Of methylpyrazines

Figure C3.3.6. Doppler-line profiles for molecules scattered into the CO COO O J= 72) state by collisions with hot methylpyrazine molecules as depicted by the equations above each half of the figure. The energy of methylpyrazine...

A somewhat different approach to this series of compounds involves the reaction between a carbanion and an aromatic nitrile. Thus, a series of methylpyrazines 253 is first treated with lithium diisopropylamide (LDA) to generate an anion at the methyl group. Addition of an aromatic nitrile produces 254 (Equation 89) <2003JME222, 2004EUP1388541>. Many other examples have been reported <2003JME222>, including some with substituents at the open position in structure 254. 

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... 

The sodio derivative of methylpyrazine (20) reacts with aldehydes and ketones to give secondary and tertiary pyrazine carbinols, respectively.175, 178 Yields in the range 21-99% are obtained when the molar ratio of methylpyrazine sodamide carbonyl compound used is 2 2 1. Oppenauer oxidation of 1-phenyl-2-pyrazylethand (21), the aldol addition product of methylpyrazine and benzaldehyde, gives phenacylpyrazine (22) in 18% yield.176... 

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... 

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... 

Cyanopyrazine is obtained in 90% yield by the reaction of phos-phoryl chloride and carboxamidopyrazine. The reactants are first kept at room temperature for 5 hours and then heated under reflux for 40 minutes.228 Commercially, cyanopyrazine is prepared by reaction of methylpyrazine with a mixture of ammonia and air in the presence of a catalyst. The catalysts used are Co, Fe, Sn, and Ag vanadates and vanadium phosphotungstate.229 Bromopyrazines are readily converted into cyanopyrazines by treatment with cuprous cyanide in boiling y-picoline.230... 

Treatment of methylpyrazine with chlorine in carbon tetrachloride at 40° gives two products and the total yield of monochloro derivatives is 65%.281-283 The major product is 2-chloro-3-methylpyrazine and the minor product, originally thought to be the isomeric 2-chIoro-5-methyl derivative, was later shown to be 2-chloro-6-methylpyrazine [Eq. (16)].284 2,5-Dimethylpyrazine also undergoes ring substitution... 

The reaction mechanism on a vanadia-titania catalyst has been re-investigated using FTIR spectroscopy [114], although the conclusions were not markedly different from earlier proposals. The interaction of methylpyrazine with the catalyst surface involves a consecutive transformation of co-ordinatively bound methylpyrazine into oxygenated surface compounds, namely an aldehyde-like complex and an asymmetric carboxylate. The main reaction product, amidopyrazine, is formed through the interaction of the surface oxy-intermediates with adsorbed ammonia species. 

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. 

Other oxidations include that of methylpyrazine with selenious acid in pyridine to give 64% of 2-carboxypyrazine (669) and 2,5-dimethylpyrazine with selenium dioxide to 2,5-dicarboxypyrazine (676) a patent (677) claims oxidation of methylpyrazine with sodium dichromate and aqueous phosphoric acid in an autoclave at 225-350° to give 74% 2-carboxypyrazine. likewise, 2,5-dimethylpyrazine gives 67% 2,5-dicarboxypyrazine, and 2,6-dimethylpyrazine gives 59%... 

Vapor phase chlorination of methylpyrazine in carbon tetrachloride at 545° in 15 times the molar ratio of chlorine gave tetrachloropyrazine (684). 

Diquatemary salts of methylpyrazines have been prepared by treatment with triethyloxonium fluoroborate (621, 622). Steric hindrance has a considerable effect on the reaction as illustrated by the yield as follows pyrazine (97%), 2,5-dimethylpyrazine (95%), 2,6-dimethylpyrazine (46%), and 2,3,5,6-tetramethyl-pyrazine (5%). 

The first studies of the reactions of methylpyrazine A(-oxides with acetic anhydride were carried out by Koelsch and Gumprecht (625). They found that... 

Vapor phase chlorination of methylpyrazine in carbon tetrachloride (10%w/w) at 545° with 15 times the molar ratio of chlorine for 13 sec has been claimed to give tetrachloropyrazine (776) and chlorine passed into a refluxing solution of 2-chloro-3-methylpyrazine in acetic acid gave 2-chloro-3-dichloromethylpyrazine (688). 

The methyl group of a methylpyrazine is activated similarly to the methyl group of 2- and 4-methylpyridines (the a- and y-picolines). Thus treatment with strong base (e.g., sodamide in liquid ammonia) generates a reactive anion which may undergo aldol-type addition, acylation, alkylation, and nitrosation. These and other features of the reactivity of methylpyrazines are illustrated by reference particularly to the work of Levine and his co-workers. 

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