2-Amino-5-chloro-3- pyrazine

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... 

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). 

N-Amidinopyrazine carboxamides. The synthesis and biological activity of a great number of compounds of this type were described in a series of papers between 1965 and 1 68 [159—162]. The first of these described the diuretic activity in adrenalectomised DOC A-treated rats of a series of A -amidino-3-amino-6-halopyrazine carboxamides. In the second paper, it was discovered that the introduction of a 5-amino group into the pyrazine ring increased the diuretic potency. One of the compounds, amiloride (A -amidino-3,5-diamino-6-chloro-pyrazine carboxamide (Figure 1.13)) later became widely used in clinical practice, particularly in combination with other diuretics. Its use in combination with diuretics acting more proximally in the nephron is related to the prevention of potassium loss which results when an excess sodium load is delivered to the distal tubule. Thus, amiloride is a potassium-sparing diuretic [163]. 

H-Pyrido[2,l-i]purine-9-carboxylic acid, 7-oxo-methyl ester, 5, 566 Pyrido[2,3-6]pyrazine, amino-nucleophilic attack, 3, 253 Pyrido[2,3-h]pyrazine, 6-chloro-reactions... 

The quaternization of pyrazine compounds has not been extensively studied, and, therefore, a detailed discussion of the effect of substituents is not possible. Recently Cheeseman has shown, from spectroscopic evidence, that 2-amino- and 2-diethylamino-pyrazine (50, Y = NH2 and NEt2) quatemize at N-4, although protonation occurs at position-1. Other substituted pyrazines from which quaternary salts of structure 51 are formed include 2-chloro- and 2-... 

The conversion of DAMN into 2,3-dicyanopyrazines substituted in the 5-and 6-positions with various combinations of amino, cyano, chloro, and hydroxyl groups will be described in this section along with transformations of these initially formed materials into a variety of other multifunctional and fused ring pyrazines. 

Regioselectivity in the chlorination of pyrazine /V-oxides with phosphoryl chloride depends upon the substituent on the C-3 carbon. Thus, 3-aminopyrazine 1-oxide is chlorinated with loss of the /V-oxide oxygen to give 2-amino-3-chloropyrazine as the sole product whereas 3-methoxy and 3-chloropyrazine 1-oxides form approximately equal amounts of 3-chloro- and 6-chloro-2-substituted pyrazines along with a trace of the 5-chloro derivatives. 

The amino group of 2-(4-aminophenyl)perhydropyrido[l,2-a]pyrazine was arylated with 4-chloro-2,3-dimethylquinoline (06JMC6351). 

There are few reports of the nitration of the pyridazines and pyrazines. The nitration of phenylpyridazines has been stated to occur exclusively in the phenyl ring (73MI1). The use of fuming nitric acid at 0°C forms only the 4-nitrophenyl derivative (95%), as does 4-chloro-2-phenyl-3-pyridazone (100%), and 4-amino-2-phenyl-3-pyridazone (60%) (47JCS549). 

Bromo derivatives of 2-amino-3-chloro- and 2-amino-3-bromo-pyrazines are obtained by bromination with bromine in 20% hydrobromic acid at 5°. Similar treatment of 2-amino-5-bromopyra-zine-3-carboxylic acid gives 2-amino-3,5-dibromopyrazine.291 292... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

The reaction of 2-chloro-3-(7V-substituted amino)pyrazines (233) with thioglycolates gives 2,3-dihydro-4-substituted-(4//)-pyrazino[2,3-6][ 1,4]thiazin-3-ones (234) <71JAP32670, 74JAP(K)49041397> with analgesic properties (Equation (34)). 

The stabilities of pyridine-2- and -4-diazonium ions resemble those of aliphatic rather than benzenoid diazonium cations. Benzenediazonium ions are stabilized by mesomerism which involves electron donation from the ring, but such electron donation is unfavorable in 2- and 4-substituted pyridines. On formation, pyridine diazonium cations normally immediately react with the aqueous solvent to form pyridones. However, by carrying out the diazotization in concentrated HC1 or HBr, useful yields of chloro- and bromopyridines 752 can be obtained. Iodinated pyridines can be obtained in good yield using the Sandmeyer reaction. Aminopyridazines and -pyrazines, 2- and 4-aminopyrimidines, and amino-1,2,4-triazines behave similarly. Nucleophilic fluorination via the BalzSchiemann reaction of diazonium fluoroborates yields fluoropyridines, including 2-fluoropyridines. Fluoroborates can also be converted into fluoro compounds by ultraviolet irradiation. 

N- a-Chloro- a- [bis(trifluoromethyl)amino]methylene -N- a, a-dichloro-a-[bis-(trifluoromethyl)amino]methyl amine (293) gave 2,3,5,6-tetraks[bis(trifluo-romethyl)amino] pyrazine (294) (Ph3P, 120°C, 6 h 6% as a distillate/subli-mate a mechanism was suggested).1321... 

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