2,5- Dimethyl-3-methylpyrazines

Some meat flavor-contributing pyrazines patented for use for synthetic purposes are methylpyrazine, 5,7-dihydro-5,7-dimethyl-fur o-(3,4-b)pyrazine, and 5-methyl-(7H)-cyclopenta[b]pyrazine (20). 

Quantitatively, dimethylpyrazine production was also lower, suggesting fewer available carbonyl fragments and mechanistically less desirable conditions exist for formation of dimethyl versus unsubstituted or methyl pyrazine. A linear relationship of hi< i correlation was found to exist between pH and the rate of formation of pyrazines, with r2 values of 0.974 and 0.999 for pyrazine and 2-methylpyrazine, respectively. Effect of pH on yield was investigated under standard conditions (2 hr heat treatment at 95°C). pH was found to have a great effect on yield, with a total of 13,000 ppb pyrazines produced at pH 9.0 and only 24 ppb at pH... 

Koehler and Odell236 already studied a number of factors affecting the formation of pyrazines, based on a system of glucose and asparagine (0.1 mol of each), heated for 24 h at 120 °C in diethyleneglycol/water (10 1, v/v). The dichloromethane extract of a distillate was analysed by GC. Below 100 °C, essentially no pyrazines were formed, but the yield increased steeply as the temperature was increased. At 120 °C, the yield increased rapidly with time, up to about 24 h, when it levelled off. Methylpyrazine was the major product in the first 3 h, but the ratio of dimethyl/methyl derivatives continued to increase for about 9 h, when it remained essentially constant at about 3. Altering the proportions of the reactants to 3 1 decreased the yield of methylpyrazine 10-fold and that of the dimethyl compounds 25 times, whereas a proportion of 1 3 decreased the former only by about a one-fourth and hardly affected the latter. Adding... 

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... 

Polarographic studies on pyrazine and methylpyrazines indicate that 1 4-dihydropyrazines are the products of reduction. The reduction of pyrazine itself at the dropping mercury electrode proceeds reversibly. The substitution of methyl groups makes the reduction more difficult with an increased number of methyl groups an increased tendency toward irreversible reduction is noted.102-104 The half-wave reduction potentials for pyrazine, methylpyrazine, 2,6-dimethyl-pyrazine, and tetramethylpyrazine are 2.17, 2.23, 2.28, and 2.50 eV, respectively. Pyrazine is thus more easily reduced than pyridine which has a half-wave potential of 2.76 eV, and less easily reduced than quinoxaline which has a half-wave potential of 1.80 eV.105... 

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... 

Pyrazinecarboxylic acid has been obtained by selenious acid oxidation in pyridine of methylpyrazine or aqueous permanganate oxidation of ethylpyrazine, in yields of 64 and 48%, respectively.171,218 It has also been obtained in 70% yield by partial decarboxylation of pyrazine-2,3-dicarboxylic acid on heating in vacuo at 210°.219 Aqueous permanganate oxidation of 2,5-distyrylpyrazine gives the 2,5-dicarboxylic acid.220 Pyrazine-2,5-dicarboxylic acid has also been prepared in 45% yield by direct carboxylation of pyrazine with carbon dioxide at 50 atm pressure at 250° for 3 hours in the presence of a potassium carbonate and calcium fluoride catalyst.221 Pyrazine-tricarboxylic acid (57), obtainable in only very poor yields by oxidation of 2,5-dimethyl-3-ethylpyrazine, is prepared in 87% yield by alkaline permanganate oxidation of 2-(D-arabo)tetrahydroxybutyl-quinoxaline (56).222 Decarboxylation of the tricarboxylic acid by... 

Pyrazine 1-oxide, 2-methylpyrazine 4-oxide, and 2,6-dimethyl-pyrazine 4-oxide are unreactive toward acetic anhydride, but 2,5-dimethylpyrazine 1-oxide, 2,6-dimethylpyrazine 1-oxide, and 2,3,5,6-tetramethylpyrazine 1-oxide react to give 2-acetoxymethyl derivatives. The following mechanism (Scheme 44) is consistent with the observation that an acetoxymethyl derivative is only formed when a methyl group is adjacent to the AT-oxide function.407 However, in... 

Correction to allow for isomeric products (fcisomer — /ctota, x % isomer) changes /cre to 1.65 for 2-methylpyrazine, which forms the 1,3-dimethyl salt. A linear free-energy relationship was found involving rate coefficients for the formation of 3-substituted pyridinium and pyrazinium ions, with the slope of correlation (1.06) demonstrating the slightly larger substituent effects in the... 

Only methyl groups seem to cause little steric hindrance, and hence 2-methylpyrazine was converted by peracetic acid into a 3 2 mixture of 1- and 4-oxides (78JOC3367), the preponderance of the former arising from the +1, + M effects of methyl. The 2,6-dimethyl compound has been variously reported to form a 1 1 mixture of monoxides, with a small amount of dioxide (59JA5160), or a 1 2 mixture of 1- and 4-oxides (83JHC311). Both the 2,3-(82JHC465) (32 R = Me) and 2,5-dimethyl isomers (58JOC1603), and... 

Tomato (fresh) Solanum 2-acetyl-1 -pyrroline, dimethyl trisulfide, 2,3-diethyl-5-methylpyrazine (Z)-3-Hexenal, hexenal, 1 -octen-3-one, methional 131,169... 

Chloro-3,6-diethylpyrazine (119, R = H) gave 2,5-diethyl-3-methylpyrazine (118) [Me3Al, Pd(PPh3)4, dioxane—C6H14, A, reflux, 2 h 88%] 280 2,5-dichloro-3,6-diethylpyrazine (119, R = Cl) gave 2,5-diethyl-3,6-dimethyl-pyrazine (120) (likewise but reflux, 4 h 93%) 280 and many homologues and their TV-oxides were made similarly.280,282... 

Dimethylpyrazine 1-oxide (280) gave 2-acetoxymethyl-3-methylpyrazine (281) (neat Ac20, reflux, 30 min 77%) 1272 the isomeric 2,6-dimethyl-pyrazine 1-oxide gave a separable mixture of 2-acetoxymethyl-6-methylpyrazine (282, R = Ac) and 2-hydroxymethyl-6-methylpyrazine (282, R = H), the latter arising presumably by hydrolysis during the work up (neat Ac20, reflux, 1 h 40 and 12%, respectively).1307... 

Dimethylamino-7V-hydroxy-2-pyrazinecarboxamide 6-Dimethylamino-7V-hydroxy-2-pyrazinecarboxamidine 2-Dimethylamino-5-iodopyrazine 2-Dimethylamino-6-iodopyrazine 2-Dimethylamino-5-iodopyrazine 4-oxide 2-Dimethylamino-3-isobutylpyrazine 2-Dimethylamino-6-isobutylpyrazine 2-Dimethylamino-5-methoxy-3,6-dimethylpyrazine 2-Dimethylaminomethyl-3,6-bismethylthiopyrazine 2-Dimethylamino-6-methyl-5-phenylpyrazine 4-oxide 2-Dimethylamino-3-methylpyrazine 2-Dimethylamino-6-methylpyrazine 2-Dimethylamino-3-methylpyrazine 4-oxide Dimethyl 5-amino-6-oxo-1,6-dihydro-2,3-pyrazinedicarboxylate 2-Dimethylamino-5-phenylpyrazine 2-(3-Dimethylaminopropyl)-6-methylpyrazine... 

Dimethylbut-l-enyl)-6-methylpyrazine 2-(2,3-Dimethylbutyryl)pyrazine Dimethyl 5-chloro-6-methoxy-2,3-pyrazinedicarboxylate Dimethyl 5,6-diamino-2,3-pyrazinedicarboxylate Dimethyl 5,6-dichloro-2,3-pyrazinedicarboxylate... 

Ethyl 5-bromo-2-pyrazinecarboxylate 2-(2-Ethylbut-1 -enyl)-6-methylpyrazine Ethyl 5-carbamoyl-2-pyrazinecarboxylate Ethyl 5-chloro-2-pyrazinecarboxylate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboximidate Ethyl 3-cyano-5,6-dimethyl-2-pyrazinecarboxylate Ethyl 3,5-diami no-6-chloro-2-pyrazi necarboximidate Ethyl 6-diethylamino-2-pyrazinecarboxylate 2-Ethyl-3,6-diisobutyl-5-methylpyrazine 2-Ethyl-3,6-diisobutylpy razi ne 2-Ethyl-3,6-diisobutylpyrazine 1 -oxide 2-Ethyl-3,6-diisobutylpyrazine 4-oxide 2-Ethyl-3,6-diisopropylpyrazine /V-Ethyl-AyV -dimethyl-3,5-bismethylamino-2,6-pyrazinedicarboxamide Ethyl 3,6-dimethyl-5-oxo-4,5-dihydro-2-pyrazinecarboxylate... 

Key to Figures 16 and 17 1, Pyrazine 2, 2-Methylpyrazine 3, 2,6-Dimethyl-pyrazine 4, Quinoxaline 5, 2-Methylquinoxaline 6,, 4-Diazabicyclo, 2,2 -octane 7, Pyridine 8, Dioxan 9, Tetramethylammonium bromide 10, Tetror ethylammonium bromide 11, Tetrcq>ropylaminonium bromide 12, Tetrabutyl-ammonium bromide 13, n-propanol. 

Cocoa Butter Cocoa butter is one of the most Uked and highly prized food ingredients because of its desirable flavor and unique melting behavior. As early as 1961, van Elzakker and van Zutphen (32) studied and identified 23 volatile compounds in the vacuum steam distillate of cocoa butter. Later, Rizzi (33) identified nine alkylpyrazines including methylpyrazine, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, 2,3-dimethylpyrazine, 2-ethyl-5-methylpyrazine, trimethylpyra-zine, 2,5-dimethyl-3-ethylpyrazine, 2,6-dimethyl-3-ethylpyrazine, and tetramethyl-pyrazine in the basic fraction of a vacuum steam distillate of cocoa butter. 

Pyrazines have been prepared by heating 1,2-dicarbonyl compounds with a-amino acids. Thus Rizzi (308) observed that under the conditions of the Strecker degradation, equimolar amounts of DL-valine (44) and butane-2,3-dione in refluxing bis(2-methoxyethyl) ether, diglyme, gave isobutyraldehyde, tetra-methylpyrazine (9%), and a mixture of cis- and trans-2-isopropyl-4,5-dimethyl-3-oxazoline (4%). He proposed a reductive amination mechanism in which butane-23-dione was converted to 2-aminobutan-3-one which underwent self-condensation to the pyrazine. Tetramethylpyrazine was also prepared when the same reactants were heated in dimethylformamide at 123° for 5 hours (and other pyrazines prepared similarly) (308a). 

Methylpyrazine is methylated with methyl iodide in dimethyl sulfoxide at room temperature to give l-methyl-3-methylpyrazinium iodide and i-methyl-2-methyl-pyrazinium iodide, in a ratio of 3.9 I. The rate of methylation relative to pyrazine was 2.06 (666). The reaction of 2,5-dimethylpyrazine with iodo- or bromoacetic acid to give the 1,2,5-trimethylpyrazinium salt has been investigated (3). A kinetic study of the reaction of sodium hydroxide on quaternary pyrazinium salts (667, 668) has been made using a conductivity method to follow the progress of the reaction (11=5 12). In the case of 1,2,5-trimethylpyrazinium hydroxide, equilibrium lies toward (11), which slowly disappears, presumably forming the ether (13) (668). When 1,2,5-trimethylpyrazinium bromide was heated in a sealed tube trimethyl- and tetramethylpyrazine were produced (660). 

Monomethiodides of pyrazine and methylpyrazines have been readily prepared (3, 32, 272, 565, 660). Rates and position of quatemization of 2-substituted pyrazines with methyl iodide in dimethyl sulfoxide at room temperature have been determined by a kinetic competition method (666) 2Hnethylpyrazine gave 13-dimethylpyrazinium iodide as the major product (704), with some 1,2-dimethylpyrazinium iodide (666). 

In the pyrazine series, the Mannich reaction was applied first to 2,5-dimethyl-pyrazine by Linder and Spoerri (715). Of the amines tried, positive reactions were obtained only with dime thy lamine, piperidine, and morpholine, and it was found that one, or more usually two, of the hydrogen atoms of each of the methyl groups could be substituted. Thus 2,5-dimethylpyrazine, dimethylamine hydrochloride, and formalin in refluxing isopentyl alcohol gave 2,5-bis[bis(dimethylaminomethyl)-methyl]pyrazine and 2,5-bis(j3-dimethylaminoethyl)pyrazine. Reaction of 2-methyl-pyrazine with formalin and diethylamine hydrochloride gave 2- 3-diethylamino-ethylpyrazine (716) similarly dimethylamine hydrochloride gave 2-dimethyl-aminoethylpyrazine (17) and some 2-[bis(dimethylaminomethyl)]methylpyrazine (18) (657). 

A patent (726) has described the preparation of 2methyl-pyrazine by reaction with ammonia and air at 350° over a catalyst containing vanadium pentoxide and potassium sulfate a series of cyanomethylpyrazines has been prepared from the corresponding methylpyrazines by reaction with sodium amide in liquid ammonia followed by Af-methyl-A -phenylcyanamide in dioxane (644). 2-Hydroxyiminomethylpyrazine has been prepared from 2-methylpyrazine, sodium amide, and liquid ammonia with butyl nitrite (727, 728), and 2-hydroxy-iminomethyl-3,6-dimethyI-5-pentylpyrazine similarly from 2,3,5-trimethyl-6-pentylpyrazine (648). Nitrones (28) have been prepared from 23-and 2,5-dimethyl-and tetramethylpyrazine through the substituted methylpyridinium (perchlorates) (27) by reaction with p-nitroso-A, fV-dimethylaniline (729). Dehydrogenation of ethylpyrazine at 600° over a calcium cobaltous phosphate catalyst gives 2-vinyl-pyrazine (658). 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

Preparations of the corresponding hydrazino compounds from 2-chloro-3(or 6)-methylpyrazine and 2-chloro-3,6-dimethylpyrazine with 98% hydrazine in absolute ethanol at reflux (775) and from 2-chloro-3,5-dimethyl-, 2-chloro-3,5,6-trimethyl-, 2-chloro-5- and 6-methyl-3-propyl-, or 2-chloro-5,6-dimethyl-3-propylpyrazines with excess hydrazine hydrate in a sealed tube at 110-130° for 24 hours or for a similar period under reflux in butanol (826) have been described. 

Castle and co-workers (1013) showed that 2-chloro-3-methylpyrazine with phosphorus pentasulfide in boiling pyridine afforded 2-mercapto-3-methylpyrazine, and 3-chloro-2,5-dimethylpyrazine similarly treated gave 3-mercapto-2,5-dimethyl-pyrazine. 

Dichloropyrazine in anhydrous ether with methyl magnesium iodide at 10° gave 2-chloro-6-methylpyrazine and 2,6-dimethylpyrazine and 2,3-dimethyl-pyrazine was likewise obtained from 2-chloro-3-methylpyrazine (687). A Grignard derivative has been prepared from 2-chloro-3,5,6-trimethylpyrazine and magnesium turnings in tetrahydrofuran and on treatment with diethyl sulfate produced 2-ethyI-3,5,6-trimethylpyrazine (330). 

Methylation of 2-hydroxy-3-7V-phenylcarbamoylpyrazine with dimethyl sulfate and potassium carbonate in boiling acetone gave l-methyl-2-oxo-3-A -phenylcarbamoyl-1,2-dihydropyrazine and the 3-(A -methyl-Af-phenylcarbamoyl) analogue was prepared likewise (1055). Similar methylation of 2-hydroxy-3-(o-methylaminophenyl)pyrazine produced 1 -methyl-3-(o-methylaminophenyl)-2-oxo-1,2-dihydropyrazine (1055). A series of 24iydroxy-3-(a-hydroxybenzyl)pyrazines has been methylated with dimethyl sulfate in aqueous sodium hydroxide to the 2-methoxy analogues (1045) and 2-benzyl-3,6-dihydroxy-5-methylpyrazine with diethyl sulfate and sodium ethoxide formed 2-benzyl-3,6-diethoxy-6-methylpyrazine (1066). 

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