2 -Pyrazinone 4-oxide

Other reactions with their counterparts in the pyridine series are also well known. Thus, 2,3-dimethylpyrazine 1,4-dioxide reacts with acetic anhydride to yield 2,3-bis(acetoxy-methyl)pyrazine (S3) in good yield (72KGS1275). Pyrazine 1-oxide also reacts directly with acetic anhydride to yield 2(ljH)-pyrazinone by way of the intermediate acetate (Scheme 22). The corresponding reaction in the quinoxaline series is not so well defined and at least three products result (Scheme 23) (67YZ942). 

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. 

Condensation of phenylalaninenitrile, prepared from phenyl acetaldehyde, with 1-oxime of pyruvaldehyde afforded the pyrazine N-oxide, which was further rearranged to give the N-acetyl pyrazinone. The acetyl groups were removed by treatment with hydrazine to give the target 6-aminopyrazinone. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

The same authors reported in a later study <2000H(3)69> that pyrazinone 340 is also a suitable starting material for a such transformation. The reaction proceeds in two steps the starting pyrazinone 340 when treated with benzonitrile oxide yields an addition product 341 which undergoes oxidative cyclization in the presence of iodine-potassium iodide to the ring-closed [l,2,4]oxadiazolo[4,5-tf]pyrazines 342. 

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>. 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

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). 

The only examples of this synthesis employed isoxazolopyrazine substrates that were themselves made from pyrazines. Thus l-benzyl-5,6-dihydro-2(l//)-pyrazi-none 4-oxide (99) underwent addition by ethynylbenzene to give 5-benzyl-2-phemi-6,7-dihydro-3a//-isoxazolo[2,3-a]pyrazin-4(5//)-onc (100) (60%), which subsequently underwent ring cleavage by molybdenum hexacarbonyl in wet acetonitrile to afford l-benzyl-3-phenacyl-3,4,5,6-tetrahydro-2(l//)-pyrazinone (101) in 54% yield several analogues were made similarly.1539... 

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. 

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... 

Chloro-3-isobutylpyrazine 4-oxide gave 3-isobutyl-2( I // )-pyrazinone 4-oxide (111, R = Hu ) (5 M NaOH, reflux, 2 h 39%) 86 2-chloro-3-phenylpyrazine 4-oxide gave 3-phenyl-2( I //(-pyrazinone 4-oxide (111, R = Ph) (KOH, H20—EtOH, reflux, 1 h 30%) 1290 also analogues likewise.1290... 

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. 

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... 

Hydroxymethyl-2(l/7)-pyrazinone 4-oxide (142) gave 6-oxo-l,6-dihydro-2-pyrazinecarboxylic acid 4-oxide (143) ( Ni peroxide , NaOH, H20, 20°C, 4 h 40%).89... 

This minor route to pyrazine N-oxides involves either reductive or hydrolytic debenzylation of l-benzyloxy-2(l//)-pyrazinones, often available by primary synthesis. 

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... 

Amino-6-phenyl-2-pyrazinecarboxamide from its 4-oxide (257) (Na2S204, H20, reflux, 24 h 97%) 1517 also substituted-phenyl analogues likewise.1517 6-Phenyl-2( I //(-pyrazinone from its 4-oxide (258) (Na2S204, EtOH—H20, reflux, 30 min then more Na2S204, reflux, 30 min 59%).88 Also other examples.1457... 

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... 

Diethyl-5-methyl-3,6-dihydro-2(l//)-pyrazinone 4-oxide (301) gave dimethyl 4,4-diethyl-3a-methyl-6-oxo-4,5,6,7-tetrahydro-3a/7-isoxazolo[2,3-a]pyrazine-2,3-dicarboxylate (302) (Me02CC CC02Me, CHC13, reflux, 3 h 64%) 544 homologues likewise.544... 

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