3- Methoxy-2,5-dimethylpyrazine

Musty or potato-like flavor and aroma have been observed as a defect in milk (Hammer and Babel 1957) and Gruyere de Comte cheese (Dumont et al. 1975). This off-flavor results from the production of nitrogenous cyclic compounds by Pseudomonas taetrolens and P. perolens (Morgan 1976). Musty-flavored compounds produced by these organisms include 2,5-dimethylpyrazine and 2-methoxy-3-isopropyl-pyrazine. The Gruyere de Comte with potato off-flavor contained 3-methoxy-2-propyl pyridine, as well as alkyl pyrazine compounds (Dumont et al. 1975). Murray and Whitfield (1975) postulated that alkyl pyrazines are formed in vegetables by condensation of amino acids such as valine, isoleucine, and leucine with a 2-carbon compound. Details of the synthetic mechanism in pseudomonads are unknown. 

Acetoxy-3,6-dibenzyl-5-methoxypyrazine gave 3,6-di benzyl-5-methoxy-2(l//) -pyrazinone (29) (K2C03, MeOH—H20, reflux, 30 min > 95%) 312 2,5-diace-toxy-3,6-dimethylpyrazine gave 5-hydroxy-3,6-dimethyl-2(l//)-pyrazinone (30) (KHC03, MeOH, reflux, 50 min 53%).1386... 

Dimethoxy-3,6-dimethylpyrazine (182) gave 6,8-dimethoxy-l,4-dimethyl-2,3-dioxa-5,7-diazabicyclo[2.2.2]octa-5,7-diene (183) (hv, 02 J, CH2C12, methylene blue, h %), and thence methyl 5-methoxy-2,4-dimethyl-l-imidazolecarboxylate (184) or its isomer (Ph3P, THF—H20, 20°C, 5 days 47% mechanism suggested).165... 

Methoxy-3,6-dimethylpyrazine 4-oxide (283) gave only 2-acetoxymethyl-3-methoxy-5-methylpyrazine (284) (neat AC2O, reflux, 1 h 88%) 324 in contrast, the homologous substrate, 2,5-dibenzyl-3-methoxypyrazine 1-oxide (285), gave a separable mixture of 2-(a-acetoxybenzyl)-5-benzyl-3-methoxy-pyrazine (286) and 2-acetoxy-3,6-dibenzyl-5-methoxypyrazine (287) (neat Ac20, reflux, 90 min 55 and 20%, respectively).312... 

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... 

V-Hydroxy-6-propylthio-2-pyrazinecarboxamide V-Hydroxy-6-propylthio-2-pyrazinecarboxamidine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisobutylpyrazine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisobutylpyrazine 4-oxide 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisopropylpyrazine 2- (3-Hydroxyprop-1 -ynyl)-3,6-diisopropylpyrazine 4-oxide 2- (3-Hydroxyprop-1 -ynyl)-3,6-dimethylpy razi ne 2-(3-Hydroxyprop-1 -y nyl)-3,6-dimethylpyrazine 4-oxide 2-(3-Hydroxyprop-l-ynyl)-3,5-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-3,6-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-5,6-diphenylpyrazine 2-(3-Hydroxyprop-l-ynyl)-5,6-diphenylpyrazine 4-oxide 2-(3-Hydroxyprop-l-ynyl)-6-methoxy-5-(2-methylprop-l-enyl)pyrazine 2- (3-Hydroxyprop-1 -ynyl )-6-methoxypyrazine N-Hydroxy-2-pyrazinecarboxamide Af-Hydroxy-2-pyrazinecarboxamide 4-oxide... 

Isobutyl-6-isopropyl-2(17/)-pyrazinone 6-Isobutyl-3-isopropyl-2(17/)-pyrazinone 2-Isobutyl-3-methoxy-5,6-dimethylpyrazine 2-Isobutyl-3-methoxy-5-(2-methy]prop-1 -enyl)pyrazine... 

Ring aUylation and propenylation of methylpyrazine has been described (634) acetonylpyrazine with phenyllithium gives 2-acetonyl-6-phenylpyrazine (639) and 2,5-dimethylpyrazine with isopentylUthium gave 3-isopentyl-2,S-dimethylpyrazine (70). 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 used to alkylate the pyrazine ring in moderate to good yields (614, 640, 641). This alkylation has been successfully applied to alkyl- and dialkyl(amino- and methoxy)pyrazines, and a mechanism has been proposed for the reaction (614). For example, the reaction of potassium with methylpyrazine and ethyl methyl ketone, catalyzed by sodamide (0.25 mol) gave 88% of 2 -butyl-6-methylpyrazine. 

Many chlorinations of pyrazines have been achieved with sulfuryl chloride. A series of monoalkylpyrazines has been chlorinated specifically in the 3-position with sulfuryl chloride in the presence of 7V,A -dimethylformamide for example, 2 -butylpyrazine in MjV-dimethylformamide with sulfuryl chloride at 45° gave 2iS-butyl-3-chloropyrazine. The nucleus of 2,6-dialkylpyrazines was also readily chlorinated (687, 693). 2,6-Dimethylpyrazine and sulfuryl chloride in A. A -dimethyl-formamide gave 2-chloro-3,5-dimethylpyrazine (687, 844), and 3-methoxy-2,5-dimethylpyrazine gave 2-chloro-5-methoxy-3,6-dimethylpyrazine (844). 

The first lithiopyrazine derivative was prepared by Hirschberg et al. (1015) from 3-iodo-2,5-dimethylpyrazine and butyllithium in ether subsequent reaction with (a) carbon dioxide gave 3-carboxy-2,5-dimethylpyrazine, and (b) several aromatic aldehydes gave the carbinols (62, R = H, p-methoxy, m-nitro) (1015). Similar reactions were observed when 2-formylpyridine and 2-acetylpyridine (1016) were used as the carbonyl compounds, but with acetaldehyde attempted reactions were unsuccessful (1015). A patent also describes the preparation of many carbinols from 2,5-disubstituted 3-iodopyrazines (164). The lithio reagent derived from 3-iodo-2,5-dimethylpyrazine (with butyllithium in hexane) with 2-nitrobenzaldehyde gave 2,5-dimethyl-3[ 1 -hydroxy-1 (2"-nitrophenyl)methyl] pyrazine (1017). 

The following alkoxypyrazine Af-oxides have been prepared from the corresponding chloropyrazine A-oxides and sodium alkoxide in the appropriate alcohol (unless otherwise specified) 3-methoxypyrazine 1-oxide (838) 2-methoxypyrazine 1-oxide (no details (838) 3-ethoxypyrazine 1-oxide (978) 3-ethoxy-2-methylpyrazine 1-oxide (potassium hydroxide in ethanol) (978) 3-ethoxy-2,5-dimethylpyrazine 1-oxide (sodium ethoxide or potassium hydroxide in ethanol) (872, 978) and 3-methoxy-2,5-dimethylpyrazine 1-oxide (588). 

Dichloro-3,6-dimethylpyrazine 1,4-dioxide (91) with sodium methoxide at room temperature gave 2,5-dimethoxy-3,6-dimethylpyrazine 1,4-dioxide (92) and a trace of 2-hydroxy-5-methoxy-3,6-dimethylpyrazine 1,4-dioxide (93) (756). Similarly 2,5-dichloro-3,6-dimethylpyrazine 1,4-dioxide (a) with sodium ethoxide gave 2,5-diethoxy-3,6-dimethylpyrazine 1,4-dioxide (756, 842) and 2-hydroxy-5-... 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

Diniethylpiperazine-2,5-dione (34) on treatment with triethyloxonium fluoroborate in dichloromethane gave 5-ethoxy-l,3-dimethyl-2-oxo-l, 2,3.6-tetrahydropyrazine which was oxidized by DDQ in dry benzene to 5-ethoxy-l 3 dimethyl-2-oxo-l,2-dihydropyrazine (35) (1067). l,3,6-Trimethylpiperazine-2,5-dione similarly treated gave three products, one of which was assigned the structure 5-methoxy-l 3,6-trimethyl-2-oxo-l, 2-dihydropyrazine 3-benzyl-5-methoxy-l, 6-dimethyl-2-0X0-1,2-dihydropyrazine was also prepared similarly (1078). When 3,6-diethoxy-2,5"dimethyl-2,5-dihydropyrazine was refluxed with lead tetraacetate in dry benzene it gave a mixture of 2,5-diacetoxy-3,6-diethoxy-2,5-dimethyl-2,5-dihydropyrazine (36) (4 parts) and 2,5-diethoxy-3,6-dimethylpyrazine (1 part) (1068). 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

Crystal structures of 3,5,6-tri-t-butyl-2-hydroxypyrazine (1093) 2,5-dichloro-3-methoxypyrazine (915) and 2,3-dichloro-5-ethylamino-6-methoxypyrazine (916) have been determined. The dipole moment of 2-amino-5-bromo-3-methoxypyrazine (2.94D in benzene) is consistent with the S-cis configuration (52) (749) and the polarographic behavior of 3-hydroxy(and methoxy)-2,5-dimethylpyrazine (and their A(-oxides) at various pH values has been investigated (588). 

Methylation (666, 912) of 2-methoxypyrazine with methyl iodide in dimethyl sulfoxide at room temperature gave 3-methoxy-l-methylpyrazinium iodide with a rate of methylation relative to pyrazine of 1.05 (666). 2-Methoxypyrazine with tetracyanoethylene oxide gave a small yield of 3 ethoxypyrazinium dicyano-methylide (53) (1094). Alkylation of 2-methoxypyrazine with ethyl methyl ketone in the presence of sodium in liquid ammonia to give 2-s-butyl-6-methoxypyrazine (17%) has been described (614). The reactions of 3-hydroxy-2,5-dimethylpyrazine and alkylhalides have been examined (1095). 

Alkoxypyrazine A-oxides may also be prepared by oxidation of the alkoxypyrazine with peroxyacetic acid. In this way the following have been prepared 3-ethoxypyrazine 1-oxide (100°/20h) (978) 3-(trideuteromethoxy)pyrazine 1-oxide (757l9h) (975) 3-ethoxy-2-methylpyrazine 1-oxide (65-75724h) (978) 3-methoxy-2-phenylpyrazine 1-oxide (55720 h) (817) 3-ethoxy-2,5-dimethyl-pyrazine 1-oxide (56716 h) (872) 3-carbamoyl-2-methoxypyrazine 1-oxide (80720h) (881) and 2-cyano-5-ethoxy-3,6-dimethylpyrazine A-oxide (55720h) (288). 

Dimethylamino-23-dimethylpyrazine 1-oxide in boiling acetic anhydride gave 2-acetoxymethyl-3-dimethylamino-5-methylpyrazine (793) which was not isolated but saponified directly to 3-dimethylamino-2-hydroxymethyl-5-methylpyrazine (793). 2-Amino-3-cyano-5-methylpyrazine 1,4-dioxide refluxed with (a) acetic anhydride gave 3-acetamido-2-cyano-5-hydroxy-6-methylpyrazine 1-oxide (532) and (6) sodium methoxide gave 3-amino-2-cyano-5-methoxy-6-methylpyrazine 1-oxide (532). 

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