Pyrazine ring formation

Regioselective Formation of Biopterin by Pyrazine Ring Formation. 146... 

Stepwise pyrazine ring-formation using 5-nitropyrimidine was applied to the synthesis of 4a-hydroxytetrahydrobiopterin (95), which is an interesting intermediate in the metabolism of aromatic amino acids (see Sect. 5.2). As illustrated in Scheme 18, the 5-aminopyrimidine 97 prepared from chloroni-tropyrimidine 96 by nucleophilic substitution followed by catalytic hydrogenation was oxidized under acidic conditions to o-quinone derivative 98. 

An interesting pyrazine ring formation was detected between 5,6-diamino-1,3-dimethyluracil (309) and 6-hydroxy-6-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)-2//-pyran-3(6//)-one (310) leading to a mixture of l,3-dimethyl-7-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)lumazine (311), 1,3-dimethyl-6-[3-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)-3-oxopropyl]-lumazine (312), and 6,8-dimethyl-l-(2,3,5-tri-0-behzoyl-/ -D-ribofuranosyl)pyrrolo[l,2-/]pteridine-7,9-dione (313) (Equation (14)) <89JOC3927>. 

A novel method of pyrazine ring formation involves the electrolysis of an activated dialkene and is illustrated by the conversion of o-bis( 8-diethoxycarbonylvinylamino)benzene (26) to the tetrahydroquinoxaline 27. The latter compound decomposes on heating at about 160° to quinoxaline and diethyl malonate. ... 

A quinoxaline-related system can emerge upon the expansion not only of a five- but also a three-membered heterocycle. New frani-perhydroquinoxalin-2(lfl)-ones were prepared by the reaction of aziridines 449 with a-amino acids 312a, f as a result of the aziridine ring cleavage and pyrazine ring formation (Scheme 2.91) (Rees 1987). Note that the reaction is non-stereoselective and gives a mixture of products 450 and 451. 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

Although the heteroaryl Heck reactions of chloropyrazines with pyrrole itself were low-yielding for both mono- and bis-arylation products, better yields were obtained for N-phenylsulfonylpyrrole. Bulkier alkyl substituents on the pyrazine ring promoted the formation of C(3)-substituted pyrroles. The C(3)-substituted pyrrole 64 was the major product (62%) for the coupling of 1 and Al-phenylsulfonylpyrrole, while C(2)-substituted pyrrole 63- was a minor product (15%). 

Methoxypyrazine-2-one Af-oxides 341 were prepared from oxime derivatives 340 by one-pot cyclization in the presence of DCC/DME with subsequent interaction with Me2S04/K2C03 and NaOH (equation 148) . Similar intramolecular cyclizatiou of ester and oxime O-ethers groups iu the presence of lithium arylthiolate also leads to pyrazin-2-one ring formation . ... 

Attempts to prepare 2,3,5,6-tetraaminopyrazine (91) by Hoffman degradation of the diamide (88) were unsuccessful. This is apparently due to both intermolecular and intramolecular urea formation from the intermediate isocyanate giving a mixture of products, which upon attempted hydrolysis to 91 undergo a significant amount of attack on the pyrazine ring (70UP1). 

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. 

Interest in the influence of lipids on pyrazine formation has recently been generated by the identification of long-chain alkyl-substituted heterocyclic compounds in foods and in model systems. Pyrazines in this category include 2-heptylpyrazine isolated from french fried potato flavor (7), and 2-methyl-3(or 6)-pentylpyrazine and 2,5-dimethyl-3-pentylpyrazine, isolated from extruded zein/corn amylopectin/corn oil systems (8, 9). Only the involvement of lipids or lipid-decomposition products in the formation of these compounds could account for the long-chain alkyl substitution on the pyrazine ring. 

The pyrazine mono-iV-oxides show close similarity in their reactions to the pyridine AT-oxides.402-404 In the latter compounds the electronreleasing ability of the iV-oxide function is demonstrated by the activation of the a- and y-ring carbon atoms to electrophilic attack. Pyrazine mono-AT-oxides are predictably less activated to electrophilic substitution, and thus there have been no reports of the successful nitration of pyrazine /V-oxides. The pyrazine ring is, however, activated by the A-oxide function to nucleophilic attack, especially if the positive charge of the N atom is enhanced by formation of an intermediate with an electron acceptor. Thus, phosphoryl chloride treatment of pyrazine 1-oxide yields chloropyrazine391 and similar... 

The high 77-deficiency at C-7 is also apparent from the nucleophilic addition reaction with sodium borohydride selective formation of the 6,7-dihydro derivative (566) results with this reagent. The reaction may also proceed further by reductive loss of the 7-substitutent (76CPB235). In the pyrazine analogue (567) both LAH and sodium borohydride treatment lead to saturation of the pyrazine ring (78JOC341). 

Since 1,3-bifunctional nucleophiles usually show prototropy (see Section II) several possibilities for annelation to the pyrazine ring exist. In particular, the formation of both thiazolo- and imidazoquinoxalines can be expected in the... 

The methyl donor is methylene-tetrahydrofolate. The reaction involves formation of a methylene bridge between A(-5 of the coenzyme and C-5 of dUMP, followed by transfer of hydrogen from the pyrazine ring of tetrahydrofolate,... 

Studies on the tri-, tetra- and penta-peptides of a-methylalanine (65T3209, 73ACS1509) have shown that cyclization to the imidazo[l,2-a]pyrazine ring system occurs and a sequence for its formation from the tripeptide suggested (467) -> (468) -> (469). Another tripeptide cyclizes to a piperazine and then to the bicyclic system (78TL1009). 

One of the few examples of formation of the pyrazine ring as the last step in the synthesis of imidazo[4,5-fe]pyrazines (504) involves the reaction of biacetyl with the diamine (503) generated in situ from the 4-nitro-5-amino compound (502) (70TL1013>. Another synthesis involving the use of an imidazole is the condensation of ethylenediamine (505) with (506) to give the perhydro derivative (507). 

Conversion of a 1,2-diamine into a pyrazine ring is a common type of reaction (see Section 6.3.1.). In this dinucleophile -I- dielectrophile approach, heteroatoms function as nucleophiles and 1,2-dicarbonyl or related compounds, as the electrophilic component. The difference in relative reactivities at the termini of the individual components may influence the formation of a single product alternatively, the relative reactivities may be so similar that a mixture of isomers is formed. 

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