L- -pyrazinone

Both and H NMR data are also available for a range of 2(l//)-pyrazinones which are structurally related to the aspergillic acids (76T655). 

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. 

Aminopyrazines and 2-aminoquinoxalines, like their pyridine analogs, react with nitrous acid under aqueous conditions to give the 2(l//)-pyrazinones and 2(l//)-quinoxalinones. 2-Aminoquinoxalines are more readily hydrolyzed than typical heterocyclic amines and 2-amino-3-methylquinoxaline, for example, undergoes hydrolysis on heating at 100 °C with dilute sodium hydroxide (59JCS1132). 

Scheme 9 Introduction of substituents to the position C-3 of the 2(l//)-pyrazinone scaffold...

Scheme 28 Diels-Alder reactions of C - O linked 2( l//)-pyrazinone-triazoles with DMAD...

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>. 

Ring nitrogens in pyrazines and the benzo derivatives react with electrophiles to form quaternary ammonium species such as iV-alkylpyrazinium salts and pyrazine iV-oxides. N-Alkylation has generally been performed by treatment with a reactive alkyl iodide. The N-1 nitrogen in 2(l//)-pyrazinone 5 is methylated using chloro(chloromethyl)dimethyl-silane followed by desilylation with cesium fluoride to yield l-methyl-2(l//)-pyrazinone <2000TL4933>. 

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 can be seen in the intramolecular cycloaddition (Section 8.03.5.1), the intermolecular Diels-Alder reactions between functionalized 2(l/f)-pyrazinones 83 and dimethyl acetylenedicarboxylate (DMAD) forming bicyclo adducts 84 has been shown to be significantly rate enhanced and increased in yields by using controlled microwave irradiation compared to the conventional thermal protocols (Scheme 21) <2002JOC7904>. The microwave-assisted Diels-Alder reactions of substituted 2(l//)-pyrazinones with ethene are significantly more effective utilizing prepressurized (up to 10 bar) reaction vessels <20040BC154>. 

Since 1,4-dihydropyrazine itself is unknown, various substitutions of the ring system are required to produce stable isolable molecules. Carbonyl-stabilized 1,4-dihydropyrazines are synthesized by self-condensation of 3-chloromethyl-5,6-dihydro-l,5,5-trimethyl-2(l//)-pyrazinone <1998J(P1)289>. Another carbonyl-stabilized example is provided by WA -BOC-protected 1,4-dihydropyrazine 102, which can undergo Michael addition with nucleophiles such as 1,2,4-triazole, 3-formylindole, 4-bromothiophenol, benzylamine, or sodium methoxide to yield tetrahydropyrazines 103 (Scheme 26) <2004T8489>. Treatment of the di- and tetrahydropyrazines with trifluoroacetic acid leads to cleavage of BOC groups and/or elimination of the nucleophile to both afford dimethyl 2,5-pyrazinedicarboxylate 104. 

Although methylation of 2(l//)-pyrazinones with diazomethane gives a mixture of O- and N-methylated pyrazines as the fixed tautomers (Equation 20) <1993JOC7542>, the trimethylsilylation leads to the exclusive formation of 0-silyl compounds, which are effectively converted to bromopyrazines 42 (Scheme 33) <1999JHC783>. In the same... 

One of useful building blocks for the synthesis of 2-(l//)-pyrazinones is iV-BOC amino acids, whose carboxylic acid moiety reacts with the amino group of another component having cyano or carbonyl functionality at the a-position, such as a-amino nitriles <2004T835>, a-amino amide (Scheme 46) <2000H(53)1559>, a-amino ketones... 

An old but practical synthetic method for 2(l//)-pyrazinones is Jones procedure which involves condensation of a-amino amides with 1,2-dicarbonyl compounds (Section 8.03.9.1). A number of stepwise approaches using a-amino acids to 2(177)-pyrazinones have been discussed in Section 8.03.9.4. 

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 number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

The intramolecular Diels-Alder reaction of l-(A -a -alkenyl)-2(l//)-pyrazinones generates m-[l,7]naphthyridines in good yields (Scheme 62) <2001TL7397>. This method has been used in the development of a r-[l,7]naphthyr-idine-based scaffold on which to build a type VI external /3-turn mimic <2003EJ01868>, and for the synthesis and conformational analysis of [l,7]naphthyridine-based substance P antagonist analogues <2003T4721>. 

Similarly, from 2-chloro(l//)-pyrazinone, the azides 498a-d were obtained and these underwent reversible cyclization to the fused tetrazoles 499a-d (Scheme 62) <2004OL4223, 2005JC0490>. 

Benzyl-6-[A -(but-3-ynyl)-A -propionylaminomethyl]-5-chloro-3-methoxy-2(l//)-pyrazinone (48) underwent thermolysis to afford l-benzyl-3-methoxy-7-propio-nyl-5,6,7,8-tetrahydro-l,7-naphthyridin-2(l/7)-one (49) (PhBr, reflux, 2 h 53%, after separation from a second product) the proposed intermediate was not isolated.602... 

The stereoselective intramolecular Diels-Alder reaction of 3-alkenyl(oxy)-2(l//)-pyrazinones leading to tricyclic ring systems was investigated <02TL447>. A one-pot 7-alkoxylation of 6-arylpyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxides 169 was accomplished by using N-halosuccinimides <02EJ02109>, and the nitration of 2-(5-methyl-2-furyl)quinoxaline was shown... 

Methyl 2- 2-[Ar-(2-bromoethyl)-o-nitrobenzenesulfonamido]propionamido -2-phenylacetate (6) gave l-(a-methoxycarbonylbenzyl)-3-methyl-4-o-nitroben-zenesulfonyl-3.4.5.6-(c(rahydro-2( l//)-pyrazinone (7) [1,8-diazabicyclo [5,4,0]undec-7-ene, tetrahydrofuran(THF) > 95%].1622 Also other examples.863 1493 1772... 

Benzyloxycarbonylamino)acetamido]-3-hydroxypropionaldehyde hydrate (12) gave 6-hydroxymethyl-3,4,5,6-tetrahydro-2 (I //l-pyrazinone (13) (Pd/C, MeOH, H2) 50 atm, 20°C, 24 h 96%).1061 2-(2-Aminoethylamino)ethanol gave piperazine (14) (Cu—A1203 catalyst, continuous flow, 200°C 95%).1064 Also other examples.1330,1641... 

Methyl A-(2-diallylamino-3-hydroxyhcxyl)-2-isopropylglycinatc (42) gave 6-(l-hydroxybutyl)-3-isopropyl-3,4,5,6-tetrahydro-2(l//)-pyrazinone (43) [(Ph3P)3 RhCl, MeCN—H20, distillation (see original for details), 5 h 47%].404 Also other examples 182,189,229,703,813,843,1347,1465,1495,1498,1535,1750... 

Such substrates are seldom used but tert-butyl (I - I -W-methoxy-A-methylcar-bamoyl)-3-methylbutyl]carbamoyl -2-phenylethyl aminoformate (44) gave 3-ben-zyl-6-isobutyl-2(l//)-pyrazinone (45) (21%) by two deprotections (LiAlH4 and HC1—dioxane) and a final cyclization in acetonitrile during 13 h.1510... 

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... 

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