3-Amino-5- pyrazinone

There has been a plethora of recent hterature regarding the synthetic manipulations of the 2(lH)-pyrazinone skeleton. Even though the addition-elimination reactions at the C-3 position to decorate the pyrazinone scaffold are well documented [24], the versatihty of such approaches can be found somewhat limited. Selective attack of nucleophiles on the chloroimine group of the pyrazinone system can generate 3-alkoxy- and 3-amino-pyrazinones (Scheme 9) [27,28]. The 3-CN group was introduced via a Rosemund-von Braun reaction with copper(I)cyanide under harsh conditions (heating in NMP at 150 °C) [27] (Scheme 9). 

Another modification of die heterocycle was the amino-pyrazinone structure 47. 

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-amino-pyrazinone. 

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). 

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>. 

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>. 

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. 

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). 

Note In the foregoing syntheses, acyl halides react at their halogeno entity to afford pyrazinones however, sometimes they appear to react at their carbonyl entity (at least with primary amino cosynthons) to afford halogenopyrazines (see examples later in this subsection). 

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... 

Amino-2-phenylacetamide (192) and ethyl benzoylformate (193) gave 5-hy-droxy-3,6-diphenyl-2(l //)-pyrazinone (194) (EtONa, EtOH, reflux, 5 h 19%).1386 ... 

Amino-3-methyl-2-butanone (270) and ethyl glycinate (271) gave 5,6, 6-trimcthyl-3,6-dihydro-2( I //(-pyrazinone (272) (Et3N, PhH, reflux, 5 days ... 

Acetoxy-5-benzyl-6-diacetylamino-3-methylpyrazine (31) gave 6-amino-5-bcnzyl-3-methyl-2( I //)-pyrazinone (32) (neat H2NNH2, 20°C, 13 h 67% note additional IV-deacetylation).883 Also other examples.304 809 960,1565 1575... 

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... 

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... 

---