2.5- Dimethyl-3- pyrazine oxidation

A Diels-Alder approach to varenicline was recently published by Dr. Reddy s Laboratories. Entry to a key bicyclic intermediate is achieved by an iodide-catalyzed Diels-Alder reaction of tetrabromo dimethyl pyrazine (47) with excess norbomadiene. Dihydroxylation of 48, oxidative cleavage, and reductive amination prepares N-p-methoxybenzyl varenicline (50), which is deprotected under transfer hydrogenation conditions to give varenicline (1) in 10% yield for the sequence.47 This approach continues the theme of building the piperidine of 1 through olefin oxidative cleavage and reductive amination, but by doing so late in the sequence however, the approach... 

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... 

The marked activation of the iV-oxide function on the chlorine atom of 2-chloropyrazine 4-oxide and 2-ehloro-3,6-dimethylpyrazine 4-oxide is also demonstrated by the milder conditions under which these compounds react with ammonia and amines compared with chloro-pyrazine and 2-chloro-3,6-dimethyl pyrazine, respectively. Although 2-chloropyrazine 4-oxide undergoes the expected displacement reaction with ammonia on heating at 115°-120° for 2.5 hours, reaction at 140° for 16 hours gives 2,3-diaminopyrazine, possibly as a result of an addition-elimination reaction on the initially formed 2-amino-pyrazine 4-oxide (Scheme 47).417... 

Alkaline hydrolysis of the di-A-oxide of 2,5-dichloro-3,6-dimethyl-pyrazine (215) readily yields the monohydroxamic acid (216), but the second chlorine atom is inert. Both chlorine atoms in compound 215 may be displaced by ethoxide or benzyloxide ion. Acid treatment of the dibenzyloxy-1,4-dioxide (217) yields compound 218 which with... 

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... 

Ethoxypyrazine 1-oxide refluxed with 40% alcoholic hydrogen chloride yielded 2-ethoxy-5-hydroxypyrazine (1069). Ultraviolet irradiation of 2,5-dimethyl-pyrazine 1-oxide in water afforded 3-hydroxy-2,5-dimethylpyrazine (10%) and 2,5-diphenylpyrazine 1-oxide in benzene gave 3-hydroxy-2,5-diphenylpyrazine (3%) (742). A small yield of 2-ethyI-5-hydroxy-3,6-dimethylpyrazine has been isolated as by-product from the reaction of 2,5-dimethylpyrazine with ethyllithium in ether (615). 

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). 

Hydto xy-1,5,6-trimethy limidazo(4,5 -b ]pyrazine 60% H2S04/reflux 2-Amino-3-methylamino-5,6-dimethyl/l-oxide 907... 

Pyrazine, 2,5-dichloro-3,6-difluoro-synthesis, 3, 190-191 Pyrazine, dihydro-, 3, 177 Pyrazine, 1,2-dihydro-oxidation, 3, 178 reduction, 3, 177 Pyrazine, 1,4-dihydro-antiaromaticity, 3, 177-178 synthesis, 3, 177 Pyrazine, 2,3-dihydro-oxidation, 3, 178 Pyrazine, 2,5-dihydro-synthesis, 3, 178 Pyrazine, 3,6-dihydro-synthesis, 3, 184 Pyrazine, 2,5-dihydroxy-oxidation, 3, 175 Pyrazine, 2,3-dimethyl-1,4-dioxide... 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

An alternative method of synthesizing the pyrazine compounds was described by Ghosh et al, and the synthesis is shown is Scheme 32 [78]. Reaction of a 1,2-dione (124) with a 1,2-diamine (125) to form an imine intermediate followed by spontaneous oxidation of the dihydropyrazine intermediate, formed the protected pyrazine compound 126. The free phenol 127 was obtained by removal of the methyl-protecting groups with a boron trifluoride-dimethyl sulfide complex. Similar compounds were prepared via the same method by Simoni et al. [79]. 

Ring nitrogens in pyrazines and the benzo derivatives react with electrophiles to form quaternary ammonium species such as iV-alkylpyrazinium salts and pyrazine iV-oxides. N-Alkylation has generally been performed by treatment with a reactive alkyl iodide. The N-1 nitrogen in 2(l//)-pyrazinone 5 is methylated using chloro(chloromethyl)dimethyl-silane followed by desilylation with cesium fluoride to yield l-methyl-2(l//)-pyrazinone <2000TL4933>. 

Zu erwahnen sind schlicBlich die photochemische Umlagerung von 2,4-Dimethyl- bzw. 2,4-Diphenyl-pyrazin-l-oxid, die zu 2,4(5 )-Dimethyl- (15%) bzw. 2,4(5)-Diphenyl-imidazol (29%) fiihrt429, und die ebenfalls photochemische Herstellung von Imidazolen aus 2,3-Dihydro-pyr-azinen (s.Bd. IV/5b, S. 1107-1108). 

On anodic oxidation of 3,6-diisobutylpiperazine-2,5-dione in acetonitrile, a compound was obtained, which was suggested to be 1,6-diisopropyl-3,8-dimethyl-5//, 10//-diimidazo[ 1,5-n 1, 5 -d]pyrazine-5,10-dione (44), formed by 1,3-cycloaddition of a primary oxidation product to the solvent.96 Another heterocyclic synthesis by intermolecular coupling of 2,4,5-tri-tert-butylphenol with acetonitrile has been reported.97... 

Lipid-Protein-Carbohydrate Interactions. Evidence for such complex interaction was recently reported by Huang et al (36) who observed that the addition of corn lipids to zein and corn carbohydrates enhanced the formation of alkylpyrazines, indicating that lipid-derived free radicals may accelerate the rate of Maillard reactions. Two of the alkylpyrazines, identified in such mixtures after heating for 30 minutes at 180°C, have 5-carbon alkyl substitution at the pyrazine ring and could only be explained by interaction of lipid or lipid decomposition products. These authors suggested that condensation of amino ketones, formed by protein-carbohydrate interaction, may yield 3,6-dihydropyrazine which would in turn react with pentanal, a lipid oxidation product, to form 2,5-dimethyl-3-pentylpyrazine. 

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... 

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... 

---