinoxaline formation from benzene-1,2-diamine and benzil has been described." ... 

The preparation of quinoxaline derivatives carrying a substituent in the benzene ring requires suitably substituted o-phenylenediamines. These have been prepared by reductive cleavage (SnCl2) of appropriately substituted 2,1,3-benzoselenadiazoles (I9).21 Benzo-selenadiazoles, readily prepared from 1,2-diaminobenzenes and selenium dioxide, undergo halogenation at positions 4 and 7 and sulfonation at C-4. 5,6-Dichloro- 2,3-diphenylquinoxaline has been synthesized from benzil and l,2-diamino-3,4-dichlorobenzene, the diamine in turn was obtained from 4,5-dichloro-2,l,3-benzoselenadiazole.22... 

Reactions of 2-chloro- and 2,3-dichloroquinoxalines with carbanions give 2-quinoxalinyl ketones and 3-chloro-2-quinoxalinyl ketones, respectively e.g., 2-quinoxalinylacetophenone (151) from acetophenone anion.161 However, 2,3-dimethoxy- and 2,3-diethoxy-quinoxaline with methyl ethyl ketone and sodamide in anhydrous benzene give 2-amino derivatives rather than ketones.162... 

Only representative monofused benzene systems of pyridine, e.g. quinoline (3, 11 and 48) and isoquinoline (4-7, 12, 47 and 49), pyridazine, e.g. cinnoline (16 and 51) and phthalazine (17 and 52), pyrimidine, e.g. quinazoline (22-25, 29-30 and 55-56), and pyrazine, e.g. quinoxaline (35, 36 and 58) are presented with no effort directed towards the polybenzo derivatives or any benzo derivatives of the triazines. These latter compounds seem to be of less significance than those described and have been eliminated from a detailed discussion for the sake of brevity. 

Enantiopure A-protected a-aminoglyoxals are readily accessible by oxidation of a-diazo ketones, derived from amino acids using dimethyldioxirane, and their condensation with benzene-1,2-diamine in ethanol furnishes optically active quinoxalines in > 90% yield. 

A new series of quinoxaline derivatives have been efficiently synthesized with an environment-friendly catalyst, i.e., enzyme, mainly the laccase isolated from Ganoderma sp. rckk-02. This methodology provides an alternative route safest for the synthesis of quinoxalines. 1,2- and 1,4-Dihydroxy benzenes were used for the first time in the synthesis of quinoxalines (Kidwai et al. 2012) (Scheme 2.43). 

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