2-Chloropyrazine chlorination

Direct halogenation of quinoxaline appears to be of limited value but pyrazine may be chlorinated in the vapor phase to give monochloropyrazine at 400 °C or at lower temperatures under catalytic conditions 72AHC(14)99, and at higher temperatures tetra-chloropyrazine formation occurs in high yields. Mention has already been made of direct chlorination (see Section 2.14.2.1) of phenazine. 

Nucleophilic substitution of the chlorine atom in 2-chloropyrazine and 2-chloroquinoxa-lines has been effected with a variety of nucleophiles, including ammonia and amines, oxygen nucleophiles such as alkoxides, sodium azide, hydrazine, sulfur containing nucleophiles, cyanide, etc., and reactions of this type are typical of the group (see Chapter 2.02). 

Dihaloquinoxalines are extremely reactive and both halogen atoms are replaceable, on occasions explosively (59RTC5), whereas in the case of dihalopyrazines, and tri- or tetra-halopyrazines, there is frequently a considerable difference in reactivity of the halogen atoms. When 2,3-dichloropyrazine is treated with ammonia at 130 °C, only one chlorine atom is displaced, giving 2-amino-3-chloropyrazine (66FES799). 

Deoxidative chlorination of alkyl- or aryl-substituted pyrazine A -oxides with refluxing phosphoryl chloride for 1 h provides 76-78% yields of the chloropyrazines <1997MI1076>. 

Pyrazine is chlorinated at 400°C to give a mixture of mono-, di-, tri- and tetra-chloropyrazines, presumably by a free radical mechanism. 

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. 

Pyrazine has been chlorinated at 400°C in the vapor phase to give 2-chloropyrazine, or at lower temperatures under catalytic conditions. Higher temperatures and excess chlorine or phosphorus pentachloride gave rise to high yields of tetrachloropyrazine [72AHC( 14)99 74MI2],... 

Taft reported the conversion of chloropyrazine into 2,6-dichloro-pyrazine by chlorination with sulfuryl chloride or liquid chlorine.274 This reaction is conveniently carried out in the laboratory by heating 2-chloropyrazine and sulfuryl chloride in a sealed tube at 120° for 3 hours. More recently 2,6-dichloropyrazine has been prepared in 90% yield from chloropyrazine by reaction with chlorine in dimethyl-formamide at 70°-75° 2,3-dichloropyrazine is obtained in 84% yield... 

Only one halogen is frequently displaced in the reactions of dihalo-genopyrazines with nucleophiles. Thus, 2-amino-3-chloropyrazine is isolated in 85% yield from the reaction of 2,3-dichloropyrazine and aqueous ammonia in an autoclave at 130° for 14 hours.270 Similarly Cragoe and his colleagues report a series of displacements in which the chlorine para to the electron-attracting carbomethoxy group in the dichloropyrazine (96) is preferentially displaced.309,310 These are illustrated in Scheme 31. The reaction of 2,6-dichloropyrazine with... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

The marked activation of the iV-oxide function on the chlorine atom of 2-chloropyrazine 4-oxide and 2-ehloro-3,6-dimethylpyrazine 4-oxide is also demonstrated by the milder conditions under which these compounds react with ammonia and amines compared with chloro-pyrazine and 2-chloro-3,6-dimethyl pyrazine, respectively. Although 2-chloropyrazine 4-oxide undergoes the expected displacement reaction with ammonia on heating at 115°-120° for 2.5 hours, reaction at 140° for 16 hours gives 2,3-diaminopyrazine, possibly as a result of an addition-elimination reaction on the initially formed 2-amino-pyrazine 4-oxide (Scheme 47).417... 

Hydroxy groups in activated positions are displaced by chlorine using phosphorus chlorides as for the pyridazine (680) (71MI42900). Halogen interchange reactions are to be expected. Bromination of the chloropyrazine (681) can be effected using bromine in chloroform (75JHC451). 

Pyrazine A-oxides undergo a variety of reactions. Of these, deoxydative chlorination to C-chloropyrazines has been covered in Section 4.1.3 other reactions are discussed in the following subsections. 

Matsuura and co-workers (756) have reexamined the reactions of the A -oxides of 2,5-dimethylpyrazine and found that 2,5-dimethylpyrazine di-A -oxide (29) when heated with phosphoryl chloride at 160° gave 2,5-dichloro-3,6-dimethylpyrazine (6%) (30), 3-chloro-2,5-dimethylpyrazine 1-oxide (5%) (31), and 5-chloromethyl-2-methylpyrazine 1 -oxide (9%) (32). In addition small amounts of other chlorinated products, 3-chloro-2-chloromethyl-5-methylpyrazine (33) and 2,5-bischloromethyl-pyrazine (34), were identified. These authors also examined the action of p-tosyl chloride, methane sulfonyl chloride, and mixtures of phosphoryl chloride and concentrated sulfuric acid, but state that these did not give good results. Pyrazine 1-oxide and phosphoryl chloride have been shown to give 2reaction conditions it gave 2-chloropyrazine 1-oxide (757). Pyrazine 1,4-dioxide and benzenesulfonyl chloride also gave a low yield of 2-chloropyrazine 1-oxide (758). 

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). 

Mercaptopyrazine in aqueous hydrochloric or acetic acids was chlorinated to give the sulfonyl chloride which with excess liquid ammonia gave 2-sulfamoyl-pyrazine (1006, 1153). Direct sulfonation of the pyrazine ring has never been reported (819) but 2-sulfopyrazine (17) has been prepared from 2-chloropyrazine and aqueous sodium sulfite at 150° (819), and from 2-fluoropyrazine and aqueous sodium sulfite at reflux for 2 hours (882, 884). 2-Amino-3-mercaptopyrazine in aqueous sodium hydroxide with concentrated ammonia and sodium hypochlorite has been shown to give 2-amino-3-sulfamoylpyrazine (1101). 

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