2- Chloropyrazine carboxylation

In amphibian epithelia (skins and bladders), amiloride blocks sodium transport when applied to the mucosal fate [153,154,183-185]. The essential part of the molecule is the guanidine moiety, as the methyl ester of 3,5-diamino-6-chloropyrazine carboxylic acid is without activity [154]. Furthermore, it is necessary for the guanidine group to be protonated for blocking activity [148, 186-188]. The p/fg of amiloride is 8.7 and is therefore largely protonated in the conditions existing in the distal tubule. In the absence of calcium ions (and in the presence of a calcium chelator), amiloride fails to block sodium entry [189] although it apparently still binds to the receptor [190]. 

Alkylpyrazines with other substituents have been oxidized to carboxylic acids as follows 2-acetamido-6-methylpyrazine was oxidized in aqueous magnesium sulfate with potassium permanganate to 2-acetamido-6aqueous potassium permanganate at room temperature to 2-carboxy-3-chloropyrazine, which was also obtained by oxidation of 2-chloro-3-methylpyrazine with selenium dioxide in boiling aqueous pyridine (947). Oxidations of 2-methoxy-3-methyl-... 

The Suzuki coupling of p-phenylalanine boronic acid (60) with 2-chloropyrazine under microwave irradiation afforded 4-pyrazinylphenylalanine (61) as a free amino acid in high yield [40]. The amino group and carboxyl group were well tolerated under microwave irradiation and offered a straightforward approach to the synthesis of unprotected 4-arylphenylalanines [40]. 

Efficient Pd-catalyzed carbonylation of 2-chloropyrazine afforded pyrazine carboxylic acid esters (177) in 82% yield in the presence of dppf and dppb ligands [85]. 

An example is the reaction of methyl 3-chloropyrazine-2-carboxylate (1) with guanidine carbonate to yield 2-aminopteridin-4(3//)-one (2) in 89% yield.156... 

Methyl 3-chloropyrazine-2-carboxylate (1.0 g, 5.8 mmol) and finely powdered guanidine carbonate (2.0 g, 11.1 mmol) were mixed, and heated at 170°C for 30 min, with occasional stirring. After cooling, the residual solid was dissolved in boiling HzO (50 mL, charcoal), and the solution filtered. The hot solution was adjusted to pH 5 using 3 M HC1, and the yellow solid was collected, washed with H20, then EtOH, and dried in vacuo yield 0.84 g (89%) mp >360°C. 

Pyrazinyl ketones have been prepared by treatment of pyrazinecarboxylic esters with an organo-metallic (alkyllithium or Grignard) reagent <84MI 603-01 >. Homolytic acylation of pyrazines and quinoxalines with a-keto acids is an important method for preparation of the acyl compounds (Section 6.03.5.6.1), but the procedure for monosubstitution needs care because the electron-withdrawing effect of the first-formed monoacyl compounds facilitates further substitution. An additional synthesis of pyrazinyl ketones is the lithiation of halogenopyrazines followed by treatment with carboxylic esters or carboxamides (Equation (8) and Scheme 24). Reaction of 2-chloropyrazine... 

Palladium-catalyzed carbonylation of chloropyrazines in methanol and in amines yields the pyrazine carboxylic methyl esters and carboxamides, respectively. This procedure has been successfully applied to the synthesis of 2,5-pyrazinedicarboxylic acid derivatives and 3-methoxy-carbonylpyrazine 1-oxide from the corresponding dichloropyrazines and A-oxides <908923 >. 

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