Quinoxaline substitution reactions

Electrophilic substitution reactions of unsubstituted quinoxaline or phenazine are unusual however, in view of the increased resonance possibilities in the transition states leading to the products one would predict that electrophilic substitution should be more facile than with pyrazine itself (c/. the relationship between pyridine and quinoline). In the case of quinoxaline, electron localization calculations (57JCS2521) indicate the highest electron density at positions 5 and 8 and substitution would be expected to occur at these positions. Nitration is only effected under forcing conditions, e.g. with concentrated nitric acid and oleum at 90 °C for 24 hours a 1.5% yield of 5-nitroquinoxaline (19) is obtained. The major product is 5,6-dinitroquinoxaline (20), formed in 24% yield. 

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. 

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. 

Reactivity dealt with in the following sections is limited only to that of the heteroaromatic ring of pyrazines, quinoxalines, and phenazines, but exceptionally the reactivity on the benzo moiety of quinoxaline and phenazine is described in the Section 8.03.5.3. In general, any type of substitution reaction on quinoxaline and phenazine should be more facile than with pyrazine because of the resonance stabilization effect of the additional benzenoid ring on the transition states leading to the products. 

Quinoxalines substituted in the 5- or 6-position generally follow the pattern of reactions expected for substituted benzene derivatives, although recently there have been reports of interesting and unexpected reactions with nucleophiles (see Section III, A,2 and references 85-90). 6-Methylquinoxaline is brominated in the side chain when treated with N-bromosuccinimide in carbon tetrachloride in the presence of azobisiso-butyronitrile, to form 6-bromomethylquinoxaline.182... 

Routes via o-aminophenylpyrroles present the most convenient syntheses of a wide variety of pyrrolo[l,2-a]quinoxalines. Thus reaction of the amino compound 6 with acetic anhydride in acetic acid gave the acetamido derivative which was cyclized with phosphoryl chloride to give the 4-methyl compound 7 (R = Me) in 56% yield. The 4-phenyl compound 7 (R = Ph) has been prepared similarly. An even more convenient synthesis of 4-aryl compounds is achieved by reaction of compound 6 with aromatic aldehydes to give the 4,5-dihydro derivatives These are readily oxidized to 4-arylpyrrolo[l,2-a]quinoxalines 9 with manganese dioxide. This approach may be carried out in one step by reaction of compound 6 with aromatic aldehydes (e.g., benzaldehyde) in the presence of cupric acetate. Reaction of the aminophenylpyrrole 6 with 90% formic acid gave pyrrolo[l,2-a]quinoxaline (7, R = H) directly in 98% yield. Pyrrolo[l,2-a]quinoxalines substituted in the l-position and the 7-position have also been prepared from appropriately substituted... 

The synthesis and spectral characterization of the high-melting (>300°C) fully substituted reaction product of (NPCl2)3 and 2-[2-(2-hydroxyphe-nyl)quinoxalin-3-yl]phenol has been reported. New hexakis(/i-phenylazo-o-allylphenoxy)cyclotriphosphazenes with mono- or disubstituted phenyl groups... 

The luminescence and excited state electron transfer reactions of (dppe)Pt S2C2(2-pyridine(ium))(H) and (dppe)Pt S2C2(4-pyridine(ium))(H) are dependent on the protonation state of the pyridine [30-35]. The switching on of the luminescence in these compounds results from a change in the ordering of the electronic transitions in the pyridine and pyridinium substituted complexes. Unlike the quinoxaline-substituted complexes, the neutral pyridine complexes have a lowest lying d-to-d transition, which leads to rapid nonradiative decay of the ILCT excited states. However, upon protonation the ILCT becomes the low-lying transition. The pyridinium complexes are room temperature lumiphores with emission from ILCT and ILCT excited states (see Table Ic). 

New heat-resistant polymers containing -iiitrophenyl-substituted quinoxaline units and imide rings as well as flexible amide groups have been synthesi2ed by polycondensation reaction of a dianainoquinoxaline derivative with diacid dichlorides (80). These polymers are easily soluble in polar aprotic solvents with inherent viscosities in the range of 0.3—0.9 dL/g in NMP at 20°C. AH polymers begin to decompose above 370°C. 

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. 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

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