Chloropyrazine-«-oxide

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

The standard Sonogashira reaction conditions were not successful for the coupling reaction of 3-chloropyrazine 1-oxide (40) and 1-hexyne. In contrast, treatment of 40 and 1-hexyne with Pd(Ph3P)4 and KOAc produced 3-(l-hexynyl)pyrazine 1-oxide (41), together with the co-dimeric product, (E)-enyne 42 [34]. Presumably, the co-dimerization product 42 resulted from the cis addition of 1-hexyne to adduct 41. 

Pd-catalyzed carbonylation of 2-chloropyrazine 1-oxide failed, whereas that of 3-chloropyrazine 1-oxide (40) proceeded without deoxygenation of the IV-oxide function to give 3-methoxycarbonylpyrazine 1-oxide (73). This observation was in accord with the failure of Stille reactions of 2-chloropyrazine 1-oxide [9,18]. 

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. 

Dipole moments (D, in benzene, unless otherwise specified) of some chloro-pyrazines have been determined as follows 2-chloropyrazine [1.42 (663), 1.38 (773a)] 2-chloropyrazine 1-oxide (2.07) (733a) 3-chloropyrazine 1-oxide [1.46... 

Chloro-l-methylpyrazinium ion with liquid ammonia reacted by addition at the 2-position to give 2-amino-3-chloro-l-methyl-1,2-dihydropyrazine (24) (609). The hexafluoroantimonate salt of perfluoropyrazine has been prepared and F n.m.r. measurements used to determine the relative order of its base strength with other perfluoroheterocycles (914). Hydrogen-deuterium exchange rates of Hj and Hg in 3-chloro(and other substituted)pyrazine l-oxide(s) have been correlated with a-constants, and the logs of the H2 exchange rates have been shown to be linearly related to the pK values (745). The pK value of 3-chloropyrazine 1-oxide is - 1.05 (745). 

Marked activation of the chloro substituent by the A-oxide function to nucleophilic replacement by ammonia and amines has been demonstrated by comparison of the reactivities of chloropyrazine and 3-chloropyrazine 1-oxide. The preparation of 2-aminopyrazine in 87% yield from 2-chloropyrazine and aqueous ammonia required at least 16 hours at 140, but when 3-chloropyrazine 1-oxide was heated with an excess of aqueous ammonia at 115-120° for 2.5 hours (547a), 3-aminopyrazine 1-oxide was formed in good yield (921). [3-Chloropyrazine 1-oxide and aqueous ammonia, heated under the more usual amination conditions at 140° for 16 h, gave a mbcture of 2-aminopyrazine and 2,3-diaminopyrazine the latter product was the only one isolated when 3-aminopyrazine 1 -oxide was heated with aqueous ammonia at 140-145° for 16 h. This formation of 2,3-diaminopyrazine may involve an intermediate of the type (90) (921)]. 2-Butylaminopyrazine could not be prepared in reasonable yield by heating 2-chloropyrazine with butylamine under reflux for periods up to 16 hours, but it was prepared in 75% yield by heating the reactants in a sealed vessel at 120° for 8 hours, whereas 3-butylaminopyrazine 1-oxide was readily formed in 60% yield when 3-chloropyrazine 1-oxide was refluxed with an excess of butylamine for 30 minutes (921). 

Chloropyrazine 1-oxide and 3-chloropyrazine 1-oxide both react with sulfanilamide to give the corresponding sulfanilamidopyrazine 7V-oxides (1032, 1033) 3-chloro-2-methylpyrazine 1-oxide with piperidine at reflux gave 2-methyl-3-piperidinopyrazine I -oxide, and with dimethylamine gave 3-dimethylamino-2-methylpyrazine 1-oxide (793) 2-amino-3-chloropyrazine 1-oxide with aqueous ammonia and copper powder at 140-150 for 18 hours gave 2,3-diaminopyrazine... 

Klein et al. (978) first attempted the alkaline hydrolysis of 3-chloropyrazine 1 -oxide to 3-hydroxypyrazine 1 -oxide, and although spectroscopic evidence indicated the formation of the hydroxy compound, good quality homogeneous material could not be isolated. Later work by Berkowitz and Bardos (1034) has shown that 3-chloropyrazine 1-oxide was hydrolyzed by refluxing with two equivalents of aqueous sodium hydroxide, and treatment of the product with trimethylsilyl chloride and triethylamine gave 3-(trimethylsilyl)oxypyrazine 1-oxide. 3,6-Di-s-butyl-2-hydroxypyrazine 1-oxide has been prepared from the chloro analogue (no details given) (982). Hydrolysis of 2-amino-6-chloro-3-cyano-5-methylpyrazine... 

Chloropyrazine 1-oxide with cuprous cyanide in A(-methylpyrroIidine or dimethylformamide did not give 3-cyanopyrazine 1-oxide (838). 

Deoxygenations of halogenopyrazine A -oxides by phosphoryl chloride accompanied by nuclear (and side chain) halogenations have been included in previous discussions (Section IG and Table V.l) and have been applied to the following compounds 3-chloropyrazine 1-oxide (757, 831, cf. 737) 3,5-dichloropyrazine... 

Chloropyrazine 1-oxide with tosyl chloride in the presence of pyridine gave... 

Chloropyrazine 1 -oxide hydrolyzed with aqueous sodium hydroxide and the product treated with triethylamine and trimethylsilyl chloride gave 3-(trimethyl-silyl)oxypyrazine 1-oxide (1034). 

Methyl-2-oxo-l, 2-dihydropyrazine with phosphorus pentasulfide in pyridine at reflux was converted into l-methyl-2-thio-l,2-dihydropyrazine (18) (821,1100), and 3-chloropyrazine 1-oxide with sodium hydrogen sulflde in ethanol at room temperature gave 3-mercaptopyrazine 1-oxide (19) (1035). Whereas 3-chloro-2,5-dimethyipyrazine 1-oxide reacted slowly with thiourea in ethanol, and the use of water in place of ethanol caused some increase in reaction rate, the reaction in 2A sulfuric acid at reflux for 30 minutes gave 3-mercapto-2,5-dimethylpyrazine 1-oxide (85%), and 3-mercapto-2-methylpyrazine 1-oxide was prepared similarly (905). 

Pyrazine 1-oxide and 3-amino- and 3-chloropyrazine 1-oxide with tosyl chloride in the presence of pyridine gave 2-pyridiniopyrazine chloride (14) and 2-amino- or 2-chloro-3-pyridiniopyrazine chloride, respectively and 3-methoxycarbonyl(or morpholinocarbonyl or cyano)pyrazine 1 -oxide treated similarly gave 2-methoxy-... 

Aminopyrazine was oxidized by hydrogen peroxide in acetic acid at 20° to 3-aminopyrazine 1 -oxide and at 50° for 15 hours to 2-aininopyrazine 1,4-dioxide (51%) (also obtained by similar oxidation of 3-aminopyrazine 1-oxide) (1189). m-Chloroperoxybenzoic acid was also used for the oxidation of 2-aminopyrazine to its 1-oxide (1258). The following aminopyrazine TV-oxides have been prepared by oxidation (reagent and conditions) 2-amino-3-methoxycarbonylpyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (880, 1222) 2-amino-5-chloro-3-methoxycarbonyl(and methylcarbamoyl)pyrazine 1-oxide (m-chloroperoxybenzoic acid in chloroform at reflux) (1222) 2-amino-5-bromo-3-methoxycarbonylpyrazine 1-oxide (wperoxyacetic acid) (906) 2-amino-3-bromo-5,6-dimethylpyrazine 1-oxide (peroxyacetic acid) (907) and 2,3-bis(pyridin-2 -yl)pyrazine 1,4-dioxide (hydrogen peroxide in sulfuric acid at room temperature) (754). 

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