Hydroxypyrazines

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. 

The progression from hydroxypyrazines/quinoxalines through the halo derivatives to the amines is a logical sequence in that, for practical purposes, this is the best method of synthesis of the amino compounds (see preceding Section). The ammonolysis proceeds most easily in the case of fluoro compounds. Fluoropyrazine reacts with aqueous ammonia at room temperature, whereas the reaction with chloropyrazine requires higher temperature and pressure. 

The possible mechanisms of inhibition of flavin by (—)-deprenyl, as an irreversible acetylenic inhibitor, were studied by ab initio methods with the 6-31G basis set using simplified model compounds, 3-formyl-2-imino-l-hydroxypyrazine, and propargylamine. The formation of two energetically stable cyclic adducts, the 0,N adduct 286 and a C,N adduct, was shown <1999THA147>. 

The diversity of structural types within this group of compounds is well recognized. Sammes arbitrarily divided DKPs into five main structural types or groups (1) simple dioxypiperazines, (2) the echinulins and related derivatives, (3) hydroxypyrazine derivatives, (4) sulfur-bridged derivatives, and (5) bicyclomycin and dibromophakellin. 

The diazinone tautomers are identified by using terminology such as 3(2//)-pyridazinone for the carbonyl tautomer of 3-hydroxypyrazine. The 3(2//) prefix signifies the position of the oxygen (3-pyridazinone) and specifies the NH is at position 2. Note that, in addition to the diazine-diazinone tau-tomerism, when the nitrogens have a 1,3-relationship there is further tautomerism possible, e.g. 4(1//)-pyrimidone 4(3//)-pyrimidone. 

PIPERAZINES AND PYRAZINES The classical synthetic method for constructing 2-aminopyrazines is illustrated by the synthesis of ampifzine (117), a CNS stimulant. Condensation of aminomalonamide and glyoxal leads to pyrazine 114. Hydrolysis to the acid and decarboxylation gives 2-hydroxypyrazine (115). Reaction with PCl produces chloride 116, and heating with dimethylamine completes... 

This same 3-methoxy-2-aminopyrazine (33.1.36) is synthesized from 3-hydroxypyrazin-... 

It should be noted that, as all carbon positions in pyrazine are identical, the locant 2- in a monosubstituted derivative is unnecessary. All possible reduced derivatives of pyrazine 1, and several of those of its benzo analogues quinoxaline 2 and phenazine 3, are known. There are four dihydropyrazines, the 1,2-, 2,3-, 1,4-, and 2,5-isomers, two tetrahydropyrazines, the 1,2,3,4- and 1,2,3,6-, and hexahydropyrazine or piperazine, the last of which is omitted in this chapter. The reduced quinoxalines are the 1,2- and 1,4-dihydro compounds and 1,2,3,4-tetrahydroquinoxaline. The only known reduced phenazine is 1,4-dihydrophenazine. Hydroxypyrazine 4 and hydroxyquinoxaline 6 have been shown to exist in the tautomeric amide form by spectral studies, and therefore they are formulated as 2(1//)-pyrazinone 5 and 2(l//)-quinoxalinone, respectively. In contrast, aminopyrazine and aminoquinoxaline exist as described in the amino rather than the imino forms (Figure 1). 

A typical example of tautomerism is represented by the equilibrium between hydroxypyrazine 4 or 7 and 2(1//)-pyrazinone 5 or 8, in which the latter keto form predominates over the hydroxyl or enol form. A similar situation exists in hydroxylquinoxaline 6. The tautomeric equilibrium, however, is susceptible to the additional substituents. For example, 6-amino-2(l//)-pyrazinone 8 (R = Me, = Bn, R = NH2) has been shown to predominate over the hydroxyl form 7 <1993JOC7542>. On the contrary, 6-methoxy-2-hydroxypyrazines 7 (R = Me, R = Ph, R = OMe) exist in the hydroxyl form rather than as the tautomeric amide <1997J(P1)3167>, and these examples have a predominance of the hydroxyl form parallel the isomeric 5-methoxy-2-hydroxypyrazines as well as the chloro-hydroxypyrazine field <1996CHEG-II(6)233>. 

The elucidation of the hydroxypyrazine-pyrazinone tautomerism has been made using spectral methods. An IR spectral analysis focuses on the carbonyl absorption of the amide group in the keto tautomer. A more useful method is UV spectroscopy, that is, the objective structure in solution is easily estimated by comparison with the UV spectra of bond-fixed compounds related to the two tautomers, namely O-methylated and N-methylated derivatives 9 and 10, which are prepared by methylation of the hydroxypyrazines or pyrazinones with diazomethane (Scheme 1). The above two investigations were achieved by this methodology. 

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>. 

Sato and Narita provided an improved synthesis of various halopyrazines in which hydroxypyrazines 160 were activated with TMSCl to give silyl ethers 161 <99JHC783>. Subsequent treatment of 161 with the appropriate phosphorus-based halogen source provided halopyrazines 162 in 46-94% overall yield. This two-step process was accomplished without isolation of intermediate 161 and provides a milder, more convenient approach than the traditional heating of hydxoxypyrazines with PX directly. 

Recently, Patey et al. (69) identified three hydroxypyridines and seven hydroxypyrazines from fifteen different caramel colorings. 

Condensation of 1,2-diaminopropane and 2,3-dioxobutane similarly gives 5,6-dihydro-2,3,5-trimethylpyrazine which is oxidized to the corresponding pyrazine in 58% yield by treatment with potassium hydroxide pellets.111 Hydroxypyrazines are very conveniently prepared from a,j8-dicarbonyl compounds and a-amino acid amides [Eq. (1)],30,112 and pyrazinecarboxylic acids have been prepared by condensation of an a,)5-diketone with an a,/ -diaminocarboxylic acid, followed by oxidation (Scheme 2). Thus, condensation of benzil and... 

The classical route to chloropyrazines is by treatment of a hydroxy-pyrazine with phosphoryl chloride bromopyrazines are similarly prepared by using phosphoryl bromide, phosphorus tribromide, or a mixture of both. Thus, treatment of hydro xypyrazine with phosphoryl chloride gives chloropyrazine in 92% yield,147 and treatment of the hydroxy compound with a mixture of phosphoryl bromide and phosphorus tribromide gives bromopyrazine in 58% yield.266 The use of phosphorus pentahalides frequently leads to substitution products (Scheme 22) for example, when hydroxypyrazine is treated with a mixture of phosphoryl bromide and phosphorus pentabromide both monobromo- and 2,6-dibromopyrazines are formed.287,268 Bromina-tion of hydroxypyrazine with bromine in the presence of small... 

Pyrazines with hydroxyl groups are generally in the oxo form however, substituents like chlorine may profoundly influence the position of the tautomeric equilibria. Ultraviolet measurements indicate that in ethanol solution 2-chloro-6-hydroxypyrazine (125a) exists predominantly in the hydroxy rather than in the oxo form (125b) 272 trifluorohydroxypyrazine also does not tautomerize appreciably to a pyrazinone.279... 

Hydroxypyrazines are also prepared from halopyrazines either directly by hydroxide ion treatment, e.g., the conversion of fluoro-... 

Direct ring syntheses are also available for the preparation of hydroxypyrazines. Thus, haloacylation of an a-aminoketone, followed by reaction with ammonia and oxidation represents a general synthesis of 5,6-disubstituted and 3,5,6-trisubstituted 2-hydroxypyrazines.339 This is illustrated by the preparation of 5,6-dimethyl-2-hydroxy-pyrazine (Scheme 39). Hydroxypyrazines are very conveniently... 

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. 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

Hydration of the diazaoxepine (226) takes place at the less hindered carbon-nitrogen double bond to give the substituted propene (222). The hydroxypyrazine (126) arises from isomerization of the oxaziranes (224) and (225). Ultraviolet irradiation of 2,5-diphenylpyrazine... 

---