Pyrazine A-oxide

Pyrazine A-oxides have continued to attract much attention in recent years, perhaps because the presence of an A-oxide entity can substantially modify the properties of the whole system, especially in respect of activities at other positions on the ring. For example, the aromaticity index for 2-methoxypyrazine is decreased by 23% on formation of its 4-oxide and formation of an A-oxide activates adjacent positions toward direct bromination, deuteration, and other electrophilic attack.  

Some pyrazine A -oxides have been made by primary synthesis (see Chapters 1 and 2). Other preparative routes are discussed in the following subsections. 

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

For example, l-bcnzyloxy-2(l//)-pyi a/in()nc (217, R = H) afforded 70% of 1-hydroxy-2(17/)-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. The homologous l-benzyloxy-5,6-dimethyl-2(l/7)-pyrazinone (217, R = Me) gave l-hydroxy-5,6-dimethyl-2(17/)-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). 

This reaction is the most used route to pyrazine 7V-oxides. The choice of oxidant is not always clear but the following classified examples may afford some help. In each case, the substrate was the corresponding A -deoxypyrazine, unless stated otherwise. 

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Protonation of pyrazine A-oxides takes place at the unsubstituted ring nitrogen as revealed by examination of their UV spectra and ionization constants in water. The same holds for unsubstituted quinoxaline A-oxide and the 3-amino derivative. Pyrazine and quinoxaline di-A-oxides are protonated at one A-oxide oxygen atom (74KGS1554). 

The pyrazine ring is stable toward permanganate oxidation, and this explains a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines or benzo-fused quinoxalines. In contrast, alkyl side chains on pyrazines are effectively oxidized by permanganate, selenious acid, selenium dioxide, or dichromate to afford the corresponding carboxylic acids (Section 8.03.7.1). Oxidation of pyrazines with hydrogen peroxide or percarboxylic acids gives pyrazine A -oxides and/or A, A -dioxides (Section 8.03.5.2). 

Deoxidative chlorination of alkyl- or aryl-substituted pyrazine A -oxides with refluxing phosphoryl chloride for 1 h provides 76-78% yields of the chloropyrazines <1997MI1076>. 

Pyrazine A -oxides have been conveniently synthesized by oxidation of pyrazines (Section 8.03.5.2), and by condensation of a-amino nitriles with a-oximino ketones (Section 8.03.9.3). 

Phosphoryl chloride rearrangement of suitably substituted pyrazine A-oxides is a convenient route to some substituted chloropyrazines. Thus, Palamidessi, Bernardi, and Leone obtained tri-chloropyrazine from 2,6-dichloropyrazine 4-oxide (Scheme 27).296... 

Pyrazine A-oxides are usually prepared by direct oxidation, and a common technique is to add hydrogen peroxide of varying strength (30-85% w/w) to a solution of the pyrazine in acetic acid. Alternatively oxidation is carried out in either formic acid or trifluoroacetic acid. 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

In the ReissertHenze reaction, quinoline A-oxide reacts with benzoyl chloride and potassium cyanide to give 2-cyanoquinoline in good yield (Scheme 42). Pyridine 1-oxides undergo the ReissertHenze reaction readily when the reaction is carried out in nonaqueous medium using PhCOClMe3SiCN (Scheme 43). Pyrimidine A-oxides and pyrazine A-oxides also undergo ReissertHenze reactions. 

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. 

Pyrazine A-oxides undergo a variety of reactions. Of these, deoxydative chlorination to C-chloropyrazines has been covered in Section 4.1.3 other reactions are discussed in the following subsections. 

B. Properties of Pyrazine A-Oxides and their C-Alkyl Derivatives... 

The strong base-weakening effect of an A-oxide substituent upon a para-situated sp nitrogen atom is exemplified by a comparison of the of pyrazine [0.65 (122)] with that of pyrazine A-oxide [0.05 (745)]. The pKg of 3-methylpyrazine 1-oxide is 0.46 (745). Pyrazine A-oxides form salts thus 2,5-dimethylpyrazine A-oxide forms 1 1 addition products with hydrogen chloride, methyl iodide, and benzyl chloride (625). Thermodynamic parameters for the second protonation of tetramethylpyrazine 1,4-dioxide have been determined from measurements at 25, 40,60,80, and 90° (746). 

Kinetics have been studied for ring D exchange in MeOK-MeOD for pyrazine A-oxide (590), and the first-order rate constant at 120° for H-D exchange for pyrazine A-oxide in liquid ND3 has been determined as 1.0x10 sec (747). 

Pyrazine A -Oxides, their C-Alkyl and C-Aryl Derivatives TABLE IV.l OXIDATION OF PYRAZINES TO PYRAZINE A-OXIDES... 

Hydrogen-deuterium exchange rates of H2 and in some 3-substituted pyrazine 1 -oxides in Na0D-D20 have been correlated with a constants, and the log of the H2 exchange rates have been shown to be rectilinearly related to the pK values of these compounds (745). A considerable exchange-rate enhancement was caused by replacement of the =C4-H function in a pyridine A-oxide by a =N4 with formation of a pyrazine A-oxide (745). 

Pyrazine A -oxide with potassium metal in vacuo has been shown to give the pyrazine anion radical accompanied by removal of the oxygen atom (752). The cation radical of pyrazine di-A -oxide has been generated electrochemically and its e.s.r. spectrum recorded (753). 

Infrared absorption spectra of pyrazine A -oxides and alkylpyrazine A -oxides have been recorded and discussed (575, 625, 626). The ligand 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide and its complexes with cobalt(II), nickel(II), and copper(II) have been prepared and are polymeric octahedral in structure (754). 

TABLE IV.2 REACTION OF PYRAZINE A-OXIDES WITH ACETIC ANHYDRIDE... 

G. Pyrazine A -Oxides with Phosphoryl Chloride (and Other Acid Chlorides)... 

In the reactions they examined no 2,5-disubstituted pyrazines could be detected in the products. A mechanism of substitution in the -position of pyrazine A -oxides has been proposed (838). 

Preparations of pyrazine A -oxides containing extranuclear hydroxyl groups are also described in Qiapter III as follows Section III.l, 2-aminopyrazine 1-oxides from a-amino nitriles and a-hydroxyimino carbonyl compounds (540, 541) Section III.2, 3-substituted pyrazine 1-oxides from 2-amino-2-deoxy-D-glucose(or mannose) oxime with glyoxal (543, 544) and Section III.5, ring closure of the C-C-N-C-C-N-0 system (553). 

Most methods of preparation of aminopyrazines and their A-oxides have been described in detail in earlier chapters under pyrazine and pyrazine A-oxide ring syntheses, and their reactions. These are discussed only briefly below reference made to the relevant chapter and literature references. 

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