3- Amino-1 -methyl-2 -pyrazinone

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>. 

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-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... 

Pyrazinediamine (145, R = H) gave 3-imino-4-methyl-3,4-dihydro-2-pyraz-inamine hydriodide (146, R = H) (Mel, MeN02, 20°C, 6 days —90%), which in alkali underwent hydrolysis to 3-amino- l-methyl-2( l//)-pyrazinone (148, R = H) rather than Dimroth rearrangement into 3-methylamino-... 

Amino-5-azido-2,6-pyrazinedicarbonitrile 3-Amino-5-benzoyl-6-bromo-2-pyrazinecarbonitrile 3-Amino-5-benzoyl-2-pyrazinecarbonitrile 3-Amino-5-benzoyl-2-pyrazinecarboxamide 3-Amino-6-benzylamino-2-pyrazinecarboxylic acid 6-Amino-5-benzyl-3-methyl-2(177)-pyrazinone 3-Amino-6-benzylsulfinyl-2-pyrazinecarboxylic acid 3-Amino-6-benzylthio-... 

Amino-6-methyl-2(l//)-pyrazinethione l-Amino-3-methylpyrazinium iodide 3-Amino-l-methyl-2(l//)-pyrazinone 3-Amino-5-methyl-2(l//)-pyrazinone 3-Amino-6-methyl-2(l//)-pyrazinone... 

Amino-6-methyl-2(l//)-pyrazinone 3-Amino-6-methylsulfonyl-2-pyrazinecarboxylic acid... 

Methoxy- 2(1 77)-pyrazinethione 3 -Methoxy- 2(1 77)-pyrazinone 6-Methoxy-2(177)-pyrazinone 2-Methoxy-3-trimethylsilylpyrazine Methyl 6-acetamido-2-pyrazinecarboxylate Methyl 3-acetoxy-2-pyrazinecarboxylate Methyl 5-acetoxy-2-pyrazinecarboxylate Methyl 6-acetoxy-2-pyrazinecarboxylate Methyl 5-acetyl-3-amino-2-pyrazinecarboxylate Methyl 6-acetyl-3,5-diamino-2-pyrazinecarboxylate Methyl 5-allylamino-3-amino-6-chloro-2-pyrazinecarboxylate... 

The co-occurrence of these three methoxypyrazines is consistent with a biosynthetic pathway (Figure 2) proposed over 20 years ago 14), The amino acid leucine is envisaged as the source of the C4 side chain of the methoxypyrazine, through condensation of its amino amide with an unspecified C2 component, and methylation of the initial pyrazinone condensation product. This proposed biosynthetic pathway readily accommodates all three methoxypyrazines through incorporation of either leucine, isoleucine or valine, all of which are commonly available amino acids in plants. Although the validity of this pathway in vines or other plant material is unknown, the major features of this proposed pathway have been shown to apply to the biosynthesis of isopropylmethoxypyrazine by certain bacteria (75, 16). 

Amino-iV-(l-chloroacetyl-3-metliylbutyl)butyrainide (25, R = H), prepared in situ as hydrochloride by treatment of its A-tert-butoxycarbonyl derivative (25, R = CO2BU ) in HCl-dioxane, gave 3-ethyl-6-isobutyl-5-methyl-2(l7/)-pyrazinone (26) (MeOH, reflux, 2 h 90%) many analogues were made similarly. - "- -1 ... 

Amino-5-benzyl-3-methyl-2(l//)-pyrazinone 210 exists predominantly in the oxo form 210a in aqueous buffered solution (XT 2000), but as the tautomer 210b in dioxane. The equimolar mixture of tautomers was observed in dioxane/aq. buffer = 90 10. The linear dependence of the tautomerization constant on the solvent polarity was established. No imino tautomer 210c was observed (93JOC7542). 

Lacey et al., 1991 Allen and Lacey, 1993 Hashizume and Umeda, 1996 Hashizume and Samuta, 1997 1999 Roujou de Boubee et al., 2002). The biosynthetic pathway of these compounds involves formation of the amide of the appropriate amino acid, formation of a pyrazinone, and methylation as shown in Fie. 4.4 (Murray and Whitfield, 1975). 

Another useful method for the elucidation of the hydroxypyrazine-pyrazinone tautomerism is UV spectral analysis. The objective structure in solution is easily estimated by comparison with the UV spectra of the proton-fixed compounds of two tautomers, O-methylated (22) and A-methylated derivatives (23), which are prepared by methylation of the hydroxypyrazines or pyrazinones with diazomethane (Scheme 2). For example, 6-amino-5-benzyl-3-methyl-2(177)-pyrazinone (21 R = Me, R = CHzPh, X = NH2) has been shown to predominate over the hydroxy form (20) because of its nearly identical UV spectrum with the corresponding V-methylated derivative (23) <93JOC7542>. In contrast, 6-chloro-2-hydroxypyrazines (20 R, R = Me or Ph, X = Cl) exist in the hydroxy form rather than as the tautomeric amide, which is an exceptional example of predominance of the hydroxy form with parallels in the chloro-pyridinone field <7UCS(C)2977>. 

---