2-Chloro-6-methoxy pyrazine

Comparison of the ortho and para indirect deactivation in 155 and 156 with that in 151 and 152 would reveal the relative effectiveness of the two effects and the influence of the ring-position. Additional examples of deactivation are ortho indirect in 2-chloro-6-methoxy-pyrazine ortho direct in 4-chloro-5-methoxypyrimidine para direct in 2-chloro-5-methoxypyrimidine ortho and para indirect in the... 

It would appear that this type of addition may not be confined to the addition of NH2 in liquid ammonia, since it has been observed that treatment of 2-chloro-3-dichloromethyl-pyrazine with an excess of methoxide results in the introduction of a methoxy group into the 6-position of the pyrazine ring (Scheme 9) (68TL5931). This reaction is best rationalized in terms of addition of the methoxide ion at the 6-position, followed by loss of chloride ion from the dichloromethyl side chain. 

Pyrazine, l,4-bis(trimethylsilyl)-l,4-dihydro-synthesis, 3, 178 Pyrazine, 3-s-butyl-2-methoxy-occurrenoe, 3, 193 Pyrazine, chloro-reactions... 

Directed ort o-metalations are also applied to quinoxalines possessing 2-chloro, 2-methoxy, and pivaloylamino substituents <1993JHC1491>, but successful syntheses via the lithio intermediates are far fewer compared to pyrazines. In fact, no example of metalation on aromatic carbons can be found in the literature since 1994. However, lithiation on benzene carbons of 6-chloro-2,3-dimethoxyquinoxaline was reported <1999T5389>. 

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. 

Chloro-3,5-diphenylpyrazine (118, R = Cl) gave 2-methoxy-3,5-diphenyl-pyrazine (118, R = OMe) (MeONa, MeOH, reflux, 3 h 97%) homologues likewise.1307... 

Dichloropyrazine gave 2-chloro-6-[m-methoxy-a, a-(trimethylenedithio)-benzyl]pyrazine (196), the acetal of an acylpyrazine [2-(m-methoxyphenyl)-1,3-dithiane anion (made in situ), 2-Me—THF, -100 — 20°C 14%].1482 2-Chloropyrazine gave several Ni or Pd complexes.566,581 Also other examples.374,882... 

Amino-5-chloro-6-thioxo-1,6-dihydro-2-pyrazinecarbohydrazide 3-Amino-6-chloro-5-thioxo-4,5-dihydro-2-pyrazinecarbohydrazide 3-Amino-6-cyano-5-methoxy-2-pyrazinecarboxamide 3-Amino-6-cyano-5-methoxy-2-pyrazine-carboxylic acid... 

Dimethylbut-l-enyl)-6-methylpyrazine 2-(2,3-Dimethylbutyryl)pyrazine Dimethyl 5-chloro-6-methoxy-2,3-pyrazinedicarboxylate Dimethyl 5,6-diamino-2,3-pyrazinedicarboxylate Dimethyl 5,6-dichloro-2,3-pyrazinedicarboxylate... 

Both 2-methylpyrazine 1- and 4-oxides (625) (obtained by oxidation of 2-methyl-pyrazine with peroxyacetic acid) on treatment with phosphoryl chloride have been claimed to give 2-chloro-3-methylpyrazine(626)but the 2-methylpyrazine-4-oxide used is now known to have been a mixture of the 1- and 4-isomers (734). More recently other workers (735, 736) have claimed that the mixed 2-methylpyrazine 7V-oxides with phosphoryl chloride gave a mixture of 2-chloro-3-, -5-, and -6-methylpyrazine but Nakel and Haynes (686) have shown that 2-methylpyrazine 1-oxide with phosphoryl chloride followed by sodium methoxide gave 2-methoxy-3-methylpyrazine and 6-methoxy-2-methylpyrazine, and 2-methylpyrazine 4-oxide (3-methylpyrazine 1-oxide) similarly treated gave only 2-methoxy-6-methylpyrazine. 3-Trifluoromethylpyrazine 1-oxide with benzenesulfonyl chloride at 1(X)° has been shown to give 2-chloro-6-trifluoromethylpyrazine (44%) (759). 

Many chlorinations of pyrazines have been achieved with sulfuryl chloride. A series of monoalkylpyrazines has been chlorinated specifically in the 3-position with sulfuryl chloride in the presence of 7V,A -dimethylformamide for example, 2 -butylpyrazine in MjV-dimethylformamide with sulfuryl chloride at 45° gave 2iS-butyl-3-chloropyrazine. The nucleus of 2,6-dialkylpyrazines was also readily chlorinated (687, 693). 2,6-Dimethylpyrazine and sulfuryl chloride in A. A -dimethyl-formamide gave 2-chloro-3,5-dimethylpyrazine (687, 844), and 3-methoxy-2,5-dimethylpyrazine gave 2-chloro-5-methoxy-3,6-dimethylpyrazine (844). 

Okada et al. (838), from comprehensive studies of the reactions of 3-substituted pyrazine 1-oxides (12) with phosphoryl (thionyl and sulfutyl) chloride, concluded that when the substituent was an electron-withdrawing group (e.g., methoxy-carbonyl) the substitution would be at the 5-position to give the 2,6-disubstituted pyrazine (e.g., 13, R = COOMe), whereas the 2-chloro compound (e.g., 14, R = NHj) would be obtained when the substituent was electron-donating (e.g., amino). When a weak electron-donating group (e.g., methoxy) was present both types of pyrazines (e.g., 13 and 14, R = OMe) would be formed. 

Cyano-6-methylaminopyrazine was also prepared from the chloro compound with methylamine hydrochloride and sodium hydroxide in aqueous dioxane (945) and 2-cyano-6-(2, 2 -dimethylhydrazino)pyrazine was prepared similarly (945). 2-Chloro-6-cyanopyrazine with methanol (and similarly with ethanol) and triethylamine gave 2-methoxy-6-(C-methoxyformidoyl)pyrazine (32) [see Section 5D(2)], and 2-chloro-6-carbamoylpyrazine with concentrated aqueous ammonia at 170-175° gave 2 -amino-b-carboxypyrazine (744). 2-Chloro-3-cyano-5,6-diphenylpyrazine with ammonium hydroxide and potassium iodide formed 2-amino-3-carbamoyl-5,6-diphenylpyrazine, but on fusion with ammonium acetate it gave 2-amino-3-cyano-5,6-diphenylpyrazine (848). 

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