Quinoxalines 1,4-dioxides

The Beirut reaction involves the condensation of benzofurazan oxide (BFO) 1 with an enamine 2 or an enolate anion 3 in an alcohol solvent to give the corresponding quinoxaline-1,4-dioxide 4. ... 

In 1965, Haddadin and Issidorides, at the American University of Beirut, observed that combining 1 with morpholinocyclohexene 5 in methanol afforded quinoxaline-1,4-dioxide 6 in 48% yield." Shortly thereafter, the same authors reported that 1 also reacts with 1,3-dicarbonyl compound 7 in the presence of triethylamine to give the quinoxaline-1,4-dioxide 8 in 38% yield. This reaction has been referred to in the chemical literature as the Beirut reaction to acknowledge the city in which it was discovered. 

There is some debate in the literature as to the actual mechanism of the Beirut reaction. It is not clear which of the electrophilic nitrogens of BFO is the site of nucleophilic attack or if the reactive species is the dinitroso compound 10. In the case of the unsubstituted benzofurazan oxide (R = H), the product is the same regardless of which nitrogen undergoes the initial condensation step. When R 7 H, the nucleophilic addition step determines the structure of the product and, in fact, isomeric mixtures of quinoxaline-1,4-dioxides are often observed. One report suggests that N-3 of the more stable tautomer is the site of nucleophilic attack in accord with observed reaction products. However, a later study concludes that the product distribution can be best rationalized by invoking the ortho-dinitrosobenzene form 10 as the reactive intermediate. 

In the case of unsubstituted BFO 1 reacting with an enamine, the following mechanism is generally accepted in the literature. The first step is nucleophilic addition of an enamine 2 to electrophilic BFO 1 to form the intermediate 12. Ring closure occurs via condensation of the imino-oxide onto the iminium functionality to give 13. Finally, P-elimination of the dialkyl amine produces the quinoxaline-1,4-dioxide 4. 

Quinoxaline 1,4-dioxides have also been prepared by condensation reactions carried out on the surface of solid catalysts such as silica gel, " molecular sieves, " or alumina. " As a representative example, " BFO 1 and the P-dicarbonyl compound 16 were combined with silica gel in methanol. The excess methanol was removed by evaporation and the silica gel with adsorbed reagents was allowed to stand for two weeks without drying. The quinoxaline 1,4-dioxide 17 was obtained in 90% yield after elution from a silica gel column. 

BFO reacted readily with 1,3-diketones to give 2,3-disubstituted quinoxaline 1,4-dioxides. In the case of unsymmetrical 1,3-diketones, mixtures of isomeric quinoxaline dioxides were obtained, and the ratio of isomers was influenced by the steric bulk of the carbonyl substituent. When BFO 1 was combined with 1,3-diketone compounds 18 in the presence of triethylamine, the isomeric quinoxaline 1,4-dioxides 19 and 20 were obtained. When R = Me, 19 was the only product observed. As the steric bulk of R increased, increasing amounts of isomer 20 were observed. When R = tBu, 20 was the only product detected in the reaction. 

BFO 1 also reacted with 2-acetylbutyrolactone 21 to give the quinoxaline 1,4-dioxide 22 (n = 2) containing a primary hydroxyl group, which can be further... 

Heteroaromatic substituents can be incorporated onto the quinoxaline 1,4-dioxide ring system by condensing BFO with the appropriately substituted enamine, cyanomethyl, or 1,3-dicarbonylcompound. 2-Cyanomethyl-l,3-benzothiazole 27 reacted readily with BFO 1 in the presence of potassium carbonate to give the quinoxaline 1,4-dioxide 28 in good yield. 

The authentic quinoxaline AT -oxide (108) is prepared from quinoxaline 1,4-dioxide by the following route ... 

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxanie) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-A -oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

Benzoxadiazole 1-oxide (481) with 3-acetyltetrahydro-2-furanone (2-acetyl-butyrolactone 482) gave 2-(2-hydroxyethyl)-3-methylquinoxaline 1,4-diox-ide (483) (KOH, MeOH-HaO, 20°C, 24 h 50%) but with 2-acetylacetaldehyde dimethyl acetal (484), in the presence of morpholine as base, it gave 2-(2-morpholinovinyl)quinoxaline 1,4-dioxide (485) (PhH, reflux, water separation, 9 h 47%) ... 

The same substrate (494) gave 2-(2-diethylaminovinyl)quinoxaline 1,4-dioxide (496) (Et2NCH=CHCH=CH2, Et20, 20°C, 4 h 80%) analogs with or... 

Several of these oxadiazoloquinoxaline 5-oxides have been converted into quinoxaline 1,4-dioxides. For example, 2-oxo-2//-[l,2,4]oxadiazolo[2,3-a]quinoxa-line-4-carbonitrile 5-oxide (572) in refluxing ethanol or 2-propanol for 2 h gave 3-ethoxycarbonylamino- (573, R = Et) or 3-isopropoxycarbonylamino-2-quinoxa-linecarbonitrile 1,4-dioxide (573, R = Pr ) in 61% or 74% yield, respectively 10 other analogous products with 6- and/or 7-substituents were made unambiguously in a similar way. ... 

Benzyl-3-phenylquinoxahne 1,4-dioxide afforded 2-(a-bromobenzyl)-3-phenyl-quinoxaline 1,4-dioxide (162) (Bf2, AcOEt, reflux, 4h 70%). " ... 

Bis(hydroxymethyl)quinoxaline 1,4-dioxide (dioxidine 173, R = H) and methyl isocyanate gave 2,3-bis(A(-methylcarbamoyloxymethyl)quinoxaline 1,4-dioxide (173, R = CONHMe) (for details, see original). 

Quinoxaline gave quinoxaline 1,4-dioxide (235) (AcOH, AC2O, 30% H2O2... 

Quinoxaline 1,4-dioxide (282) gave 2-quinoxalinecarboxamide (283) (neat HCONH2, 200°C, 1 h 30%, after separation from other products) other simple quinoxalinecarboxamides were made similarly but all in <10%... 

Quinoxaline 1-oxide gave complexes with the chlorides of Cr, Mn, Fe, Co, Ni, Cu, and Zn also with the perchlorates of the same metals. Quinoxaline 1,4-dioxide gave complexes with the chlorides of Cr, Mn, Fe, Co,... 

Quinoxalinecarbaldehyde 1,4-dioxide (178) gave its acetal, 2-(diethoxy-methyl)quinoxaline 1,4-dioxide (179) (HCl gas/EtOH, reflux, 1 h 47%) and thence the corresponding hydrate 2-(dihydroxymethyl)qumoxalme... 

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