2-methylpyrazine synthesis

In a similar way to that described for the synthesis of furo[2,3-6]pyrazine (Section 3.17.2.1.4, Scheme 29), the dianion of 3-methylpyrazine-2-thione reacts with aromatic esters to give side-chain acylated 3-methylpyrazine-2-thiones (367). The cyclization to thieno[2,3-f ]pyrazines (368) was effected by warming these compounds in 10% methanolic hydrochloric acid solution (Scheme 108) (78RTC81, 78RTC151). 

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... 

Acid extraction yielded the following pyrazine derivatives tetramethylpyra-zine, 2,6-diethyl-3-methylpyrazine (47), 2,3-dimethyl-5-ethylpyrazine, 2-methoxy-3-isopropoxy-5-methylpyrazine, and 2,6-dimethoxy-3-isopropoxy-5-methylpyra-zine.38 All structures were confirmed by synthesis. Pyrazine derivatives had previously been isolated from green peas (Pisum sativum).39... 

The formation of pteridine-2,4-diamines by this process is exemplified by the synthesis of 7-methylpteridine-2,4-diamine (1) from 3-amino-5-methylpyrazine-2-carbonitrile.148... 

A one-step synthesis of the antitubercular drug 2-methylpyrazine has been achieved by cyclization of ethylenediamine with 1,2-propanediol [20]. The role of Pd in the Pd/Zn0-ZnCr204 catalyst is to enhance selectivity by accelerating the final dehydrogenation step (Scheme 6). Aromatization is also favored by the unusually high temperature (350-400 °C). Despite the complexity of the reaction (ca 30 different products are detected) 90 % selectivity at 80 % conversion could be achieved after optimization of the key reaction parameters. 

Behun and Levine (1961) described its synthesis by alkylation of methylpyrazine (0.2) with methyl iodide in liquid ammonia, in the presence of sodium amide. 

The synthesis has been carried out by Kamal et al. (1962) through an Hofmann exhaustive methylation of the Mannich product obtained by reaction of methylpyrazine with formaldehyde and dimethylamine hydrochloride. Goldman (1963) prepared vinylpyrazine by pyrolysis of pyrazine-ethanol. 

The synthesis has been described in a patent of Polak s Frutal Works and Douwe Egberts (1968) by application of a scheme used for the preparation of acetylpyridines (Kolloff and Hunter, 1941). The corresponding monocarboxylate is condensed with ethyl acetate in the presence of anhydrous sodium ethoxide, and the condensation product then hydrolyzed with aqueous hydrochloride. Another procedure has been applied by Mookherjee and Klaiber (1972) who treated 2-ethyl-3-methylpyrazine (0.8) successively with A-bromosuccinimide and the sodium salt of 2-nitropropane or pyridine 1 -oxide (66% overall yield). Another method has been published by Wolt (IFF, 1975a). 

It has been prepared from 2-cyano-5-methylpyrazine (obtained by dehydration of the corresponding amide) by reaction with methylmagnesium iodide and decomposition with ice and hydrochloric acid (Schwaiger and Ward, 1972). A synthesis has also been described by Wolt (1975a). 

Reaction of pyrazines with diphenylcyclopropenone provides a useful synthesis of 7,8-diphenyl-substituted compounds. Thus pyrazine reacts with two molecules of the reagent to give the acryloyl ester 37 in 31% yield. 2,6-Dimethylpyrazine reacts with one molecular equivalent of the reagent to give an 80% yield of the hydroxy compound 8 on standing with the cyclopropenone in methanol for three days at room temperature. Similarly cycloheptenocyclopropenone reacts with 2,6-dimethylpyrazine to give the tricyclic system 38. It has been assumed that 2-methylpyrazine reacts with both cyclopropenones to give the less hindered compounds 39 rather than the isomers 40. 

In the synthesis of (III. 15) and (III.16) by Rosowsky and Chen [21], which was an application of the regioselective Taylor pteridine synthesis [22-24], 2-amino-5-chloromethyl-3-cyano-6-methylpyrazine A-oxide was condensed with diethyl A-[4-(A-methylamino)benzoyl]-L-glutamate, the A-oxide group was removed with triethyl phosphite in DMF at 125 °C, and the resultant pyrazine amino nitrile was condensed with gujmidine. Brief hydrolysis (15 min, 1 M NaOH in refluxing EtOH) led to (III. 15), and chlorination of (III.15) at 5 °C afforded the 3, 5 -dichloro derivative (III.16). Ultraviolet absorption spectra of (III. 15) and (III. 16) in 0.1 M NaOH were consistent with those reported in the literature for MTX and DCM, except for small... 

The dealkoxycarbonylation of pyrazines, using lithium iodide in aqueous dimethylformamide, has been described for example, the synthesis of 2-amino-3-cyano-5-methylpyrazine (217) from (216) and also the synthesis of the pyrazine N-oxide (219) from the N-oxide (218). 192... 

The cyclization of ethylenediamine (EDA) and propylene glycol (PG) over a mixture of zinc and chromium oxides to 2-methylpyrazine (MP) is a basic step in the synthesis of 2-amidopyrazine, a well-known antitubercular drug. This is a highly complex reaction in which EDA and PG each react independently to give a variety of products, as shown in Table 5.1. (Forni and Miglio, 1993). We desire to find the number of independent reactions from this set. 

Fomi, L. and MigUo, R., Catalytic synthesis of 2-methylpyrazine over Zn-Cr-O/Pd a simplified kinetic scheme. Heterogeneous Catalysis and Fine Chemicals 111, 329-336,1993. 

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