2- Ethyl-3-methyl-5,6-dihydropyrazine

The 5-[2-(2-methoxyethoxymethoxy)ethylated] 2,5-dihydro-2-isopropyl-3,6-dimethoxypy-razines 2 can be hydrolyzed with 2 equivalents of 0.1 N hydrochloric acid to give the (2-melh-oxyethoxymethyl)-protected homoserine methyl ester 3 in 49-73% yield. In some cases (entries 1 and 2) enrichment of the dominant (2/f)-diastereomer is observed, indicating that the / -configurated dihydropyrazine 2 is hydrolyzed faster than the S -epimer. Further hydrolysis... 

The only reported example of this synthesis involved the treatment of 1,5-di-methyl-2,4-diazabicyclo[3.1.0]hexan-3-one (84) with aqueous barium hydroxide at 140°C (sealed) for 60 h, followed by an acidic work up, to give 2,2,3,5,5,6-hexam-ethyl-2,5-dihydropyrazine (85) in 42% yield, presumably via the cyclopropane derivative shown.1190... 

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-... 

Preparations of some A-substituted 2-oxo-l, 2-dihydropyrazines have been discussed in Section 11.2 from the reactions of di-, tri-, and tetrapeptides with glyoxal (380-382) and Cheeseman and co-workers (1111) have described the preparation of 1-benzyl-3-hydroxy-2-oxo-l, 2-dihydropyrazine (83) (and similarly its 1-methyl analogue) from ethyl A-(2, 2 -dimethoxyethyl)oxamate and benzyl-amine through A-benzyl-A -(2, 2-dimethoxyethyl)oxamide (84) by the application of a standard procedure (482). 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

Various methods of synthesis have been described by Marion (1967, 1971) ethylation of trimethylpyrazine (0.21), methylation of tetramethylpyrazine (0.31) or of an ethyldimethylpyrazine. The product can also be obtained by condensation of 2,3-diaminobutane with 2,3-pentanedione or from 2,3-diaminopen-tane with 2,3-butanedione, followed by oxidation of the corresponding dihydropyrazine. 

To 1050 mL THF solution containing 22.4 g 3(R)-isopropyl-2,5-diethoxy-3,6-dihydropyrazine (105.5 mmol) at —78°C, was added 42.2 mL 2.5 M n-BuLi in hexane, and the resulting solution was stirred for 1 h. Then 116 mL THF solution of 10.35 g propenylphosphonate (58.1 mmol) was added drop wise. After being stirred at —78°C until the completion of the reaction, the reaction mixture was quenched with AcOH and warmed to room temperature. Upon removal of the solvent in vacuo, the resulting material was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04 and evaporated, and the residue was purified by flash column chromatography (silica gel, EtOAc/hexane, 2 1-4 1) to yield 13.4 g (25, 5R,l R)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-l-(methyl)ethyl]-2,5-dihydro-5-isopropylpyrazine as a colorless oil, in a yield of 59%, Rf = 0.46 (EtOAc). 

The dihydropyrazine 87, a possible food flavour intermediate, was obtained from 3,S,6-tri-0-methyl-D-glucose by sequential treatment with p-toluidine, phenacyl bromide and glycine ethyl ester. Sequential reaction of o-phenylenediamine and m-fluorophenylhydrazine with dehydroisoascOTbic acid gave products analogous to those obtained previously om dehydroascorbic acid (V0I.22, p. 116-7). ... 

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