Hydroxypyrazines phenylation

Hydroxypyrazines or 2(l//)-pyrazinones are also subject to electrophilic halogenation. A new result is that 1-benzyl- or 1-phenyl-substituted 2(l//)-pyrazinones undergo bromination with NBS or A -iodosuccinimide (NIS) to give the 5-bromo or iodo-2(l//)-pyrazinones in 66-82% yields <2004TL1885, 2005T3953>. 

As already mentioned, hydroxypyrazines exist in tautomeric equilibria with the corresponding pyrazinones which are normally the predominant species in the equilibria. Some of the reactions of hydroxypyrazines are reminiscent of those of phenols they can, for example, be coupled with diazonium salts and brominated and nitrated in either the ortho or para position to the hydroxyl group. Coupling with diazonium salts occurs in neutral or weakly alkaline solution, but if the reaction is carried out in 1 M sodium hydroxide solution, arylation of the pyrazine ring takes place. From hydroxy-pyrazine and benzenediazonium chloride 47% 2-hydroxy-3-phenyl-and 4% 2-hydroxy-3,6-diphenylpyrazine are obtained. 

Dichloropyrazines have also been prepared from the corresponding hydroxy compounds as follows 2,3-dihydroxypyrazine with phosphoryl chloride containing pyridine (481, 757) [see Schneller and May (828) re the use of phenylphosphonic dichloride at 150-170°] 2,3-dihydroxypyrazine and its methyl, dimethyl, phenyl, diphenyl, and 5-methy 1-6-phenyl derivatives with phosphoryl chloride (483, 829) [N.B. error in work of Minovici and Bente (830)] 2-chloro-5-hydroxypyrazine with phosphoryl chloride (831) 2-chloro-6-hydroxypyrazine with phosphoryl chloride at reflux for 6hours (832) and 2,5-dihydroxy-3-phenylpyrazine and3,5-dihydroxy-2-phenylpyrazine with phosphoryl chloride at 180-200° (829). 

Hydroxypyrazine with phosphoryl bromide and phosphorus pentabromide has been found to give a mixture of 2-bromopyrazine and 2,6-dibromopyrazine (818, 865) the former was converted to the latter under similar reaction conditions (865). Phenyl-substituted 2-hydroxypyrazines were found to be transformed in good yield by phosphorus tribromide alone to the corresponding... 

Iodopyrazine and six mono- and dialkyl- and phenyl-substituted 2-iodopyrazines have been prepared (30-60% yield) by displacement of the chloro substituent from the corresponding chloro compounds with a solution of sodium iodide and hydriodic acid in ethyl methyl ketone (887). Attempts to prepare iodopyrazine by treating the hydroxypyrazine with phosphorus triiodide were unsuccessful (887). 

Diazotization of 2-aminopyrazine with nitrous acid in dilute or concentrated sulfuric acid gave 2 hydroxypyrazine (to 67% yield) (86, 477, 720, 818). Many such conversions have been described, mostly using nitrosylsulfuric acid in concentrated sulfuric acid solution. Preparations of hydroxypyrazines from the aminopyrazines are summarized as follows 2-hydroxy-3-methylpyrazine (sodium nitrite in concentrated sulfuric acid-acetic acid) (681), 2Jiydroxy-3,5-dimethylpyrazine (aqueous nitrous acid, then at 60°) (524), 3-hydroxy-2,5-dimethylpyrazine (477), 2,5-diethyl-3-hydroxypyrazine (aqueous nitrous acid) (478), 2-hydroxy-6-phenyl-pyrazine (365a), 24iydroxy-3,5-diphenylpyrazine (nitrous acid in N hydrochloric acid) (524), 3-hydroxy-2,5-diphenylpyrazine (282), 2-s-butyl-3-hydroxy-5-isobutyl-pyrazine (93), 5TS-butyl-3 hydroxy-2-isobutylpyrazine (92, 536), 2,5-di-s-butyl-3-hydroxypyrazine (89, 720), 3-hydroxy-2-isobutyl-5-isopropylpyrazine (103, 525), 2,3-dihydroxypyrazine (from 2 amino-3-hydroxypyrazine) (757, 1055) and its... 

Oxidation of nuclear and extranuclear hydroxypyrazines (and derivatives) to their Af-oxides has been achieved with hydrogen peroxide in acetic acid, and with m-chloroperoxybenzoic acid in 1,2-dichIoroethane. 3-Hydroxy-2,5-diisobutyl-pyrazine was oxidized with 30% hydrogen peroxide in acetic acid at 70 to 3-hydroxy-2,5-diisobutylpyrazine 1-oxide (101), 3-hydroxy-2-(Af-methyl-A -phenyl-carbamoyl)pyrazine 1-oxide (90) was also prepared from the conesponding pyrazine [its A -4-methyl derivative was prepared similarly and also by methylation of (90) (1055)], and 3-hydroxy-2-(A -methyl-AAp-tolylcarbamoyl)pyrazine 1-oxide (1055) was synthesized analogously. 

The preparation of arylazo derivatives from hydroxypyrazines has been described in Section VI.6E and from l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahydro-pyrazine to give l,4,6-trimethyl-2-oxo-3-phenykzomethylene-l,23,4-tetrahydro-pyrazine in Section VI.9B. In addition to these reactions Princivalle (1122) reports that 2reacted with benzenediazonium chloride and p-toluenediazonium chloride by elimination of the carboxy group para to the hydroxy group and coupling to form 2-hydroxy-3,6-dimethyl-5-phenyl-azo(and p-tolueneazo)pyrazines, respectively (1122), identical to those prepared from 3-hydroxy-2,5 -dimethylpyrazine. 

Carboxy-3-hydroxypyrazine refluxed with phosphorus tri(Af-methylanilide) in toluene gave 2-hydroxy-3-(A -methyl-A -phenyl)carbamoylpyrazine, and 2-hydroxy-... 

Hydroxypyrazines, or rather tautomeric 2(l//)-pyrazinones, undergo electrophilic substitution such as nitration and bromination ortho or para to the hydroxy or oxo substituent under mild conditions <53JA5517,56JA4071, 78JHC665). When phenyldiazonium chloride is added to 2(l//)-pyr-azinones in alkaline solution, phenylation of the nucleus takes place with evolution of nitrogen in the same substitution pattern as above. 

A comprehensive theoretical smdy of some pyrazolones has been presented. The predicted tautomeric equilibrium constants of these compounds were found to be in good agreement with existing experimental data, indicating that the oxo tautomers are present in aqueous solution whereas, in the main, the hydroxy tautomers predominate in the gas phase. It has been shown that, in solution, the most abundant tautomer of both l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one and its 1-phenyl derivative is dependent on the solvent used, while an NMR study of a number of l(2)//-dihydropyrazolo[3,4-fc]pyridin-6-ones has revealed that they all exist as 2//-tautomers both in solution and in the solid state. DFT and ab initio calculations have been carried out to investigate the stability of different tautomers of 2-hydroxy- and 2,3-dihydroxy-pyrazine in the gas phase and in different media. The data obtained indicated that 2-hydroxypyrazine is more stable than its 2-keto tautomer in the gas phase, whereas in solution the stability order is reversed. For 2,3-dihydroxypyrazine it appears that the intramolecular hydrogen-bonded hydroxyoxo and the a-diketo tautomers are the most stable species at all theoretical levels in the gas phase. Both spectroscopic and theoretical studies of the tautomerism of 2,1,3-benzothiadiazinone 2,2-dioxides and other related fused heterocyclic amides have predicted that the keto form (415) is the most abundant tautomer in the gas phase, whereas the NH hydroxy form (416) is the preferred tautomer in solution and in the solid state. 

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