Tautomeric Pyrazinones

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. 

There are no recent general reviews specifically on oxypyrazines but most aspects of 2,5-piperazinediones 13,6-dihydro-2,5( l //,4//)-pyrazincdioncs have been covered in some detail.472,743 

There is no longer any real doubt that simple tautomeric pyrazinones like 2(1//)-pyrazinone (1) exist predominantly in their oxo forms. However, largely confirmatory theoretical,1042,1430,1623,1675 NMR,1424 and IR studies1398 on such pyrazinones have appeared recently in addition, 2,3(1 H,AH)-pyrazinedione (9) appears to exist substantially as such,1623,1675 whereas the 2,5-isomer [2,5(l//,6A)-pyrazinedione ] appears to prefer an equilibrium mixture (10) of 2,5-dihydroxypyrazine and 

5- hydroxy-2(l//)-pyrazinone on theoretical grounds.1430 Related studies on tau-tomerism have also appeared.57,465,931,932 An X-ray analysis of 3-carboxymethyl- 

6- methyl-3,6-dihydro-2,5(l//,4//)-pyrazinedione (11) has confirmed its fine structure in the solid state.  

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The N-alkylation, N-arylation, and in particular N-heteroarylation of piperazines is an important process because of the common propensity (justified or not) for introducing a piperazino grouping into structures perceived as potentially bioactive in a variety of drug-related areas. The various routes to such N-alkylated piperazines are outlined in this section, which also includes examples of the N-alkylation of di- or tetrahydropyrazines the N-alkylation of (tautomeric) pyrazinones and the like is covered in Section 5.1.2.2. 

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. 

The following alkylations illustrate the results to be expected from various types of tautomeric pyrazinones and a variety of reagents and conditions. The examples are grouped according to the type of substrate and the given percentages represent isolate yields except when stated otherwise. 

Several rarely used but quite important reactions of tautomeric pyrazinones are typified in the following examples ... 

Most alkoxy- or aryloxypyrazines have been made by primary synthesis (see Chapters 1 and 2), by addition of alcohols to alkynylpyrazines (see Section 3.2.4.9), by alcoholysis or phenolysis of halogenopyrazines (see Sections 4.2.3 and 4.4), by O-alkylation of tautomeric pyrazinones or extranuclear hydroxypyrazines (see Sections 5.1.2.2 and 5.2.2), or by epoxidation of alkenylpyrazines (see Section 3.2.4.1). Some of the few remaining routes (presently of minor preparative value) are illustrated briefly in the following recent examples ... 

These pyrazine ethers, both nuclear and extranuclear, undergo several useful reactions. Their hydrolysis to tautomeric pyrazinones or hydroxyalkylpyrazines has been covered in Sections 5.1.1 and 5.2.1. Other reactions are illustrated in the following examples ... 

Tautomeric pyrazinones may be rendered nontautomeric by O-alkylation to afford alkoxypyrazines (see Section 5.3.1) or by N-alkylation to furnish 1-alkyl-2( I //(-pyrazinones or l-alkylpyrazinium-3-olates (see Section 5.1.2.2). 

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... 

Note Like tautomeric pyrazinones (Section 5.1.2.1), nontautomeric pyrazinones undergo thiation easily. 

Most tautomeric pyrazinethiones have been made by primary synthesis (see Chapters 1 and 2), thiolysis of halogenopyrazines (see Section 4.2.4), or thiation of tautomeric pyrazinones (see Section 5.1.2.1) a few nontautomeric pyrazinethiones by primary synthesis (see Chapters 1 and 2) or thiation of nontautomeric pyrazinones (see Section 5.4.2) and nearly all extranuclear pyrazinethiols by thiolysis of extranuclear halogenopyrazines (see Section 4.4). Other routes to such pyrazinethiones and pyrazinethiols are illustrated in the following examples ... 

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