Pyrazines and Quinoxalines

Synthesis of the tricyclic pyrano[2,3-b] quinoxalines (Fig. 18) 102, with a hydroxymethyl function at the 2-position was described by reaction of o-phenylenediamine with phenylhydrazone derivatives of sugars [157]. 

The reaction of kojic acid with one and two equivalents of l,2-diamino-4,5-dimethylbenzene afforded 2-hydroxy-5,6-dihydro-8,9-dimethylpyrido[ 1,2-a] quinoxahne 103 and 2,3,10,1 l-tetramethyl-5,6-dihydro-13H-quinoxahno[2,  

Pyrazine is a colorless solid with a melting point of 54-55 °C and a boiling point of 115 °C. It turns to a light-amber color upon exposure to air and/or light. Pyrazine is miscible with water. 

Quinoxaline is a crystalline solid with a low melting point range 29-32 °C. TTiis diazine has a boiling point of 220 C and has a moderate solubility in aqueous solutions. It is isomeric with quinazoline, phthalazine, and cinnoline.  

Pyrazines, with 6 Ji-electrons, are cXoctron-d cient (also known as electron-poor) aromatic heterocycles because of the increased electronegativity of the nifrogen atoms. Due to the presence of the electronegative nitrogen atoms, the electron density on the ring carbons is less than one. The lone-pair electrons do not take part in the delocalization so this molecule can act as a mild base. 

Structurally speaking, pyrazine is a planar hexagon, similar to benzene, in both bond angles and lengths. As expected, the C-N bonds and C-N-C bond angles are shorter than their C-C and C-C-N counterparts. 

Due to its symmetry, the H-NMR of pyrazine in chloroform has a single peak at 8.87 ppm. The proton signal is further downfield than the traditional aromatic ring protons because of the increased electro-negativity of the neighbouring nitrogen atoms. As for the C-NMR, the sole signal is present at 144.9 ppm. 

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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). ... 

Conflicting reports on the nitration of phenazine have appeared, but the situation was clarified by Albert and Duewell (47MI21400). The early work suggested that 1,3-dinitroph-enazine could be prepared in 66% yield under standard nitration conditions however, this proved to be a mixture of 1-nitrophenazine and 1,9-dinitrophenazine (24). As with pyrazines and quinoxalines, activating substituents in the benzenoid rings confer reactivity which is in accord with valence bond predictions thus, nitration of 2-methoxy- or 2-hydroxy-phenazine results in substitution at the 1-position. 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

Although most of the reactions of preparative importance involving the a-alkyl carbanions are usually carried out under controlled conditions with NHa /NHs being used as the base, a number of reactions using less severe conditions are known, both in the pyrazine and quinoxaline series. In the case of alkylquinoxalines, where an increased number of resonance possibilities exist, mildly basic conditions are usually employed in condensation reactions. 

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

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). 

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. 

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). 

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 reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>. 

Reactivity of Nonconjugated Rings of Pyrazines and Quinoxalines. 7 Reactivity of Substituents Attached to Ring Carbon Atoms. 7.1 Carbon Substituents. 7.2 Nitrogen Substituents. 7.3 Oxygen Substituents. 7.4 Su Ifu r Su bstituents... 

Efforts in the 1990s toward the lithiation/trapping sequence for pyrazines and quinoxalines have been reviewed <2001T4489, B-2002MI2>. 

Pyrazino[2,3-fc]pyrazines365 and pyrazino[2,3-h]quinoxalines366 (230) are reduced similarly to pyrazines and quinoxalines to the 1,4- and 5,10-dihydro derivatives, respectively [Eq. (127)], with which they form reversible systems. 5,10-Dihydropyrazinoquinoxaline gives an ill-defined wave near the background discharge, but the structure of the product is unknown. 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of a-keto acids react selectively at the a- or y-position of the protonated heterocyclic nitrogen. Pyridines, quinolines, pyrazines and quinoxalines all react as expected yields are typically 40 to 70%. Similarly, pyridines can be carbamoylated in acid media at C-2 (Scheme 38). 

Introduction Pyrroles Indoles Pyridines Thiophenes and Benzo[b]thiophenes Furans and Benzo[b]furans Thiazoles and Benzothiazoles Oxazoles and Benzoxazoles Imidazoles Pyrazines and Quinoxalines Pyrimidines... 

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