Methylpyrazines chlorination

It has been discovered that direct chlorination of pyrazines can be accomplished and this has also been used to make candidate drugs. For example, when 2-methylpyrazine (120) is heated with chlorine in carbon tetrachloride, a mixture of the 3-chloro (121) and the 6-chloro derivatives result. After separation, 121 is heated with piperidine to give modaline (122), an antidepressant. 6... 

Bourguignon and coworkers in their preparation of thieno[2,3-6]pyrazine used methyl-pyrazine (364 Scheme 107) (80JHC257) as starting material. The chlorination of (364) yields 2-chloro-3-methyl- and 2-chloro-6-methyl-pyrazine in a ratio of 80 20. Without separation this mixture is treated with ethyl mercaptoacetate in the presence of sodium ethoxide to give (365) in 91% yield (based on 2-chloro-3-methylpyrazine). Oxidation of the methyl group to an aldehyde function and subsequent base catalyzed ring closure yields (366), which is transformed to (363) by the method depicted already in Scheme 106. 

Treatment of methylpyrazine with chlorine in carbon tetrachloride at 40° gives two products and the total yield of monochloro derivatives is 65%.281-283 The major product is 2-chloro-3-methylpyrazine and the minor product, originally thought to be the isomeric 2-chIoro-5-methyl derivative, was later shown to be 2-chloro-6-methylpyrazine [Eq. (16)].284 2,5-Dimethylpyrazine also undergoes ring substitution... 

Two very simple precursors combine to produce 2-arylpyrrolo[2,3-6]pyrazines. The anion derived from 2-methylpyrazine (173) adds to a benzonitrile (e.g. (174)) to give the product (175) (Equation (59)). This reaction is not the favored pathway displacement of chlorine is preferred <89TL935> although a similar reaction without the chloro substituent does provide the pyrrolopyrazine as the major product <8iTLi2i9>. However, this reaction does not seem to have been investigated for additional examples. In another simple reaction, 2-aminopyrazine (176) reacts with ethyl chloro-acetoacetate to give ethyl 6-methyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylate (177) (Equation (60)) <89BSF467>. 

Vapor phase chlorination of methylpyrazine in carbon tetrachloride at 545° in 15 times the molar ratio of chlorine gave tetrachloropyrazine (684). 

Chlorination of 2-methylpyrazine in acetic acid at 100° gave 2-trichloromethyl-pyrazine (685, 686), whereas 2-chloro-3-methylpyrazine under similar conditions gave 2-chloro-3-dichloromethylpyrazine (685, 687, 688). Chlorine bubbled into a stirred solution of 3-dimethylamino-2,5-dimethylpyrazine in chloroform gave the 6[Pg.80]

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). 

Vapor phase chlorination of methylpyrazine in carbon tetrachloride (10%w/w) at 545° with 15 times the molar ratio of chlorine for 13 sec has been claimed to give tetrachloropyrazine (776) and chlorine passed into a refluxing solution of 2-chloro-3-methylpyrazine in acetic acid gave 2-chloro-3-dichloromethylpyrazine (688). 

Some chlorinations have been reported with thionyl chloride. 23-Dicyano-5,6-dihydroxypyrazine refluxed with thionyl chloride in pyridine was reported to give 23-dichloro-5,6-dicyanopyrazine (862) and 2-hydroxy-3-nitro-5,6-diphenyl-pyrazine with thionyl chloride gave 2-chloro-3-hydroxy-5,6-diphenylpyrazine (817, 841) but with thionyl chloride and pyridine it gave the betaine of 2-hydroxy-5,6-diphenyl-3-pyridiniopyrazine chloride (5) (863), which was hydrolyzed in acid to 2,3-dihydroxy-5,6-diphenylpyrazine (863). No product could be isolated from 2-methylpyrazine when refluxed with thionyl chloride (864). 1,4-Dimethylpiperazine-... 

The oxidations of 2-amino-3-cyanopyrazine 1-oxides to the 1,4-dioxides are described in Section VIII.3A(4) and deoxygenations of some 2-amino-3-cyano-pyrazine 1-oxides and 1,4-dioxides with phosphorus trichloride or sodium dithionite in Section VIII.3C(4). Deoxygenation and chlorination of aminocyanopyrazine 1-oxides are reported in Section V.IG, and deoxygenation and acetoxylation or alkoxylation of 2-amino-3-cyano-5-methylpyrazine 1,4-dioxide in Section VIII.3C(5). Hydrolysis of cyanopyrazine Y-oxides to carbamoylpyrazine Af-oxides are given in Section 10A(3) and ring closure reactions of 2-amino-3-cyanopyrazine 1-oxides to pteridine 8-oxides in Section V11I.3C(3). 

Chlorination of 2-methylpyrazine occurs under such mild conditions that it is almost certain that an addition/elimination sequence is involved, rather than a classical aromatic electrophilic substitution. Halogenation of pyrimidines may well also involve such processes. ... 

In the synthesis of (III. 15) and (III.16) by Rosowsky and Chen [21], which was an application of the regioselective Taylor pteridine synthesis [22-24], 2-amino-5-chloromethyl-3-cyano-6-methylpyrazine A-oxide was condensed with diethyl A-[4-(A-methylamino)benzoyl]-L-glutamate, the A-oxide group was removed with triethyl phosphite in DMF at 125 °C, and the resultant pyrazine amino nitrile was condensed with gujmidine. Brief hydrolysis (15 min, 1 M NaOH in refluxing EtOH) led to (III. 15), and chlorination of (III.15) at 5 °C afforded the 3, 5 -dichloro derivative (III.16). Ultraviolet absorption spectra of (III. 15) and (III. 16) in 0.1 M NaOH were consistent with those reported in the literature for MTX and DCM, except for small... 

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