2-Amino-3- pyrazine, with guanidine

An unequivocal synthesis of (637), protected as its A-2 -acetyl derivative (643), was successfully accomplished as shown in Scheme 3.140 [40]. Pyruval-dehyde dimethylacetal was first converted into its enamine (108). Condensation of (108) with the O-tosyl derivative of oximinomalononitrile gave the azadiene (638), which was converted to 2-amino-3-cyano-6-dimethoxymethyl-pyrazine (639) with ammonia. This latter compound was condensed with guanidine and the product (640) hydrolyzed first with base (to remove the 4-amino group) and then with acid to give pterin-7-carboxaldehyde (641). Acetylation of (641) followed by condensation with di-t-butyl p-aminobenzoyl-glutamate (235), reduction and hydrolysis gave (643). 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

A series of 2-amino-3-guanidinocarbonylpyrazines has been prepared from the corresponding 2-amino-3-alkoxycaibonylpyrazine when refluxed with guanidine or with a guanidine salt and sodium alkoxide in the alcohol. Some pyrazine esters that have been converted with guanidine to guanidinocarbonyl compounds by the above method are as follows 2-amino-3-methoxycarbonyl (787, 802) 2-amino-3-methoxycarbonyl-5-methyl(ethyl, cyclopropyl, cyclohexyl, phenyl, and... 

Iminoethers were also prepared from 2-amino-3-cyanopyrazine with ethanolic hydrogen chloride (792, 1218) [the product with guanidine and sodium methoxide in methanol formed 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878, 1218)] from 2,6-diamino-3-chloro-5-cyanopyrazine with ethanolic hydrogen chloride at 0 (the product heated with ethanol gave 2,6-diamino-3-chloro-5-triethoxymethyl-pyrazine) (1432) from 2-amino-5-chloro-3-cyanopyrazine the product with... 

Iminothioethers have similarly been prepared from nitriles. 2-Amino-3-cyano-pyrazine with sodium methanethiolate (other alkanethiolates reached similarly) in ethanol gave 2-amino-3-(Cimino-C-methylthiomethyl)pyrazine (60) (792, 878, 1075) [which with guanidine hydrochloride and sodium methoxide in methanol gave 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878)] 2-amino-5-chloro-3-cyanopyrazine with methanethiol and sodium hydroxide in methanol gave 2-amino-5-chloro-3-(C-imino-C-methylthiomethyl)pyrazine (877, 1218) [which with... 

Diamino-3-chloro-5-hydrazinocarbonylpyrazine with nitrous acid at 50-55° formed 2,6-diamino-3-azidocarbonyl-5-chloropyrazine, which, refluxed with a solution of guanidine hydrochloride and sodium isopropoxide in propan-2-ol, gave 2,6-diamino-3-chloro-5-guanidinocarbonylpyrazine and many similar preparations were reported (1371). 2-Amino-5-chloro-3-hydrazinocarbonylpyrazine treated with nitrous acid gave 2-amino-3-azidocarbonyl-5-chloropyrazine, which was pyrolyzed to 5-chloro-2-hydroxyimidazo(4,5-Z)]pyrazine (1226). 

Benzamidine reacts with the pyrazinooxazinone 14 at room temperature to give the acylamidine 15. Guanidines react similarly to give the acylguanidines 16. This approach to acylguanidines is particularly useful when the guanidine component is insufficiently nucleophilic to react directly with esters of pyrazine amino acids. The reaction has been extended to other substituted pyrazine amino acids. ... 

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