Reactions of Quinoxaline A-Oxides

Several recent general papers on the properties of quinoxaline A -oxides have 

Some aspects of the deoxidative C-substitution of quinoxaline N-oxides (see Section 4.6.2.2 for cross-references) and the photoinduced rearrangement of quinoxaline dioxides into quinoxalinediones (see Section 4.5.1) have been discussed already. The remaining reactions of quinoxaline A -oxides are covered in the following subsections. 

---

Some minor reactions of quinoxaline A -oxides are illustrated in the following classified examples. 

Cycloaddition reactions of quinoxaline A-oxides and quinoxaline di-A-oxides have been reviewed. ... 

A particular class of quinoxaline A-oxides can be synthesized by a reaction sequence starting from condensation of anilines with a-oximino ketones (Scheme 50) <1998S1769>. The key step is oxidation of the oxime to an a-acetoxy nitroso group, which behaves as an electrophile leading to the formation of the quinoxaline ring. 

Studies of the reactions of quinoxaline N-oxides under Reissert reaction conditions have led to some very interesting and unusual results. Thus, treatment of quinoxaline IV-oxide with PhCOCl/KCN in methanol or water under standard Reissert conditions gave 6-chloroquinoxaline as the major product (ca. 45%), and only small amounts of the desired 2-cyanoquinoxaline. Use of 3 equivalents of TMSCN in place of KCN and dichloromethane as solvent, however, gave 2-cyanoquinoxaline in 72% yield. When 2,3-diphenylquinoxaline iV-oxide was treated with 1 equivalent of PhCOCl in the presence of 3 equivalents of either KCN or TMSCN a mixture of products was always obtained irrespective of the solvent used. The most interesting of these products was the ring cleaved compound 1. 

A mixture of 2- and 6-chloroquinoxalines is obtained by reaction of quinoxaline 1-oxide with phosphoryl chloride, sulfuryl chloride, or acetyl chloride (Scheme 12). Reaction with benzenesulfonyl chloride gives a... 

Other lH-2,3-dihydro 2-oxo compounds have been prepared by more specialized routes. Reaction of quinoxaline N-oxide (61) with phenyl isocyanate gives a mixture of anilinoquinoxaline 62 and the (presumably) derived diphenyl oxo compound 63. Recently it has been shown that the alloxazine derivative (64) on treatment with di-n-butylamine undergoes a Lossen rearrangement to give the 2-oxo compound 65. Alkali treatment of compound 65 gives the 1,3-unsubstituted product 59. 

It was also reported that the use of quinoxaline A-oxide gives rise to coupling in even a higher yield than the parent indole-pyridine coupling reaction (Scheme 8) [26], The coupling reactions with isoquinoline, phthalazine, and pyrimidine A-oxides proved to proceed smoothly, and their regioselective outcomes were found to be consistent with the parent coupling reaction. 

Quinoxaline A-oxides undergo rearrangement under a variety of conditions. Thus on treatment of 2-ethoxy- and 2-methoxy-quinoxa-line 4-oxide with hydrochloric acid, rearrangement and hydrolysis occurs to give quinoxaline-2,3-dione. A possible intramolecular mechanism of rearrangement is shown in Scheme 7. Reaction of 2,3-... 

These major routes to quinoxalmecarbonitriles have been covered already by primary synthesis (Chapter 1), by cyanalysis of halogenoquinoxalines (Section 3.2.5), by deoxidative cyanation of quinoxaline N-oxides (Section 4.6.2.2), by cyanolysis of nitroquinoxalines (Section 6.1.2.2), from primary quinoxalina-mines by a Sandmeyer-type reaction (Section 6.3.2.3), from quaternary ammonio-quinoxalines with cyanide ion (Section 6.3.2.4), and by dehydration of quinoxalinecarboxamides (Section 7.4.2). Those remaining preparative routes that have been used recently are illustrated in the following examples. 

The reaction provides access to a number of quinoxaline-1,4-dioxide derivatives, by reaction of the benzofurazan oxide with 1,3-diketones, 3-ketoesters, enals, enamines, phenols and a, 3-unsaturated ketones. 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzo-furazan oxide (171) with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Earlier developments to 1981 were surveyed by Porter <84CHEC-I(3)157>, and later progress has been reviewed by Haddadin and Issidorides <93H(35)1503> who first demonstrated this reaction. Dienamines and azadienes (172) also react with benzofurazan oxide to yield... 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides. A methoxy group is also displaced with phosphoryl chloride to yield chloropyrazine when the period of reaction is prolonged or the reaction is carried out at higher temperatures <78JHC665>. Chloro- and bromopyrazine N-oxides are obtained by diazotization of aminopyrazine A-oxides in concentrated hydrochloric acid and hydrobromic acid, respectively (see Section 6.03.5.4.2). 

Quinoxaline 1-oxide (32) can be reduced to the parent base by hydrogenation in the presence of a Raney nickel catalyst or by treatment with phosphorus tribromide. Reaction of the N-oxide with acetic anhydride gives initially a mixture of quinoxaline (33) and quinoxalin-2-one (34) but on more prolonged reaction a third product, l-(2-quinoxalinyl)-quinoxalin-2-one (35), is formed. ... 

Reaction of quinoxalin-2(lH)-one 4-oxide (33) with potassium cyanide gives the cyanoquinoxalinone 35. The latter compound may be converted into the amide 36 by treatment with hydrogen chloride in acetic acid. The amide can be converted into the corresponding acid by reaction with warm aqueous acetic and sulfuric acids. A smilar sequence of reactions is not possible with the N-methyl compound 34 because in this case aqueous potassium cyanide treatment gives the quinoxalinedione 37. ... 

Habibi D, Nematollahi D, Meshldnghalam S, Varmaghani E (2014) An unexpected oxidative decarboxylation reaction of 2,3-dihydroxybenzoic acid in the synthesis of new dibenzylte-trahydroquinoxalinediones. Tetrahedron 70 4361-4366. doi 10.1016/j.teL2014.04.077 Haddadin MJ, Issidorides CH (1976) Application of benzolurazan oxide to the synthesis of heteroaromatic A-oxides. Heterocycles 4(4) 767-816. doi 10.3987/R-1976-04-0767 Haddadin MJ, Agopian G, Issidorides CH (1971) Synthesis and photolysis of some substituted quinoxaline di-A-oxides. J Org Chem 36(4) 514-518. doi 10.1021/jo00803a005 Haddadin MJ, Bitar H, Issidorides CH (1979) Synthesis and some reactions of o-nitrosoaniline. 

Quinoxaline A -oxides were generated in a metal-free reaction through a dehydrogenative cychzation between imines and tert-butyl nitrite (Scheme 3.66) [72], The reaction was significantly accelerated in the presence of TBAB, and an assortment of imines were successfully converted into the heterocycles. One of the attractive aspects of this chemistry was the ability to carry out the reactions in air. It should also be noted that the reactions were extremely fast and high yields of the desired Af-oxides were obtained in 15 min at room temperature. 

Pyrazine and quinoxaline fV-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine fV-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine fV-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

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. 

Perhaps one of the most exciting developments in the chemistry of quinoxalines and phenazines in recent years originates from the American University of Beirut in Lebanon, where Haddadin and Issidorides first made the observation that benzofuroxans undergo reaction with a variety of alkenic substrates to produce quinoxaline di-AT-oxides in a one-pot reaction which has subsequently become known as the Beirut reaction . Many new reactions tend to fall by the wayside by virtue of the fact that they are experimentally complex or require starting materials which are inaccessible however, in this instance the experimental conditions are straightforward and the starting benzofuroxans are conveniently prepared by hypochlorite oxidation of the corresponding o-nitroanilines or by pyrolysis of o-nitrophenyl azides. 

The reaction of isobenzofuroxan (131) with the morpholine enamine of cyclohexanone results in a 1,4 cycloaddition to form quinoxaline-di-N-oxide 132 (777). Quinone dibenzenesulfonimide has been found to undergo... 

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. 

---