Of quinoxalines

The precise numerical values of the calculated electron densities are unimportant, as the most important feature is the relative electron density thus, the electron density at the pyrazine carbon atom is similar to that at an a-position in pyridine and this is manifest in the comparable reactivities of these positions in the two rings. In the case of quinoxaline, electron densities at N-1 and C-2 are proportionately lower, with the highest electron density appearing at position 5(8), which is in line with the observation that electrophilic substitution occurs at this position. 

The NMR spectrum of quinoxaline has been measured in CDCI3 and the chemical shift values are as shown in (16) (69JA6381). Curiously, C NMR spectra of phenazine and its derivatives have been recorded in benzene solution and the chemical shift values quoted relative to benzene however, for consistency the values in (17) are quoted relative to TMS. 

The UV spectra of quinoxalines have been examined in several solvents. In cyclohexane, three principal absorptions are observed (Table 2). In hydroxylic solvents the vibrational fine structure disappears and in methanol or water the weak n- ir transitions are obscured by the intense ir->ir transition (79HC(35)l). 

Table 2 Absorption Maxima of Quinoxaline in Cyclohexane (b-55MI2I400)...

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. 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Treatment of both pyrazine 1-oxide and quinoxaline 1-oxide with POCI3 results in the formation of the corresponding chlorinated derivatives (SO) and (SI). However, in the case of quinoxaline 1-oxide the 2-chloroquinoxaline is accompanied by 6-chloroquinoxaline (S2) (67YZ942). 

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. 

Direct halogenation of quinoxaline appears to be of limited value but pyrazine may be chlorinated in the vapor phase to give monochloropyrazine at 400 °C or at lower temperatures under catalytic conditions 72AHC(14)99, and at higher temperatures tetra-chloropyrazine formation occurs in high yields. Mention has already been made of direct chlorination (see Section 2.14.2.1) of 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. 

No practical type B syntheses of quinoxalines are commonly in use, largely because of the fact that type A syntheses are more facile however, some phenazine syntheses of this type are known, particularly those described in the older chemical literature. Hillemann (38CB42) has effected dimerization of 0-bromoaniline by heating its solution in nitrobenzene with K2CO3 and copper powder. The reaction is believed to proceed through the intermediacy of 5,10-dihydrophenazine, but the latter has not been isolated (Scheme 68). 

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. 

The predominance of the oxo forms of quinoxalin-2-one (125) and its 3-methyl derivative in aqueous solution was established by Cheese-man using the pK method, only a lower limit beii obtained for Kt (log Kt> 1.6 and 0.9, respectively) because similar cations are... 

Pyrazine-2-thione (213) and quinoxaline-2-thione (214) probably exist in the thione form since their ultraviolet spectra are different from those of the 2-methylthio analogs. The basicity of quinoxaline-2-thione is 1.4 pK units less than that of 2-methylthio-quinoxaline, and the ultraviolet spectra of the cations are dissimilar. Presumably quinoxaline-2-thione and its 2-methylthio derivative do not form similar cations (215, P = alkyl, H), and it would appear that either the thione gives the cation 216 or the 2-thioether gives the cation 217. Similar considerations apply to pyrazine-2-thione. 

A number of quinoxalines carrying substituents in the benzene ring base have been quaternized, including 5-ethoxy,6-methyl, 6-chloro, and some 2-phenyl derivatives, but in none of these cases has the position of quatemization been ascertained. 5-Hydroxy-quinoxaline gives a methiodide which can still form metal complexes, indicating that salt formation occurred on N-1. ... 

The effect of nuclear substituents on nucleophilic substitution of quinoxalines is included in Section II, E, and in section III, A,... 

C. Preparation of Quinoxalines Using a-Amino Acid Intermediates 210... 

The classical synthesis of quinoxalines involves the condensation of an aromatic o-diamine and an -dicarbonyl compound. 

C. Phepaeation of Quinoxalines Using a-AMiNO Acid Intermediates... 

This method is widely applicable to the unambiguous synthesis of quinoxalin-2-ones." It involves the intermediate preparation of a l,2,3,4-tetrahydro-2-oxoquinoxaline by the reductive ring closure of the o-nitrophenyl derivative of an a-aminoacid. These derivatives are formed readily from the aminoacid and an o-nitrohalogenobenzene. The final step of oxidation of the tetrahydro- to the dihydro-quinoxa-line is carried out with potassium permanganate or hydrogen peroxide. The preparation of 7-nitroquinoxalin-2-one illustrates the application of this synthesis ... 

A careful study of the phenylation of quinoxaline with benzoyl peroxide, various benzenediazonium salts, and A -nitrosoacetanilide indicates that the 2-position is most reactive to phenyl radicals and that the 5-position is more reactive than the 6. The yields of 2-, 5-, and 6-phenylquinoxaline are in the ratio of 40 10 1, Benzoyl peroxide and A—nitrosoacetanilide are the most effective phenylating reagents. 

Quinoxalines undergo facile addition reactions with nucleophilic reagents. The reaction of quinoxaline with allylmagnesium bromide gives, after hydrolysis of the initial adduct, 86% of 2,3-diallyl-l,2,3,4-tetrahydroquinoxaline. Quinoxaline is more reactive to this nucleophile than related aza-heterocyclic compounds, and the observed order of reactivity is pyridine < quinoline isoquinoline < phenan-thridine acridine < quinoxaline. ... 

Attempts to isolate 1,4-dihydroquinoxalinc itself were not successful, but the polarographic behavior of quinoxaline and 6-substituted quin-oxalines in buffered aqueous media suggests that in all cases reduction stops at the 1,4-dihydro stage/ - 2,3-Dimethylquinoxaline and 2-d-araho-tetrahydroxybutylquinoxaline show similar polarographic be-havior, ... 

Hydrogenation of quinoxaline, or 1,2,3,4-tetrahydroquinoxaline, over a 5% rhodium-on-alumina catalyst at 100°C and 136 atm, or over... 

In the preparation of quinoxaline N-oxides, it is advantageous to use peracetic acid rather than aqueous hydrogen peroxide as the... 

Substituents in the 2-position generally inhibit 1-oxide formation for example, oxidation of 2-alkoxy- ° and 2-carbethoxy-quinoxalines" furnishes the 4-oxides. Treatment of quinoxaline 2-carboxy-A -methyl-anilide (38) with 1 mole of peracetic acid gives the 4-oxide (39), and oxidation with excess of peracetic acid the 1,4-dioxide (40). ... 

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... 

The formation of quinoxaline quaternary salts is often difficult. However, reaction of quinoxaline with ethyl iodide in boiling acetonitrile gives ethyl quinoxalinium iodide in 76% yield, and treatment of the parent base with methyl toluene-p-sulfonate at room temperature gives methyl quinoxalinium toluene-p-sulfonate in quantitative yield. ... 

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