Pyrazines 2-chloro-, nucleophilic substitution

Replacement of a chloro group on the pyrazine by nucleophilic substitution with the anion of an activated methylene species is the major pathway in the synthesis of pyrrolo[2,3-3]pyrazines. The symmetrical pyrazine 250a undergoes reaction with malononitrile and K2CO3 in acetonitrile to form 251a (Scheme 24). Reaction of this intermediate with benzylamine in acetonitrile affords 252a <2001MC152>. 

A recent communication is based on the nucleophilic substitution of N-silylated iminophosphoranes (Scheme 8), where activated chloro- (12) and nitro heterocycles (13) (triazines, pyrazines, and pyridines) are transformed into monosubstituted iminophosphoranes (14). Of special advantage are the mild reaction conditions and the preferential formation of monosubstituted... 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Nucleophilic substitution takes place on the six-membered ring. Typical reactions are shown in Scheme 4 for a l-chloropyrrolo[l,2-c]pyrimidine (75) <78JOC3544>. Similar sequences are reported for 2-chloropyrrolo[l,2-a]pyrimidines <78JOC3544> and for l-chloropyrrolo[l,2-u]pyrazines <89JOC1074>. In both cases the chloro compound is formed from the corresponding oxo derivative. The... 

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. 

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