5-Hydroxy-2 -pyrazinone

Following the discovery of penicillins, an extensive program for the screening of culture fluids and residual mycelial material commenced which resulted in the discovery of a large number of pyrazinones and related 1-hydroxy-2-pyrazinones with pronounced antibiotic character. Some examples are shown in Table 4. One of the earliest substances to be isolated, aspergillic acid (110 = OH, = Me, R = Et, R = R = H, R = Pr ), was found... 

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. 

Other synthetic routes to pyrazinones and quinoxalinones are from the halo compounds, by dealkylation of ethers (8lJCS(Pl)3111> or by diazotization of the corresponding amines, but since the halo derivatives are normally derived from the hydroxy compounds, and the amines from the halo derivatives, direct synthesis seems to represent the most practical approach. 

A rather different route to hexadentate ligands containing 3-hydroxy-2-p5rridinone units is based on the reaction of an appropriate pyrazinone with dimethyl acetylene dicarboxylate, which replaces one of the ring-nitrogen atoms by carbon (82). 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

A general type of [3 + 3] heterocyclization involves initial nucleophilic attack on the electrophilic three-membered heterocycle by a 1,3-electrophile-nucleophile. Aziridines (330) with either a-mercapto ketones (329) or with a mixture of a ketone and sulfur give 5,6-dihydro-1,4-thiazines (330 — 331 — 332). Azirines (333) can be used for the preparation of pyrazinones (334) from ot-amino esters R2CH(NH2)C02Et and of 1,4-oxazinones from a-hydroxy esters (83TL1153). 

Heating with phosphoryl chloride converted 1 -hydroxy-3-phenyl-2( 1H )-pyrazinone (52) into the 2,5-dichloro derivative (53) via the 5-monochIoro species. It had been expected that chlorination would take place at C-6, but this occurred only to a minor extent. The observed chloride attack /3 to the oxygen function might be accounted for in terms of the sequence illustrated in Scheme 46 (86JHC149). Reaction mechanisms have been proposed to explain the observed a- and /3-chlorination when 2- and 3-substituted pyrazine Af-oxides are subjected to the Meisenheimer reaction. /3-Chlorination was rationalized in terms of electron withdrawal by the unoxidized nitrogen atom [84JCR(S)318] (Scheme 46). 

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],... 

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. 

Af-Benzyl-/V- (/V-o-methoxyphcnylcarbamoyl)mcthyl glycine (29) underwent de-hydrative cyclization to 4-benzyl-6-hydroxy-l-o-methoxyphenyl-3,4-dihydro-2(1 H)- pyrazinone (30) (l,r-carbonyldiimidazole, THF, 30 —> 65°C, 17 h 83% other reagents gave lower yields).487... 

Iminodipropiononitrile (53) gave 6-hydroxy-3,5-dimethyl-3,4-dihydro-2(l//)-pyrazinone (54) (HCl/EtOH, 0°C, 12 h then Na2C03—H20 18% by a yet unconfirmed mechanism).577 Also other examples 436 747,749,1180,1284... 

V-(l-Acetyl-l-methylethyl)-2-chloro-(V-hydroxyacetamide (69) gave 1-hydroxy-5,6,6-(rimc(hyl-3,6-dihydro-2( I //(-pyrazinone (70) (NH4OH—I (OH—dioxane, 20°C, 3 days 8%) likewise one homologue.424 Aldehydes gave better results under reductive conditions.1768... 

Bis(carboxymethyl)amine (84, R = H) gave 4-formyl-6-hydroxy-3,4-dihydro-2( I //)-pyrazinone (83, Q = CHO) [HC02NH4, Me2NCHO—PhMe, Dean-Stark H20 removal, 150-170°C (bath ), 4 h 58%], and thence... 

Amino-2-methyl-l-propylaminopropane (148) and acetone cyanohydrin (2-hydroxy-2-methylpropionoitrile 149) gave 3,3,5,5-tetramethyl-l-propyl-3,4,5,6-tetrahydro-2(l/7)-pyrazinone (150, X = 0), presumably via the imine (150, X = NH) (PhCH2Et3NCl, NaOH, CHC13—H20, 5°C, >5 h 70%) also analogues.187... 

Chloro-3-isobutyl-6-isopropylpyrazine 1-oxide (109) gave l-hydroxy-3-isobutyl-6-isopropyl-2(l//)-pyrazinone (110) (KOH, H20—MeOH, reflux, 2 h 84%) 92 homologues likewise.1250... 

Reductive debenzylation. 2-Benzyloxy-3,6-diisobutyl-5-methoxypyrazine 4-oxide (21) gave 3,6-diisobutyl-5-methoxy-2(l//)-pyrazinone 4-oxide (22) (H2, Pd/C, EtOH, h 90% structure confirmed by X-ray analysis) 310 2,5-dibenzy-loxy-3,6-diphenylpyrazine likewise gave 5-hydroxy-3,6-diphenyl-2(l//)-pyrazinone (23) (43%).82... 

Acetoxy-3,6-dibenzyl-5-methoxypyrazine gave 3,6-di benzyl-5-methoxy-2(l//) -pyrazinone (29) (K2C03, MeOH—H20, reflux, 30 min > 95%) 312 2,5-diace-toxy-3,6-dimethylpyrazine gave 5-hydroxy-3,6-dimethyl-2(l//)-pyrazinone (30) (KHC03, MeOH, reflux, 50 min 53%).1386... 

For example, I -bcnzyloxy-2(l //)-pyrazinone (217, R = H) afforded 70% of 1-hydroxy-2( I //)-pyrazinone (218, R = H) [sometimes written as its tautomer, 2-pyrazinol 1-oxide (218a, R = H) on catalytic hydrogenation over palladium-on-charcoal in methanol for 20 min.588 The homologous l-benzyloxy-5,6-dimethyl-2( I //(-pyrazinone (217, R = Me) gave l-hydroxy-5,6-dimethyl-2(l//)-pyrazinone (218, R = Me), either by a similar hydrogenation (76%) or by hydrolysis in acetic acid-hydrogen bromide under reflux for 10 min (81%, as hydrobromide).588 1085... 

Hydroxy-6-mcthyl-3-phcnyl-2(l//)-pyrazinone from its 4-oxide (259) (TiCl3, THF, 40°C, N2, 2 h 57%) 1250 also analogues likewise in mediocre yields.1250... 

Hydroxy-5,6-diisopropyl-2(l//)-pyrazinone (264, R = H) gave 1-benzoyloxy-5,6-diisopropyl-2(l//)-pyrazinonc (264, R = Bz) (BzCl, pyridine, CH2C12, 5 20°C, 12 h 64%) 1515 several analogues like 5-chloro-1 -(p-chloroben-zoyloxy)-6-ethyl-2(l//)-pyrazinone (265), were made similarly.1011515... 

Hydroxyaspergillic acid (H 6), l-hydroxy-6-(l-hydroxy-l-methylpropyl)-3-isobutyl-2(l//)-pyrazinone, an Aspergillus sp metabolite.727... 

Benzyl-5-ethoxy-6-methyl-2 (I //)-pyrazinono 6-Benzyl-3-ethyl-l-hydroxy-2n //)-pyraz,inone 6-Benzyl-3-ethyl-5-methyl-2(l//)-pyrazinone... 

Benzyloxy-5,6-diphenyl-2(l//)-pyrazinone 5- Benzyloxy-1 -hydroxy 3,6-dimethyl-... 

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