Vinylpyrazines

Perhydropyrazino[l,2-c]pyrimidincs were all synthesized by formation of the pyrimidine ring. The antifilarial agent, Centperazine, 166, was built from [6+0] fragments by bond formation a to the ring junction nitrogen (Scheme 21). Compound 165 was prepared in two steps from 2-vinylpyrazine and the yield over five steps was 23% < 1998IJB1149>. 

Minuscule quantities of naturally-occurring pyrazines have been found in some foodstuffs and are largely responsible for their flavor and aroma. For example, 3-isopropyl-2-methoxypyrazine is isolated from green peas and wine and a seasoned wine connoisseur can identify a ppt quantity. In addition, 2-methyl-6-vinylpyrazine exists in coffee. 

A few reports of pyrazine monomers have appeared in the literature (70Millloo). The most extensive study of pyrazine monomers involves their use to prepare photodegradable polymers <76MI11104). 2-Vinylpyrazine (145) copolymers and poly(2,5-distyrylpyrazine)... 

Methylpyrazine reacts with formaldehyde and dimethylamine to give the expected product (40) of Mannich reaction. This is converted in 63% overall yield to vinylpyrazine (41) by quaternization with methyl iodide followed by sodium hydroxide treatment.196... 

Ozonolysis of vinylpyrazine in methanol at — 30° furnishes pyrazine aldehyde in 73% yield.196 Vinylpyrazine undergoes a variety of addition reactions and pyrazylethyl derivatives of amines, ketones, ethyl phenyl acetate, phenylacetonitrile, and acetamide have been obtained.197-199 2-(2-Pyrazylethyl)cyclohexanone (42) has been prepared both by the condensation of vinylpyrazine with cyclohexanone in the presence of sodium metal and by interaction of vinylpyrazine with the pyrrolidine enamine of cyclohexanone followed by hydrolysis.200... 

Chloromethyl-5-methylpyrazine (160) gave 2-methyl-5-triphenylphospho-niomethylpyrazine chloride (161) (PPh3, Me2NCHO, 75°C, 6 h 81%), and thence 2-methyl-5-vinylpyrazine (162) (HCHO, Na2C03, H20—CH2C12, 20°C, 2 h 37%).1446... 

Vinylpyrazine (333, R = H) gave 2-[2-(ethylamino)ethyl]pyrazine (334) (EtNH2, MeOH, AcOH, 60°C, 24 h >90%).1662 Also other examples.847... 

Ethylthio-2-pyrazinecarbonitrile 6-Ethylthio-2-pyrazinecarbonitrile 6-Ethylthio-2-pyrazinecarbothioamide 3-Ethylthio-2-pyrazinecarboxamide 6-Ethylthio-2-pyrazinecarboxamide 3-Ethylthio-2-pyrazinecarboxylic acid 6-Ethylthio-2-pyrazinecarboxylic acid 3-Ethylthio-2,5-pyrazinedicarboxamide 2-Ethylthiopyrazine 1-oxide 2-Ethyl-3,5,6-trimethylpyrazine 2-Ethyl-3,5,6-triphenylpyrazine 2-Ethyl-3-vinylpyrazine 2-Ethynyl-3,6-dimethylpyrazine 2-Ethynyl-3-methylpyrazine 2-Fluoro-5,6-dimethoxy-3-methylpyrazine 2- Fluoro- 5,6-dimethoxypyrazine 2-Fluoro-3,6-dimethylpyrazine 2-Fluoro-3-(l-hydroxyethyl)pyrazine 2-Fluoro-3-iodopyrazine 2-Fluoromethyl-5-methyl-3,6-diphenylpyrazine 2- Fluoro- 5-phenylpyrazine 2-Fluoro-3-phenylthiopyrazine... 

Tris(chloromethyl)-6-methylpyrazine 6-Ureido-2,3,5-pyrazinetricarboxylic acid 2-Valerylmethylpyrazine 2-Vinylpyrazine... 

A large number of alkyl- and vinylpyrazines have been identified in coffee (53),... 

To illustrate further the general methods of preparation described above, literature preparations of methyl-, dimethyl- and vinylpyrazine are summarized below. 

Vinylpyrazine. This has been prepared by dehydration of 2-hydroxyethyl-pyrazine with molten potassium hydroxide (470) and pyrolysis (low yield) (656). A better preparation is claimed from -dimethylaminoethylpyrazine through /l-(pyrazinyiethyl)trimethylammonium chloride by removal of the iodide ion and treatment with alkali (657). Dehydrogenation of 2-ethylpyrazine over a CaO-P2OS-C0O catalyst at 600 also gives 2-vinylpyrazine (658). 

The enhanced activity of alkyl groups attached to the pyrazine nucleus is illustrated by methylpyrazine, which undergoes aldol type condensations with aldehydes and ketones. Methylpyrazine (14) formed an adduct (IS) with chloral in pyridine solution (405) with paraformaldehyde at 165°, it gave 2-hydroxyethylpyrazine (470) (which was subsequently dehydrated with molten potassium hydroxide to 2-vinylpyrazine) and with benzophenone and sodamide it gave the corresponding carbinol (705). 

A series of aminoethylpyrazines (C4H3N2CH2CH2N=) has been prepared by the reaction of vinylpyrazine with amines in the presence of methanolic acetic acid or metallic sodium as the catalyst (730) and likewise 2-[2 -(r -oxocyclohexan-2" yl)ethyl] pyrazine from vinylpyrazine and cyclohexanone (731). 

Ethoxyethyl)-5-hydroxy-2-methylpyrazine heated in acetic acid saturated with hydrogen bromide formed a crystalline bromine-containing compound which with 5% sodium carbonate gave 5-hydroxy-2-methyl-3-vinylpyrazine (248). Heteromacrocyclic ethers have been quaternized (989). 

A series of aminoethylpyrazines has been prepared in high yields by the reaction of 2-vinylpyrazine with ammonia or amines using methanolic acetic acid or metallic sodium as catalyst (730) 2-vinylpyrazine with acetamide and sodium at 120-130° gave 2-(2-acetamidoethyl)pyrazine (18) (731). 

Dimethylaminoethyl)pyrazine was quaternized by methyl iodide to give 2-(2 -trimethylammonioethyl)pyrazine iodide (48) (which with aqueous sodium hydroxide gave 2-vinylpyrazine) (657) and 2-hydroxy-3-nitro-5,6-diphenylpyrazine... 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

Ozonolysis of 2-vinylpyrazine in methanol formed 2-formylpyrazine (732) and oxidation of 2-amino-3-hydroxymethylpyrazine with manganese dioxide in chloroform at room temperature gave 2-amino-3-formylpyrazine (1075). 

Vinylpyrazine undergoes a Michael condensation with cyclohexanone, cyclo-pentanone, and acetophenone for example, 2-vinylpyrazine with cyclohexanone and sodium gave 2-[2 -(r -oxocyclohexan-2"-yl)ethyl]pyrazine, and with acetophenone and sodamide in liquid ammonia gave low yields of 2-(3 -benzoylpropyl)pyrazine (monopyrazylethylation) and the bis Michael adduct (731). 

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