Preparation of Pyrazine

Apart from the pyrolysis of 2-tert-butylsulfonylpyrazine to afford pyrazine (1) [in 49% yield with loss of sulfur dioxide and unsaturated ( ) hydrocarbon]239 and the reduction of pyrazine to piperazine (2) (in 76% yield by treatment of an alkaline solution with Ni—A1 alloy),479 no new or improved routes to pyrazine or piperazine appear to have been reported in recent years nor has any di- or tetrahy-dropyrazine been prepared. Both pyrazine and piperazine are now available commercially at modest cost. 

Distillation of a mixture of piperazine or piperazine hydrochloride with lime and zinc dust also gives pyrazine (32). In addition, pyrazine has been prepared from oxidation of aminoacetaldehyde with mercuric chloride and sodium hydroxide (23, 255, 256) from bromoacetaldehyde and ammonia in ether followed by the action of mercuric chloride (237) from 2-aminoacetal by heating with anhydrous oxalic acid at 110-190° or by heating its mercuric chloride or platinic chloride double salt with hydrochloric acid (30,31) and from diacetylamine (28). 

Pyrazine has also been prepared by decarboxylation of 2-carboxypyrazine (564), 23-dicarboxypyrazine (397, 564), 2,5-dicarboxypyrazine (22, 272, 564, 565), 23 5-tricarboxypyrazine, and tetracarboxypyrazine (564). It is also produced on heating glucose with 25% aqueous ammonia at 100° (33), on heating 2,6-dioxo-morpholine with hydrazine or hydroxylamine in hydrochloric acid solution, and on heating morpholylsemicarbazide with 20% hydrochloric acid (28). 

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Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

An important preparation of pyrazines (303) is from a-amino ketones RCOCH2NH2 or their monooximes which spontaneously condense to give 2,5-dihydropyrazines (302). The a-amino ketones are often prepared in situ by reduction of isonitroso ketones, and the dihydropyrazines are usually oxidized to pyrazines before isolation icf Section 3.2.2.3.3). Catalytic reduction of a-azido ketones also leads to 2,5-dihydropyrazines (80OPP265). Similarly, a-nitro ketones may be reduced to the a-amino ketones which dimerize spontaneously (69USP3453278). 

Preparation of Pyrazines and Piperazines (1,4-Diazines), and of their Fused Derivatives... 

Imidazoles have proved to be quite useful as substrates for the preparation of pyrazines. Various routes are illustrated in the following examples ... 

Pyrazin-2-yl)imidazo[l,2-a]pyrazine (475) was obtained as a by-product (10%) in the ammonium chloride-catalyzed preparation of pyrazine carbaldehyde dimethyl acetal from the aldehyde (474) and trimethyl orthoformate (71TL1441). 

An improved dissymmetrization of imidazole-4,5-dicarboxylic acid 869 for the synthesis of Ar,AT -disubstituted dicarboxamides 872 involves the preparation of pyrazine-dione diphenyl ester 870. Selective amide formation at the pyrazine carbonyl at low temperatures affords the mixed amide ester 871, which is subsequently converted into 872 (Scheme 213) <2002JOC7151>. 

Procedures involving the reduction of oxirane and ammonia in the vapor phase over an Al203-Si02 catalyst have been patented for the preparation of pyrazine, piperazine, and morpholine. The formation of quinoxalines is illustrated in Eq. 225. ... 

The parent compound of this series, pyrazine, was first prepared in trace amounts by Wolff (30) by heating aminoacetaldehyde diethyl acetal [H2NCH2CH(OEt)2] with anhydrous oxalic acid at 110-190°C, and later in better yield by heating the mercuric or platinic chloride double salts (of the aminoacetaldehyde acetal) with hydrochloric acid (31) it was also obtained from aminoacetaldehyde with mercuric chloride in sodium hydroxide (23). Wolff in 1893 (22) also prepared pyrazine by decarboxylation of the tetracarboxylic acid, obtained by oxidation of tetramethyl-pyrazine and Stoehr (32) prepared it by the distillation of piperazine with lime and zinc dust. Brandes and Stoehr (33) in 1896 described the preparation of pyrazine by heating glucose with 25% aqueous ammonia at 100°C. 

Table ll.l lists literature (89, 165-186) preparations of pyrazines from preformed a-amino carbonyl compounds. 

Table 11.2 lists literature preparations of pyrazines by this general method with a wide selection of reducing agents (8,15,16,18,23,32,166,191-239). 

This method has been widely used for the preparation of pyrazines, and was first employed by Staedel and Riigheimer (10) for the preparation of 2,5-diphenylpyrazine (9) from co-chloroacetophenone (7) and aqueous ammonia. 

Both these series of bicyclic compounds have been used as important starting materials for the preparation of pyrazines by the oxidative removal of the benzene ring from quinoxaline and by cleavage of the pyrimidine ring in pteridines. Both preparative procedures are discussed in detail in Sections 4 and 5. 

Some preparations of pyrazines that are not classified elsewhere are included in this miscellaneous section and are tabulated below. In some of these reactions, products other than pyrazines are also formed but these compounds have not been recorded in Table 11.13 (28,190,305,508-523). 

The primary syntheses of pyrazine JV-oxides from aliphatic components only are described in this chapter. The preparations of pyrazine JV-oxides by oxidation of pyrazines are dealt with under the reactions of the appropriately substituted pyrazines for example, those of pyrazine and alkylpyrazine TV-oxides are described in Chapter IV, and of halogenopyrazine JV-oxides in Chapter V. The cleavage of JV-oxides of pteridines and related systems to aminopyrazine JV-oxides is described in Section VIII.3A(2). 

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). 

Additional data, relevant to the preparation of pyrazine esters described in Section II. 5, are given in Reference 1161. 

Scheme 7. Preparation of pyrazine dimers using triphenylphosphine for azide reduction.

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