Pyrazines, aromaticity

Nonbonded complexes. The equilibrium constants, enthalpies, and entropies for the weak complexation of pyrazine with dichloromethane, chloroform, or carbon tetrachloride have been determined from changes in the n — 77 absorptions of solutions at various concentrations (in cyclohexane) and temperatures 568 similar data for pyrazine-aromatic hydrocarbon complexes were obtained from variations in the H NMR chemical shift values.1037 The spectral effects of complexation with borane have been studied in the pyrazine diborane adduct and its methyl derivatives.254... 

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

In many instances the primary reaction product is a dihydropyrazine and aromatization may be required as a final step. In addition, many pyrazines are prepared by the structural modification of a preformed pyrazine ring and hence would be classified as a reaction of the ring rather than a ring synthesis such processes are discussed more fully in Section 2.14.2. 

Classically, type B pyrazine syntheses involve self-condensation of an a-aminoacyl compound to yield a 3,6-dihydropyrazine which is subsequently oxidized to the pyrazine (Scheme 54) (70CC25). The aromatization usually proceeds under very mild conditions. 

Both 2- and 3-methyl groups in pyrido[2,3-Z ]pyrazines are acylated by ethyl oxalate (71TH21500). They give (preferentially 3-) styryl derivatives with aromatic aldehydes and oximes with pentyl nitrite. 

The only other type noted concerned the photocyclization of the unsaturated pyrazine amide (425) to (426) with subsequent selenium dioxide aromatization (72CPB2264). 

Elimination of nitrogen from D-A adducts of certain heteroaromatic rings has been useful in syntheses of substituted aromatic compounds.315 Pyrazines, triazines, and tetrazines react with electron-rich dienophiles in inverse electron demand cycloadditions. The adducts then aromatize with loss of nitrogen and a dienophile substituent.316... 

The high selectivity that the system shows to pyrazine 20 compared to the stronger base pyridine, indicates that the diamine is chelated between the carboxylic acid functions as in 21. Spectroscopic evidence in the form of upfield shifts in the NMR spectra of the complexes supports such structures. Not only aromatic diamines are accommodated but also aliphatics such as l,4-diazabicyclo[2.2.2]octane (DABCO) in complex 22. Typically, exchange rates into and out of these complexes are such that they appear fast on the NMR time scale at ambient temperature, but exchange can be frozen out at low temperatures20. For DABCO, an activation barrier of 10.5 kcal M 1 was observed at Tc = 208 °K. 

Aldehydes and the corresponding 2-aminopyridine, pyrazine, or pyrimidine are admixed in presence of a catalytic amount of clay (50 mg) to generate iminium intermediate. Isocyanides are subsequently added to the same container and the reactants are further exposed to MW to afford the corresponding imidazo[l,2-a]pyridines, imi-dazo[l,2-a]pyrazines and imidazo[l,2-a]pyrimidines (Scheme 6.48). The process is general for all the three components, e. g. aldehydes (aliphatic, aromatic and vinylic), isocyanides (aliphatic, aromatic and cyclic) and amines (2-aminopyridine, 2-amino-pyrazine and 2-aminopyrimidine). A library of imidazo[l,2-a]pyridines, imidazo[l,2-ajpyrazines and imidazo[l,2-a]pyrimidines can be readily obtained by varying the three components [151]. 

One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyI compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The N-protected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. 

The synthesis and biological testing of the pyrazine compound 123 was described by Wang et al. [34], The same benzoin intermediate 22 was formed as described in Scheme 2. A three-step reaction was then performed to obtain the desired pyrazine 123, shown in Scheme 31 (i) oxidation of Q1SO4 in aqueous pyridine, (ii) reaction with ethylenediamine in EtOH, and (iii) aromatization in the presence of elemental sulfur. 

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

Relevant examples of enantioselective hydrogenation of aromatic N-heterocycles are given below. Scheme 16.21 shows the hydrogenation of a 2-ester substituted piperazine to the corresponding 2-substituted pyrazine with a catalyst... 

The oxygen-perturbed singlet-triplet spectra of aromatic carbonyl compounds were investigated by Warwick and Wells (Fig. 23). Transitions to states were enhanced by the perturbing agent while transitions to (n,7t ) states remained unaffected. It should be mentioned, however, that Evans also observed an oxygen-perturbed increase of the intensity of the Tnn So transitions in pyrazine and acridine. 

Complexes with less extended aromaticity such as Ru(bpy/phen)2HAT [73-76] (HAT = 1,4,5,8,9,12-hexaazatriphenylene, Fig, 2) and Ru(bpy)2PPZ [77-80] (PPZ = 4,7-phenanthrolino-[6,5-b] pyrazine. Fig. 2) exhibit also characteristics most relevant to intercalation. We can mention (1) a very slow mobility of the HAT complex along the DNA double helix [81], (2) a good protection of the complex versus reagents that remain in the bulk solution [73,79], and (3) a clear hypochromic effect on the MLCT transition in the presence of DNA [73, 75, 79,80]. 

With this in mind, the coordination chemistry of 52 with different diazine structural isomers was investigated. There were no detectable changes in the H NMR spectrum of 52 in a THF-Jg solution when either pyrazine or pyrimidine were added in 1 1 or 1 2 molar ratios, which suggested that only weak interactions might occur between 52 and these bases. In contrast, incremental addition of pyridazine or phthalazine to a THF-Jg solution of 52 at 25 °C resulted in an upheld shift of the aromatic NMR resonances of the diindacycle 52 thus reflecting the formation of complexes between 52 and the 1,2-diazines. Analysis of the tritration data clearly indicated the formation of 1 1 Lewis acid-diazine complexes 52-pyridazine-(THF)2 and 52-phthalazine-(THF)2 whose stability constants are equal to 80 ( 10) and 1000 ( 150) M respectively (Scheme 29). These data, as a whole, indicate that 52 is a selective receptor for 1,2-diazines. 

Upon reaction of A -vinyliminophosphoranes (109) with aromatic isocyanates, vinylcarbodiimides (110) are formed, as shown in Scheme 47. Divi-nylcarbodiimides (111) can be obtained as side products (88CB271). With isonitriles the vinylcarbodiimides also afford pyrroles (112) via [4 + 1]-cycloaddition. Divinylcarbodiimide can also react via [4 -l- l]-cycloaddition with an isonitrile, whereupon an electrocyclic step of the initial diaza-1,3,5-trienes (113) follows. Finally, the pyrrolo[2,3-e]pyrazine 114 is obtained (88CB271). 

Aromatic 7c-systems bearing two positive charges can accept one electron to form a delocalised radical-cation, which is isoelectronic with the radical-anion from the corresponding aromatic hydrocarbon. The phenanthrene analogue 4 is one such example [30]. Pyrazine is bis-protonated and reduced in acid solution to the... 

The (Z)- and ( )-styrylpyrazine structures 20j and 20k were assigned on the base of the mass, NMR, and UV spectral data. The mass spectrum of Z isomer (20j) shows a base peak (the molecular ion) at m/z 210 with a peak at m/z 133 formed by the loss of a phenyl group firom 20j. The H-NMR spectrum shows the presence of five aromatic and two olefinic protons in addition to one heteroaromatic proton and two methyl groups attached to the heteroaromatic nucleus. Ozonolysis of the Z isomer (20j) yields 3-formyl-2,5-dimethylpyrazine (487) and benzaldehyde, confirming the styryl moiety in 20j. The ( )-styryl derivative (20k) is readily isomerized to the Z isomer (20j) on exposure to sunlight (Scheme 60). Extraction of the pyrazines from I. humillis in the dark indicates that E isomer 20k is the naturally occurring product 144,145). 

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