Pyrazines with nucleophiles

A new solid-phase synthesis of families of asymmetrically disubstituted furazano[3,4-h]-pyrazines, which overcomes selectivity problems found in solution, has been achieved by stepwise displacement of the two chlorine atoms of 5,6-dichlorofurano[3,4-b]pyrazines with nucleophiles <02TL4741>. Pyrazolo[3,4-fe]quinoxalines as a new class of cyclin-dependent kinase inhibitors have been described <02BMC2177>. 

The only reported substitution of unsubstituted pyrazines with nucleophilic reagents involves amination via the Chichibabin reaction (84MI4). 

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>. 

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). 

In contrast to benzene compounds, which undergo ready electrophilic substitution, the highly n-deficient pyrazine and quinoxaline nuclei are susceptible towards nucleophilic attack by a variety of reagents. The direct nucleophilic substitution with organolithium or Grignard reagents to form alkyl or aryl heteroaromatics, however, is rather ineffective, and the dihydro and/or tetrahydro compounds are formed preferentially. For example, reaction of pyrazine with phenyllithium affords... 

The susceptibility of s-triazolo[l,5-a]pyrazines to nucleophilic attack at the 5-position explains the decomposition products obtained when the parent heterocycle is heated with 50% aqueous sodium hydroxide solu-... 

Reaction of 5,6-dichloro-l,2,5-thiadiazolo[3,4-f)]pyrazine with di-n-propylamine gave good yields of the mono and disubstituted compounds 59 and 60, depending on the ratio of chloro compound to amine. In contrast, reaction with n-propanethiol gave only the disubstituted product 61 irrespective of the ratio of nucleophile to dichloro compound. 

The amino group in 8-aminopyrido[2,3-b]pyrazine is hydrolyzed to give the 8-0x0 compound by treatment with sodium hydroxide. Similarly the 6-amino groups in compounds 103 and 104 have been replaced by treatment with nitrous acid." Reaction of 5-alkyl quaternary salts of pyrido[2,3-b]pyrazine with a variety of nucleophiles has been recently described " (see Section IIIl). 

Compounds of structure 10 react readily with nucleophiles. Thus moisture causes rapid hydrolysis to the pyrazine amino acid, and aliphatic amines give the amides (11), which may be cyclized to pteridinones (12) by dissolving in phosphoryl chloride. Ammonia, hydroxylamine, and aniline give the pteridinones (13) directly. ... 

Patents have been published which deal with nucleophilic substitution in tetrafluoro-4-nitropyridine (c/. ref. 264), the preparation and reactions of perfluoro-quinoline and -isoquinoline (cf. ref. 267), the preparation and nucleophilic substitution reactions of perfluoro-pyridazine (cf. ref. 269) and -pyrazine (cf. ref. 270), and the preparation of reactive dyestulfs containing fluoro-pyridazine or -pyrimidine residues via displacement of fluorine from polyfluoropyridazines or 5-chlorotrifluoropyrimidine, respectively, with amino- or phenoxy-compounds. The results of the work on perfluoropyrazine are summarized in Schemes 39 and 40. 

Compared with pyridines, pyridazines, pyrimidines, pyrazines, and 1,3,5-triazines combine with nucleophiles with increasing ease. As a consequence, such heterocycles can be metalated only under optimized reaction conditions. -Butyllithium in DEE readily adds onto the 6-position of 2,4-dimethoxypyrimidine, " but it metalates the 5-position in THE. " ... 

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

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. 

---