Reactions of Pyrazine

Pyrazines are particularly unsuited to direct substitution by the usual electrophilic reagents owing to the inductive effect of the ring nitrogen atoms, and to resonating structures such as (1). 

Pyrazine is aminated to 2-aminopyrazine with sodium amide in liquid ammonia at room temperature (606), in solvents such as dioxane or pyridine at room temperature or above (yields to 16%), or in the absence of added solvent at 50-55 (yields 36-60%) (607). N.m.r. evidence has been obtained for the anionic a complex (2) in the amination of pyrazine (608). 3-Substituted 1-methylpyrazinium ions 

Pyrazine with hydroxylamine-O-sulfonic acid underwent (V-amination to give A -aminopyrazinium derivatives (610). 

Homolytic amidation of pyrazine to 2-carbamoylpyrazine can be effected in 80% yield by using concentrated sulfuric acid with carbamoyl radicals ( CONH2) generated from the action of hydrogen peroxide and ferrous sulfate on formamide (611). 

Alkylation of pyrazine has been achieved under a variety of conditions. Treatment of pyrazine in ether at — 20° with butyllithium gave a 10% yield of 2-butyl-pyrazine but with phenyllithium only polymeric material or unchanged starting material was obtained (612). Pyrazine is alkylated at the 2-position by the radical MeNHCO(CH2)4CH2 generated from 2-methyl-3,3-pentamethyleneoxazirane and ferrous sulfate (613). Aldehydes and ketones in the presence of a solution of an alkali or alkaline earth metal in liquid ammonia (or a suspension of these metals in other solvents) can be made to alkylate the pyrazine ring in moderate to good yields. Thus from pyrazine and ethyl methyl ketone, a 60% yield of 2-s-butylpyrazine was obtained (614). 

Some typical examples of recently reported reactions of unsubstituted pyrazine are mentioned here but, for pragmatic reasons, those of piperazine are simply covered piecemeal in appropriate sections and may be accessed through the Index. 

Pyrazine gave 1-dodecylpyrazinium iodide (6) (Ci2H23I, AcMe, reflux, 8 h 4%, owing to losses in purification)1475 or 1,4-diethylpyrazinediium bistetrafluo-roborate (Et3OBF4, C1CH2CH2C1, reflux, N2,45 min 75%).1667 

Pyrazine gave 1-methylpyrazinium bromide (7), and thence 1-methylpiperazine (8) (MeBr, CH2C12, 25°C, sealed, 50 h 44% then H2, Rh/Al203, EtOH—H20 30%).1337 

Pyrazine gave 1,4-pyrazinediium bis(dicyanomethylide) (9) (tetracyanoethylene oxide, PhMe, reflux, 6 h 45% X-ray confirmation of structure).62, cf 573 

Note Pyrazine may be C-alkylated directly, e.g., by alkyl radicals also by addition to give an alkylated hydropyrazine, sometimes amenable to subsequent 

Pyrazine gave 1-methylpyrazinium bromide (7), and thence 1-methylpiperazine 

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The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>. 

The reaction of pyrazine with phenyllithium in THF or TMEDA at -45°C leads quantitatively to 102, as shown by the H-NMR spectrum. The assignment of the structure is made possible by comparison with the amino anaIog31. Both H- and l3C-NMR spectra of 102 are rather poorly diagnostic because they consist of broad signals. 

Mass spectrum from V. J. Angelico, S. A. Mitchell, and V. H. Wysocki, "Low-Energy Ion-Surface Reactions of Pyrazine with Two Classes of Self-Assembled Monolayers, Anal. Chem. 2000, 72, 2603. 

Reduction of pyrazine with potassium in 1,2-diethoxyethane at — 70° gives the paramagnetic radical anion. Anions have also been generated from the low-temperature reaction of pyrazine, methyl-pyrazine, 2,5- and 2,6-dimethylpyrazines with sodium or potassium in tetrahydrofuran or 1,2-dimethoxyethane. From measurements of their ESR spectra, ion-pair formation is proposed between the alkali metal cation and the pyrazine anion.96-101... 

Recently some interesting ring isomerization reactions of pyrazines have been reported. Both under photolytic and pyrolytic conditions pyrimidines are formed. Lahmani and Ivanoff irradiated pyrazine in various organic solvents and pyrazine, methyl-, and 2,5- and 2,6-dimethylpyrazine in the vapor phase.163,164 The products of these reactions are shown in Scheme 13. The presence of 2-methylpyrimidine in the photolysis products of 2-methylpyrazine was suspected, but not proved. The authors interpret the above data as indicative of the... 

Aminopyrazines are conveniently prepared from carboxamido-pyrazines by application of the Hofmann reaction (see Section V,B). Thus, Camerino and Palamidessi prepared aminopyrazine in 80% yield from carboxamidopyrazine.312 Aminopyrazine may also be prepared from the reaction of pyrazine with sodamide in liquid ammonia,313 and 3-amino-2,5-dimethylpyrazine is the product of amination of 2,5-dimethylpyrazine with sodamide in dimethyl-aniline.311 The ammonolysis of halopyrazines also represents a useful preparative procedure for aminopyrazines (see Section V,C). This reaction proceeds most easily in the case of fluoro compounds for example, fluoropyrazine is converted into aminopyrazine in 70% yield by treatment with concentrated aqueous ammonia at room temperature for 3 days,299 whereas the corresponding reaction with chloropyrazine has been carried out in a sealed tube at 150°.147 Alkaline hydrolysis of 2,4-dihydroxypteridines followed by decarboxylation yields aminopyrazines 315 thus, high-temperature alkaline hydrolysis of 7-methyl-2,4-dihydroxypteridine (7-methyIlumazine) gives, after decarboxylation of the intermediate pyrazinecarboxylic... 

Thin-layer chromatography indicates that prolonged reaction of pyrazine 1,4-dioxide with acetic anhydride gives the mono-iV-oxide, together with other unidentified products.406 Pyrazine mono-A-oxide is also formed on reaction of pyrazine-2-carboxylic acid 4-oxide with acetic anhydride.408... 

This chapter covers the preparations, physical properties, and reactions of pyrazine and its C-alkyl, C-aryl,. V-alkyl, or A/ -aryI derivatives as well as their respective di-, tetra-, and hexahydro derivatives (the last usually known as piperazines). In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into pyrazines and hydropyrazines already bearing substituents and the reactions specific to the alkyl or aryl groups in such products. For simplicity, the term alkylpyrazine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, cycloalkyl-, and aralkylpyrazines likewise, the term arylpyrazine includes both aryl- and heteroarylpyrazines. 

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. 

Reactions of pyrazine ketones, that have been covered already, include reductive deoxygenation to alkylpyrazines (Section 3.2.1.5), reduction to extranuclear... 

Reactions of pyrazine ion-pairs have been studied dimerization and equilibration with anthracene.163,164 The ion-pair with Li features in the reaction of ethylene diamines with butyllithium to yield pyrazine derivatives.165... 

The reaction of pyrazine with allylmagnesium chioride gave an addition complex which, on hydrolysis, gave a low yield of 2-allylpyrazine and other products (618). 

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

TABLE V. 1 REACTIONS OF PYRAZINE W-OXIDES WITH PHOSPHORYL CHLORIDE (AND OTHER ACID CHLORIDES) ... 

D. By Reaction of Pyrazine 1,4-Dioxide with Phosphoryl Chloride (and Other Acid Chlorides)... 

The reactions of pyrazine with sodium amide in liquid ammonia to give the anion of 2-amino-1,2-dihydropyrazine (608), and of 3-substituted 1-methylpyrazinium ions with liquid anunonia to give 3(or 5)-substituted 2-amino-1-methyl-1,2-dihydro-pyrazines (609) have been described in Section IV. 1C. Similar reactions of pyrazine with phenyllithium at —45° in tetrahydrofuran (720a) and of 1,2,5-trimethyl-pyrazinium salts in liquid ammonia with nitromethide and ethanethiolate anions (721) have been described in Section IV.2C(8). 

This volume summarizes published pyrazine chemistry with emphasis on syntheses, properties, and reactions of pyrazines and pyrazine iV-oxides (Chapters 1-X). Treatment of theoretical aspects is minimal. Although not strictly relevant. Chapter XI is presented as a summary of earlier reviews and more recent literature of reduced pyrazines (including piperazines). The literature recorded in Beilstein to 1929 and Chemical Abstracts through 1978 (Volume 89) has been covered together with selected references to 1980. Whereas every reasonable effort has been made to incorporate most significant material, no attempt has been made to include all relevant data. Tables have been incorporated in the text to extend the range of examples. 

Acylpyrazines, constituents in foodstuffs and pheromones, have been prepared by the Minisci-type radical reactions of pyrazines even though these methods often suffer from poor regioselectivity of aromatic substitution. Alternatively, synthesis of acetylpyrazines and propionylpyrazines 33 was achieved via a Stille coupling of bromopyrazines 31 with tributyl-(l-ethoxyalkenyl)tin (32), followed by acidic hydrolysis of the ether derivative [24]. 

Reactions of Pyrazine Ketones Pyrazine Cyanates, Isocyanates, Thiocyanates, Isothiocyanates, and Carbonitrile Oxides... 

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