Quinoxaline derivatives

The structure of glucazidone, obtained by treatment of 2-D-araho-tetrahydroxybutylquinoxaline with sulfuric acid, is shown to be 2- (2 -furyl)quinoxaline (110), and not (111) as originally proposed. This follows from the synthesis of (110) from o-phenylenediamine and 2-furanglyoxal (109) 3-hydroxyglucazidone, obtained as a by-product in the preparation of glucazidone, is reformulated as 2- (3 -hydroxy-2 - 

Several quinoxaline analogs of pteroic acid (114) and pteroyl-glutamic acid (115) have been prepared. - Quinoxaline-2-aldehyde, 

Of this biologically very effective group, the carbonic acid derivatives of 2,3-dithioquinoxaline have proved to be the most active (Sasse et al.. 1960). The active compounds first became known as excellent acaricides (Unterstenhdfer, 1960 Sasse, 1960) because they were also effective against acarus species resistant to phosphoric compounds. At the same time, they have the valuable property of being toxic to powdery mildew fungi. 

Thioquinox (33), l,3-dithiolo[4,S-b]quinoxaline-2-thione, is primarily an acar-icide with mainly ovicidal properties. The compound is practically insoluble in water and is stable to the action of light and heat. It is also resistant to hydrolysis, and although sulfur is oxidised in the molecule, the biological action is not reduced. 

It is used as a contact fungicide on cucumber in greenhouse and in orchards against powdery mildew. 

The synthesis of quinomethionate starts with 4-methyl-1,2-phenylenediamine 

3-dithio derivative (38) obtained from it with sodium sulfide is converted with phosgene into the end-product. 

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This rapid formation of the crystalline quinoxaline derivative can therefore be used to identify 1,2-diketones conversely, a nuclear-substituted o-phenyl-enediamine can be identified by the quinoxaline derivative which it forms with a known 1,2-diketone such as benzil. 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

All heterocyclic enamines readily undergo condensation with o-amino-benzaldehyde. The quinoxaline derivatives thus formed have a characteristic yellow color. Therefore, this reaction can serve as evidence of the presence of an enamine in plants (295,309). 

Structure-activity studies of 5,6,7,8-tetrahdyro-5,5,8,8-tetramethyl-2-quinoxaline derivatives necessitated the preparation of thiophene-containing compound 17. Stetter conditions using thiazolium salt 20 as catalyst resulted in the preparation of 1,4-diketone 21 from 18 and 19. Condensation of 21 with phosphorus pentasulfide followed by saponification resulted in 17. In this fashion, the authors replaced the amide linker of parent compound 22 with the rigid thiophene moiety. 

Ring fusion seems to occur in the quinoxaline derivative (28), which has been stated to exist in red and blue-black forms. Other derivatives of type 28 are reported. Attempts to prepare 5,6-furo-xanobenzofuroxan by pyrolysis of the azide (29) met with no success. An early example in the literature of such a linear fused structure was shortly afterward revised to the angularly fused type (17). 

Denitrocyclization involving the primary amide group in 437 gave good yields of pyrrolo[l,2-<2]quinoxaline derivatives 438 (Eq. 39) (9ISC 1567). 

The condensation reactions of aromatic o-diamines and sugars and sugar derivatives have been studied in detail and quinoxaline derivatives have been prepared recently from osones, osonehydrazones, and dehydro-L-ascorbic acidd ... 

The electrolytic oxidation of quinoxaline at a copper anode gives pyrazine-2,3-dicarboxylic acid in excellent yield. A similar conversion may be effected with alkaline potassium permanganate, and a list of quinoxaline derivatives which can be oxidized with potassium... 

Quinoxaline Derivatives Which Can Be Oxidized to Pyrazine-2,3-dicarboxylic Acids on a Preparative Scale... 

The acidic strength of various quinoxaline derivatives is also listed in Table II. -Methyl groups have an acid-weakening effect and quinoxalin-2-one (2-hydroxyquinoxaline) is, as expected, a weaker acid than quinoxaline-2-thione (2-mercaptoquinoxaline), The marked enhancement of the acidic strength of 5-hydroxyquinoxaline 1-methiodide compared to 5-hydroxyquinoxaline itself, is due to the electron-attracting property of the positively charged nitrogen, ... 

Many furanones (including furanose carbohydrates) have been used as synthons with 1,2-benzenediamines to afford quinoxaline derivatives. The following examples illustrate the main types of such cyclocondensation reactions. 

GLANCE INDEX TO TYPICAL QUINOXALINE DERIVATIVES AVAILABLE BY PRIMARY SYNTHESES... 

Most of the chemical reactions of halogenoquinoxalines consist of facile nucleophilic replacements, thus making such substrates ideal intermediates for the preparation of aU kinds of other quinoxaline derivatives. Their conversion into alkyl- or arylquinoxalines has been discussed in Section 2.2.1.2 other reactions are outlined in the following subsections. 

This chapter covers not only nuclear and extranuclear quinoxahnecarboxylic acids (and anhydrides) but also the carboxylic esters, acyl halides, carboxamides, carbohydrazides, carbonitriles, carbaldehydes, and (ketonic) acyl derivatives of quinoxaline a few related speceis are also included. To avoid repetition, the interconversions of these quinoxaline derivatives are discussed only at the first opportunity thus the esterification of quinoxalinecarboxylic acids in covered as a reaction of carboxylic acids rather than as a preparative route to carboxylic esters, simply because the section on carboxylic acids precedes that on carboxylic esters. To minimize any confusion, appropriate cross-references have been inserted. 

Kleim J-P, Bender R, Billhardt U-M, Meichsner C, Riess G, Rosner M, Winkler I, Paessens A. Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication. Antimicrob Agents Chemother 1993 37 1659-1664. 

Invidiata and co-workeis developed another method to synthesize quinoxalines. Diketones 246 reacted with o-phenylenediamine to give 248, though in low yield. Interestingly, an alternative approach to the quinoxaline derivatives was devised employing the dioximes 247 which are easily prepared from monooximes 245. When 247 reacted with o-phenylenediamine in the presence of concentrated hydrochloric acid, product 248 was obtained in higher overall yield <00JHC355>. Direct conversion of 245 to 248 was also successful. 

Cyclization of 6-benzoyl-3-amino-2-imino-2,3-dihydrothiazolo[4,5-A quinoxaline 260 was achieved upon treatment with ethyl cyanoacetate in DMF/Et3N to yield [l,2,4]triazolo[3, 2 3,2]thiazolo[4,5- ]quinoxaline derivative 261 (Equation 34) <2000PS(157)87>. 

Many more results were reported in the area of the isomeric [l,2,4]triazolo[4,3-tf]quinoxaline derivatives. With one exception, however, all these studies applied known recognized ring-closure techniques for the synthesis of novel derivatives, in many cases of biological importance (cf. Section 11.16.8.) In Table 15, these derivatives are summarized together with the literature references. 

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