Of pyrazines

Miohaels C A, Tapalian C, Lin Z, Sevy E and Flynn G W 1995 Superoollisions, photofragmentation and energy transfer in mixtures of pyrazine and oarbon dioxide Faraday Discuss. 102 405-22... 

A different example of non-adiabatic effects is found in the absorption spectrum of pyrazine [171,172]. In this spectrum, the, Si state is a weak structured band, whereas the S2 state is an intense broad, fairly featureless band. Importantly, the fluorescence lifetime is seen fo dramatically decrease in fhe energy region of the 82 band. There is thus an efficient nonradiative relaxation path from this state, which results in the broad spectrum. Again, this is due to vibronic coupling between the two states [109,173,174]. 

Figure 9.33 shows examples of SVLF spectra obtained by tuning a frequency-doubled dye laser to the Og absorption band of the system of pyrazine (1,4-diazabenzene)... 

Interatomic distances calculated from the detailed analysis of rotational fine structure of the UV spectrum of pyrazine are in close agreement with those observed in (7) and (8), with the calculated bond lengths for C—C of 1.395, C—N 1.341 and C—H 1.085 A (60DIS(20)4291). Thermochemical data have provided a figure of 75 kJ moP for the delocalization energy of the pyrazine ring (B-67MI21400). 

The electron density at nitrogen in phenazine is intermediate between those of pyrazine and quinoxaline and the highest electron density on the carbon atoms of the benzene rings is at C-1 (with positions 4, 6 and 9 being equivalent). ... 

In deuterochloroform, pyrazine shows a single proton resonance at S 8.59 (72CPB2204). Vo, Vm and Vp values between pyrazine ring protons obtained from a number of pyrazine derivatives are 2.5-3, 1.1-1.4 and 0 Hz respectively, and these values do not appear to be affected by the nature of the ring substituents. Some substituent shielding parameters are shown in Table 1. 

The negative sign indicates a chemical shift value numerically smaller than that of pyrazine itself. 

Af-Oxidation of pyrazines appears to result in increased shielding of the a and a carbon resonances by 6-11 p.p.m., whereas the /3 and /3 carbon atoms are deshielded by 3-4 p.p.m., a trend similar to that observed with substituted pyridines. These results have been qualitatively explained in terms of resonance polar effects (80OMR(l3)l72). 

A large body of information is available on the UV spectra of pyrazine derivatives (B-61MI21400, B-66MI21400). Pyrazine in cyclohexane shows two maxima at 260 nm (log e 3.75) and 328 nm (log e 3.02), corresponding to ir->ir and n ir transitions respectively (72AHC(14)99). Auxochromes show similar hypsochromic and bathochromic shifts to those observed with the corresponding benzenoid derivatives. 

A feature eommon to the pyrazine, quinoxaline and phenazine ring systems is their remarkable stability in the mass speetrometer and in all eases with the parent heterocyeles the moleeular ion is the base peak. In the ease of pyrazine, two major fragments are observed at mje 53 and 26, and these fragments are eonsistent with the fragmentation pattern shown in Seheme 1. 

The oceurrence of a large number of pyrazines as flavouring or aroma eonstituents and as pheromones in extremely low coneentrations has led to mass spectrometry being the method of ehoiee for determining the gross struetural details of a pyrazine nueleus. The method appears to be generally applieable and relatively specifie and sensitive. 

Table 3 lists some of the basic physical properties of pyrazine, quinoxaline and phenazine (references are given in the main text). 

Table 3 Physical Properties of Pyrazine, Quinoxaline and Phenazine...

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... 

Many pyrazine and quinoxaline syntheses yield mono- or di-N-oxides (76H(4)769). The condensation of a-aminooximes with 1,2-diketones results in the direct formation of pyrazine mono-N-oxides. The a-aminooximes themselves are not easily prepared but 2-amino-2-deoxy sugars readily form the oximes, which have been condensed with glyoxal to yield the pyrazine 4-oxides (Scheme 18) (72JOC2635, 80JOC1693). 

In view of the known behaviour of pyrazines during nucleophilic substitution reactions, it comes as no surprise that anomalous reactions appear during nucleophilic substitution... 

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. 

Pyrazinones and quinoxalinones both play important roles in the chemistry of pyrazines and quinoxalines respectively, in that they are usually available by direct synthesis and serve as important starting points for halo derivatives, which in turn lead to a range of substitution products (e.g. see Section 2.14.3.3). 

In a series of detailed studies, Armand and coworkers have examined the electrochemical reduction of pyrazines (72CR(C)(275)279). The first step results in the formation of 1,4-dihydropyrazines (85), but the reaction is not electrochemically reproducible. The 1,4-dihydropyrazine is pH sensitive and isomerizes at a pH dependent rate to the 1,2-dihydro compound (83). The 1,2-dihydropyrazine then appears to undergo further reduction to 1,2,3,4-tetrahydropyrazine (88) which is again not electrochemically reproducible. Compound (88) then appears to undergo isomerization to another tetrahydro derivative, presumably (8, prior to complete reduction to piperazine (89). These results have been confirmed (72JA7295). 

The final reduction product of pyrazine, piperazine (89), is a stable compound which behaves as a typical diamine. It has found extensive use in medicinal chemistry as a linking agent and as a medicine in its own right for the treatment of helminths both in human and veterinary medicine. 

The fusion of a benzene ring to pyrazine results in a considerable increase in the resistance to reduction and it is usually difficult to reduce quinoxalines beyond the tetrahydroquinoxa-line state (91). Two possible dihydroquinoxalines, viz. the 1,2- (92) and the 1,4- (93), are known, and 1,4-dihydroquinoxaline appears to be appreciably more stable than 1,4-dihydropyrazine (63JOC2488). Electrochemical reduction appears to follow a course anzdogous to the reduction of pyrazine, giving the 1,4-dihydro derivative which isomerizes to the 1,2- or 3,4-dihydroquinoxaline before subsequent reduction to 1,2,3,4-tetra-hydroquinoxaline (91). Quinoxaline itself is reduced directly to (91) with LiAlH4 and direct synthesis of (91) is also possible. Tetrahydroquinoxalines in which the benzenoid ring is reduced are well known but these are usually prepared from cyclohexane derivatives (Scheme 30). 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

From the foregoing discussion it is evident that the most general methods for the synthesis of pyrazines, quinoxalines and phenazines fall into type A and type B categories, but other methods do exist. Although most of these are not of such general applicability, they are worthy of comment. 

Scarcely a single issue of Chemical Abstracts is published without reference to medicinal compounds containing the pyrazine or quinoxaline ring in some form, and hence it is impractical to list all applications of pyrazines, quinoxalines and phenazines. Some of the more important applications and natural products, particularly the more recent developments, are mentioned in this Section. 

Despite the fact that one of the first pteridine syntheses was based on an intramolecular Hofmann carboxamide degradation of pyrazine-2,3-dicarboxamide by action of potassium hypobromite and leads to lumazine (equation 104), (07CB4857), pyrazine derivatives in general have not often been used because of availability problems. The reaction of alkyl... 

This reaction gives good results for a variety of activated and unactivated alkyl halides [112] Oxidation of 2-bromoketones with iV-phenyltriflamide was used m a one pot synthesis of pyrazines by the sequence of reactions shown m equation 57 [II3] The procedure was successfully applied to the synthesis of deoxyaspergilhc acid [II4 ... 

The quaternization of pyrazine compounds has not been extensively studied, and, therefore, a detailed discussion of the effect of substituents is not possible. Recently Cheeseman has shown, from spectroscopic evidence, that 2-amino- and 2-diethylamino-pyrazine (50, Y = NH2 and NEt2) quatemize at N-4, although protonation occurs at position-1. Other substituted pyrazines from which quaternary salts of structure 51 are formed include 2-chloro- and 2-... 

A 1-pyridinium substituent has an activating effect on nucleophilic substitution of pyrazines and s-triazines. °... 

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