Pyrazine reactivity

Imidazo[4,5-6]pyrazine, 2-methyl-synthesis, 5, 645 I midazo[ 1,2-a]pyrazines reaaions, 5, 624 sjmthesis, 5, 642-643 Imidazo[l,5-a]pyrazines chlorination, 5, 625 reactions, 5, 625-626 synthesis, 5, 644-645 Imidazo[4,5- 6]pyrazines reactivity, 5, 626-627 synthesis, 5, 645-646... 

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. 

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. 

In accordance with observations in halodinitrobenzene derivatives, fluoropyrazines are by far the most reactive of the halopyrazines. Fluoropyrazine undergoes facile reaction with sodium azide to give azidopyrazine (27), which exists in dynamic equilibrium with tetrazolo[l,5-a]pyrazine (28) (66JHC435). 

Substitution of the pyrazine ring by electron releasing substituents reduces the reactivity of halopyrazines and more forcing conditions must invariably be employed to bring about displacement of the halogen. 

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. 

Imidazo[ 1,5-a]pyrazine, 1 -bromo-3-methyl-hydrolysis, S, 625 reactivity, 5, 625... 

Isoxazolo[4,5-6]pyrazine (176) is resistant to electrophilic halogenation because the potentially reactive site is at the ring junction. The 7-oxide, though, was converted into the 6-chloro derivative of 176 on heating with phosphoryl chloride (73JHC181). 

Because silylation with HMDS 2/TCS 14 in acetonitrile at ambient temperature converts the unreactive a-chloroketone moiety of 743 into an /Z-mixture of reactive alkyl 4-chloro-3-trimethylsilyloxycrotonates 746a, b [230, 231] which can be isolated and distilled, if humidity is excluded, silylation of 743a, b in the presence of ami dine salts such as 745 gives the desired ethyl or methyl imidazole(4,5)-acetates 748a, b via IMz and 747b. The reaction of formamidine acetate with 746a,b affords 745 (with R=H) in up to 70% yield [232, 233] (Scheme 5.79). As side reactions one must, e.g., take into account the reaction of 746 with ammonia to give 755 which subsequently dimerizes to the pyrazine 756, as discussed in Section 5.5.3. 

Alternatively, arene displacement can also be photo- rather than thermally-induced. In this respect, we studied the photoactivation of the dinuclear ruthenium-arene complex [ RuCl (rj6-indane) 2(p-2,3-dpp)]2+ (2,3-dpp, 2,3-bis(2-pyridyl)pyrazine) (21). The thermal reactivity of this compound is limited to the stepwise double aquation (which shows biexponential kinetics), but irradiation of the sample results in photoinduced loss of the arene. This photoactivation pathway produces ruthenium species that are more active than their ruthenium-arene precursors (Fig. 18). At the same time, free indane fluoresces 40 times more strongly than bound indane, opening up possibilities to use the arene as a fluorescent marker for imaging purposes. The photoactivation pathway is different from those previously discussed for photoactivated Pt(IV) diazido complexes, as it involves photosubstitution rather than photoreduction. Importantly, the photoactivation mechanism is independent of oxygen (see Section II on photoactivatable platinum drugs) (83). 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

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