Pyrazinones tautomerism

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. 

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>. 

Leszczynski et al. have shown interest in comparing experimental (matrix isolation) and calculated (B3LYP) IR data (frequency and intensity) to discuss the tautomerism of benzo-annelated pyridonone, pyrazinone, and pyrimidinone (144-148). These equilibria were well reproduced by theoretical calculations carried out at the QCISD and QCISD(T) levels. The combined experimental and theoretical results reveal links between aromaticity and tautomerism. Moreover, a UV-induced phototautomeric reaction transforming the oxo forms into the hydroxy tautomers was observed for all (except 3-hydroxyisoquinoline) studied compounds [144], The interest of Leszczynski in problems related to tautomerism, aromaticity, and proton transfer is also apparent in a study of (lH-aza-hetero-2-ylidene)-acetaldehyde and 2-azahetero-2-yl-ethanol tautomeric pairs [145],... 

Comparison of the ultraviolet absorption and ionization constants of aminopyrazine, methylaminopyrazine, and dimethylaminopyra-zine indicates that aminopyrazine exists as such and not in the tautomeric imino form.147 Aminopyrazines, like their pyridine analogs, form diazonium salts, which readily decompose to the corresponding pyrazinones. For example, nitrous acid treatment of aminopyrazine318 and 2-aminopyrazine-5-carboxylic acid210 gives the corresponding pyrazinones in 30 and 59% yield, respectively. The diazonium salt from aminopyrazine cannot be converted into bromo-pyrazine under the conditions of the Sandmeyer reaction. 

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... 

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. 

The N-alkylation, N-arylation, and in particular N-heteroarylation of piperazines is an important process because of the common propensity (justified or not) for introducing a piperazino grouping into structures perceived as potentially bioactive in a variety of drug-related areas. The various routes to such N-alkylated piperazines are outlined in this section, which also includes examples of the N-alkylation of di- or tetrahydropyrazines the N-alkylation of (tautomeric) pyrazinones and the like is covered in Section 5.1.2.2. 

With the exception of those halogenopyrazines made by primary synthesis (see Chapters 1 and 2), most chloropyrazines have been made recently by the reaction of tautomeric pyrazinones with a phosphorus chloride or by the reaction of pyrazine iV-oxides with phosphoryl chloride in contrast, most other halogenopyrazines have been made by direct halogenation or by transhalogenation of chloropyrazines. A single interesting example of the conversion of a methoxy- into a chloropyrazine is included at the end of Section 4.1.1. 

The general term oxypyrazine is used here to include derivatives such as the cy-cloamidic tautomeric pyrazinones (1), the alcoholic hydroxyalkylpyrazines (2), the etherial alkoxypyrazines (3-5), the cycloamidic nontautomeric pyrazinones (6), and pyrazine A-oxides (7, 8) in addition, related types like diketopiperazines, acy-loxypyrazines, pyrazine quinones, and endoperoxypyrazines are covered as appropriate. Some brief ancillary information on trivial names, natural occurrence, and biological activities of pyrazines (mainly oxy derivatives) is collected in a final Appendix section. 

There is no longer any real doubt that simple tautomeric pyrazinones like 2(1//)-pyrazinone (1) exist predominantly in their oxo forms. However, largely confirmatory theoretical,1042,1430,1623,1675 NMR,1424 and IR studies1398 on such pyrazinones have appeared recently in addition, 2,3(1 H,AH)-pyrazinedione (9) appears to exist substantially as such,1623,1675 whereas the 2,5-isomer [2,5(l//,6A)-pyrazinedione ] appears to prefer an equilibrium mixture (10) of 2,5-dihydroxypyrazine and... 

Irrespective of the type of reagent or the conditions used, alkylation of a tautomeric 2(l//)-pyrazinone usually gives an N-alkylated pyrazinone, sometimes accompanied by a smaller amount of the isomeric alkoxypyrazine. Occasionally, the alkoxypyrazine may predominate when a diazoalkane or trialkyloxonium tertafluo-roborate is used, when the steric and/or electronic factors associated with the reagent or substrate are favorable, or when the substrate s ring is partially reduced. 

The following alkylations illustrate the results to be expected from various types of tautomeric pyrazinones and a variety of reagents and conditions. The examples are grouped according to the type of substrate and the given percentages represent isolate yields except when stated otherwise. 

Several rarely used but quite important reactions of tautomeric pyrazinones are typified in the following examples ... 

Most alkoxy- or aryloxypyrazines have been made by primary synthesis (see Chapters 1 and 2), by addition of alcohols to alkynylpyrazines (see Section 3.2.4.9), by alcoholysis or phenolysis of halogenopyrazines (see Sections 4.2.3 and 4.4), by O-alkylation of tautomeric pyrazinones or extranuclear hydroxypyrazines (see Sections 5.1.2.2 and 5.2.2), or by epoxidation of alkenylpyrazines (see Section 3.2.4.1). Some of the few remaining routes (presently of minor preparative value) are illustrated briefly in the following recent examples ... 

These pyrazine ethers, both nuclear and extranuclear, undergo several useful reactions. Their hydrolysis to tautomeric pyrazinones or hydroxyalkylpyrazines has been covered in Sections 5.1.1 and 5.2.1. Other reactions are illustrated in the following examples ... 

Tautomeric pyrazinones may be rendered nontautomeric by O-alkylation to afford alkoxypyrazines (see Section 5.3.1) or by N-alkylation to furnish 1-alkyl-2( I //(-pyrazinones or l-alkylpyrazinium-3-olates (see Section 5.1.2.2). 

Most such pyrazinones have been made by primary synthesis (Chapters 1 and 2) or N-alkylation of tautomeric pyrazinones (Section 5.1.2.2). The minor route by rearrangement of alkoxypyrazines (H 184) appears to be unpresented in recent literature, but there are examples of the hydrolysis of nontautomeric iminopyrazines to corresponding pyrazinones. Thus 3-imino-4-methyl-3, 4-dihy-dro-2-pyrazinamine hydriodide (191, R = H) (i.e., 2,3-diamino-l-methyl-pyrazinium iodide) underwent hydrolysis in 2 M sodium hydroxide during 1 h at 100°C to afford 3-amino-1 -methyl-2(l//)-pyrazinonc (192, R = H) ( 40%) without any evidence of Dimroth rearrangement to 3-methylamino-2-pyrazinamine 1008 l-methyl-3-methylamino-2(l//)-pyrazinimine (191, R = Me) likewise gave 1-methyl-3-methylamino-2(l//)-pyrazinone (192, R = Me) ( 50%) 1008 and other examples have been reported.598... 

Note Like tautomeric pyrazinones (Section 5.1.2.1), nontautomeric pyrazinones undergo thiation easily. 

Most tautomeric pyrazinethiones have been made by primary synthesis (see Chapters 1 and 2), thiolysis of halogenopyrazines (see Section 4.2.4), or thiation of tautomeric pyrazinones (see Section 5.1.2.1) a few nontautomeric pyrazinethiones by primary synthesis (see Chapters 1 and 2) or thiation of nontautomeric pyrazinones (see Section 5.4.2) and nearly all extranuclear pyrazinethiols by thiolysis of extranuclear halogenopyrazines (see Section 4.4). Other routes to such pyrazinethiones and pyrazinethiols are illustrated in the following examples ... 

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