From Methylpyrazines

Preparations of acylpyrazines from methylpyrazines have been described in Sections IV.2A(2) (635) and IV.2A(3) (634, 642, 645-647, 650-651). Recently it has been shown that 2-hydroxy(or mercapto)-3-methylpyrazine with two equivalents of butyllithium in dry tetrahydrofuran gave the colored dilithium salt (71, X = 0 or S), which reacted with alkyl benzoates and gave 2-benzoylmethyl-3-hydroxy(or mercapto)pyrazines (72, X = O or S, Y = 0). Similar reactions occurred with thio esters to give the thiocarbonyl compounds (72, X = O or S, Y = S)(1446). 

---

The reactions of pyrazinylmethylsodium (8), prepared from methylpyrazine (7) and sodium amide in liquid ammonia, with a series of aliphatic, aromatic, and heterocyclic esters have been shown to give in most cases 2-(acylmethyl)pyrazines... 

Dimethoxyphenyllithium has been found to be more effective than phenyl-lithium (642) in the preparation of phenacylpyrazine from methylpyrazine and methyl benzoate (651). 

In more extensive studies of these condensations, Behun and Levine (706) prepared the corresponding carbinols from methylpyrazine and eight aldehydes and ketones with sodium amide in liquid ammonia generally in high yield ... 

Methylpyrazine heated with paraformaldehyde at 165° for 4.5 hours formed 2-(2 -hydroxyethyl)pyrazine (38%) (470,722), and with benzophenone and sodium amide gave 2-(2-hydroxy-2, 2 -diphenylethyl)pyrazine (705). A series of substituted 2-(2 -hydroxyethyl)pyrazines (e.g., 23) have been prepared from sodio-2-methylpyrazine (22) (from methylpyrazine and sodium in liquid ammonia) and aldehydes or ketones (706). Similarly 2-methyl-6-pyrazinylmethylsodium with aldehydes and ketones undergoes aldol-type condensations to give the corresponding secon-... 

Flash photolysis EPR and CIDEP studies of corresp. radicals derived from methylpyrazines. ... 

Bromination using NBS has been used to provide acetylpyrazine derivatives from the corresponding ethylpyrazines. Bromination of 2-ethyl-3-methylpyrazine gives 2-bromoethyl-3-methylpyrazine in quantitative yield this may be oxidized using the sodium salt of 2-nitropropane or with pyridine AT-oxide to yield 2-acetyl-3-methylpyrazine in yields of 66 and 25% respectively (Scheme 14). 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Scheme 21.—Formation of 2-Methylpyrazine from Saccharide Fragments.

IS the tosylamide of cyclooctylurea. Glipizide (163) is synthesized from 5-methylpyrazine-2-carboxylic acid (161) and 4-(2-aminoethyl)benzene sulfonamide to give sulfonamide 162, which forms glipizide (163) on reaction with cyclohexylisocyanate and base in acetone. 

Isolation and identification of pyrazine alkaloids (Table III) have been achieved in most cases by a combination of gas chromatography and mass spectrometry (35,36,38,69,97,142). Methyl-, 2,3,6-trimethyl-, and tetramethylpyrazines (23a, 21a, and 22a) from the melon fly are identified by utilizing a solid sampling technique in conjunction with gas chromatography-mass spectroscopy (147). Methylpyrazines show the molecule ion as a base peak. Fragmentation proceeds mainly by the loss of HCN or CH3CN from the molecular ion (141). Eth-... 

Alkyl-2-methoxypyrazines exhibit a base peak at miz 124 in the mass spectrum. The peak corresponds to a molecular ion in 2-methoxy-3-methylpyrazine (24a) and to a fragment ion, resulting from a McLafferty rearrangement of an alkyl group, in 3-isopropyl-2-methoxypyrazine (24b) and 3-5cc-butyl-2-methoxy pyrazine (24d) (97). 

Optically pure or almost pure a-methyl a-amino acids (alanine derivatives) can be prepared by reacting 5-substituted 2,5-dihydro-3,6-dimethoxy-2-methylpyrazines 1, which are derived from alanine and various amino acids as the chiral auxiliary, with alkylating agents, followed by hydrolysis (see Table 2). 

The composition of the products from the alkylation of lithiated 3,6-dialkoxy-2,5-dihydropy-razines with bis-alkylating reagents depends on the equivalents of electrophile employed. For example, with three equivalents of bis-alkylating electrophiles, (25)-2,5-dihydro-2-isopropyi-3,6-dimethoxy-5-methylpyrazine (I) gives high yields of the 1 1 adducts 2 or 5 with > 97% de2. These products can be further converted to the bicyclic systems (3 and 6. respectively) which, upon hydrolysis, give optically pure cyclic amino acids (4 and 7). Methyloxirane is used as an acid scavenger in order to release the free amino acid zwitterion. 

The corresponding ylid from 2-methylpyrazine with DMAD in acetonitrile gave 4% of 264, and in refluxing chloroform, 8.5% of a 2 1 mixture (NMR) of adducts that were stated to be 264 and 265 on the presumption that the initial ylid was a single substance (263).329... 

Endo-trig cyclization of anion, formed from 2-methylpyrazine by LDA in THF at — 78 °C, with methyl 3-propynoate provided 6-methyl-8H-pyrido[l,2-f ]pyridazin-8-one in 52% yield (06TL5063). 

Pyrazines occur naturally, although not in appreciable quantities. Fusel oil contains 2,5-dimethyl-, 2,5-diethyl-, trimethyl-, and tetra-methylpyrazine. The last compound has been isolated from cultures of Bacillus natto and B. subtilis and from fermented soybeans.4-6 Emimycin (pyrazine-2-one-4-oxide), a powerful antibiotic, has been obtained from Streptomyces No. 2020-1.7,8... 

The condensation of a,j8-diketones with 1,2-diamines is a classical route for the synthesis of alkyl- and arylpyrazines. For example, good yields of dihydropyrazines are obtained from reaction of 2,3-dioxo-alkanes andethylenediamine dehydrogenation over a copper chromite catalyst at 300° then gives 3-alkyl-2-methylpyrazines (Scheme 1). Attempts to carry out the dehydrogenation using a variety of milder and more convenient laboratory procedures were not successful.100,110... 

The reaction of the sodium derivative of methylpyrazine with alkyl halides in liquid ammonia gives good yields (44-81%) of mono-alkylated products phenylation has been achieved by reaction with benzyne (generated from bromobenzene and sodamide in liquid ammonia) and gives 53% benzylpyrazine.178 The alkylation of the sodio derivative of 2-methoxy-3-methylpyrazine with methyl iodide, and of the product with ethyl bromide, gives 2-methoxy-3-sec-butylpyrazine (25) a constituent of galbanum oil.31... 

Dimethyl-188 and 2,6-dimethylpyrazine react very similarly to methylpyrazine. Thus, 2,6-dimethylpyrazine can be converted into a monoanion with sodamide in liquid ammonia which can be condensed with aldehydes and ketones,179 acylated with esters,181 and alkylated with alkyl halides181 to give the corresponding 2-methyl-6-substituted pyrazines. Acylation under suitable conditions also yields diacylated derivatives. Thus, when 2,6-dimethylpyrazine, sodamide, and ethyl benzoate are reacted in 1 3 2 molecular proportion, 38% 2,6-diphen-acylpyrazine (35) and 25% 2-methyl-6-phenacylpyrazine (36) is obtained. From the preparative point of view it is better to form the diacyl derivative by the further acylation of the monoacyl derivative rather than by direct diacylation.187... 

Forexample, good yields of 2-chloropyrazine 4-oxide,391,392 2-carbox-amidopyrazine 4-oxide,392 and 2-methylpyrazine 1,4-dioxide,391 have been obtained by oxidation of the appropriate pyrazine. In general, the preferred product from oxidation of monosubstituted pyrazines at lower temperatures is the monooxide formed by oxidation on the nitrogen remote from the substituent, whereas 1,4-dioxides are obtained by prolonged heating at higher temperatures.155 Pertrifluoro-acetic acid oxidation of 2,5-dichloro-3,6-dimethylpyrazine furnishes the di-iV-oxide, whereas permaleic acid gives only the mono-iV-oxide.393... 

---