Pyrazine Unsubstituted

N-Heterocycles Pyridine Pyrazines Unsubstituted, 2,3-Dimethyl, MARM ++ 2,5-Dimethyl-3-ethyl, Methyl, 2-Ethyl-6-methyl, 2,5-Dimethyl, 2-Ethyl-5-methyl, 2,6-Dimethyl, Acetylmethyl, 2-(2-Furyl), Ethyl, 2-Methyl-5-(methylethyl), Trimethyl Pyrroles 2-Acetyl, N-Methyl-2-furyl, 1-Formyl, 1-Furfury 1-2-formyl, 5-Methvl-2-formvl Trimethylpyrazine (TMPy) (RV = 0.989)... 

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. 

Protonation of pyrazine A-oxides takes place at the unsubstituted ring nitrogen as revealed by examination of their UV spectra and ionization constants in water. The same holds for unsubstituted quinoxaline A-oxide and the 3-amino derivative. Pyrazine and quinoxaline di-A-oxides are protonated at one A-oxide oxygen atom (74KGS1554). 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

Some of the ring expansion reactions discussed in Section 2.03.3.3.1 can be extended to five-membered heterocycles containing two or more heteroatoms. Reaction of imidazoles and pyrazoles with dichlorocarbene, for example, gives chloropyrimidines together with small amounts of chloro-pyrazines or -pyridazines, and oxidative ring expansion of 1-aminopyrazole with nickel peroxide gives 1,2,3-triazine (this, in fact, constitutes the only known synthesis of the unsubstituted triazine). There are, however, a number of interesting and useful transformations which are unique to five-membered polyheteroatom systems. 

The use of an unsubstituted heterocycle as a precursor in synthetic reactions is relatively rare. For this reason, the reaction described in Equation (120) is shown. Unsubstituted pyrazine 335 is first treated with bis(trimethylsilyl)-ketene acetals, followed by treatment with methyl chloroformate. The result is the nonaromatic products 336 <2005EJO3724, 2005TL3449>. 

Quantitatively, dimethylpyrazine production was also lower, suggesting fewer available carbonyl fragments or less desirable conditions exist for formation of dimethyl versus unsubstituted or methyl pyrazine. 

Quantitatively, dimethylpyrazine production was also lower, suggesting fewer available carbonyl fragments and mechanistically less desirable conditions exist for formation of dimethyl versus unsubstituted or methyl pyrazine. A linear relationship of hi< i correlation was found to exist between pH and the rate of formation of pyrazines, with r2 values of 0.974 and 0.999 for pyrazine and 2-methylpyrazine, respectively. Effect of pH on yield was investigated under standard conditions (2 hr heat treatment at 95°C). pH was found to have a great effect on yield, with a total of 13,000 ppb pyrazines produced at pH 9.0 and only 24 ppb at pH... 

Unsubstituted perhydropyrido[l,2-a]pyrazines were obtained by hydrolysis of the 2-(4-nitrosophenyl) (59CB1510), 2-ferf-butoxycarbonyl (96MIP4), and 2-ethoxycarbonyl derivatives [93JOC690 95JCS(P1)369]. 

Flash pyrolysis of 5,7-diphenyl-2,3-dihydro-1/7-1,4-diazepine (34, R = H) at 700°C in a vacuum afforded 2-phenylpyrazine (35) in 21% yield, after separation from a pyrimidine the methyl substrate (34, R = Me) also gave a small yield of the same product (35) and 6-phenyl-2,3-dihydro-17/-l,4-diazcpine gave some unsubstituted pyrazine.176,1698... 

Some typical examples of recently reported reactions of unsubstituted pyrazine are mentioned here but, for pragmatic reasons, those of piperazine are simply covered piecemeal in appropriate sections and may be accessed through the Index. 

The following classified examples illustrate the methods that have been used recently for C-alkylation of pyrazines and hydropyrazines (see also Section 3.1.3 for the alkylation of unsubstituted pyrazine). 

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