Pyrazine bromination

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

As might be expected from a consideration of electronic effects, an amino substituent activates pyrazines, quinoxalines and phenazines to electrophilic attack, usually at positions ortho and para to the amino group thus, bromination of 2-aminopyrazine with bromine in acetic acid yields 2-amino-3,5-dibromopyrazine (Scheme 29). 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

A mixture of 1- and 3-chloro, 1,3-dichloro, and 1,3,5-trichloro derivatives was obtained on chlorination of imidazo[l, 5-a]pyrazine (172). Bromination gave similar results (75JHC207,75JOC3373 84MI24). The 8-chloro compound is best made from the 8-oxy derivative of 172. When the 1-bromo-3-methyl derivative of 172 was treated in turn with aqueous bromine and excess dilute caustic soda, the pyrazine ring was destroyed to give 4-bromo-2-methylimidazole-5-aldehyde (75JOC3373). 

Sufficient activation was present in 5-ethylamino-2-oxoimidazolo [4,5-6]pyrazine (173) for it to be halogenated in the 6-position by chlorine and bromine in acetic acid or by sulfuryl chloride (69FRP1578366 71BRP1248146). The 2-oxo group could be replaced by chlorine (75KFZ10 76KFZ35). 

In [l,2,4]triazolo[4,3-a]pyrazine (174) bromination took place at the 5-position rather than in the triazole ring (77JOC4197). It was not possible to convert the 3-hydroxy derivative into the 3-chloro analogue (68JHC485). The isomeric [1,5-a] compound (175) was also brominated at C-5 (74TL4539), whereas its 7-oxide gave the 8-chloro derivative under Meisenheimer conditions [80JCS(P1)506]. 

Pyrrolo[l,2-fl]thieno[2,3-c]pyrazine (186) brominated mainly in the fused pyrrole ring. Only the third bromine atom introduced substituted the thiophene /3-position (86JHC17). 

It is to be expected that furo[2,3-ft]pyrazines would show an appreciably lower reactivity in electrophilic substitution than benzo[fe]furans. Bromination of 2-phenylfuro[2,3-6]pyrazine requires high temperatures and long reaction times the substitution takes place in position 3. By contrast, nitration occurs mainly in the phenyl group. Reaction with peracids easily provides the N-7 monoxide. This is to be expected since quantum mechanical calculations (HMO, PPP, CNDO) all predict a higher charge density at N-7 compared with N-5. 

Pyrazine, 3-alkyl-2-ethyl-oxidation, 3, 168 Pyrazine, amino-bromination, 3, 177 reactions... 

The presence of an N-oxide function in pyrazine is not sufficient in itself to promote electrophilic halogenation, and even the presence of other weak donor groups may fail to promote reaction unless they can act in concert. Although 2-methoxypyrazine 1-oxide could not be bromi-nated, the 3-methoxy isomer [and 3-aminopyrazine 1-oxide (54)] was bro-minated in the 2- and 6-positions (ortho to oxide and ortho or para to the amino group cf. Scheme 47). Similarly, 2-aminopyrazine was brominated more readily than its Af-oxide (55 R = H) where the two groups are in opposition [83JOC1064 84H(22) 1195]. 

The classical route to chloropyrazines is by treatment of a hydroxy-pyrazine with phosphoryl chloride bromopyrazines are similarly prepared by using phosphoryl bromide, phosphorus tribromide, or a mixture of both. Thus, treatment of hydro xypyrazine with phosphoryl chloride gives chloropyrazine in 92% yield,147 and treatment of the hydroxy compound with a mixture of phosphoryl bromide and phosphorus tribromide gives bromopyrazine in 58% yield.266 The use of phosphorus pentahalides frequently leads to substitution products (Scheme 22) for example, when hydroxypyrazine is treated with a mixture of phosphoryl bromide and phosphorus pentabromide both monobromo- and 2,6-dibromopyrazines are formed.287,268 Bromina-tion of hydroxypyrazine with bromine in the presence of small... 

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... 

The amino substituent attached to the pyrazine ring facilitates electrophilic attack at the ring carbon atoms in the ortho and para positions. Thus, bromination of aminopyrazine in glacial acetic acid... 

As already mentioned, hydroxypyrazines exist in tautomeric equilibria with the corresponding pyrazinones which are normally the predominant species in the equilibria. Some of the reactions of hydroxypyrazines are reminiscent of those of phenols they can, for example, be coupled with diazonium salts and brominated and nitrated in either the ortho or para position to the hydroxyl group. Coupling with diazonium salts occurs in neutral or weakly alkaline solution, but if the reaction is carried out in 1 M sodium hydroxide solution, arylation of the pyrazine ring takes place. From hydroxy-pyrazine and benzenediazonium chloride 47% 2-hydroxy-3-phenyl-and 4% 2-hydroxy-3,6-diphenylpyrazine are obtained. 

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