Pyrazine 2-methyl-, chlorination

Pyrazine, 2-methoxy-3-sulfanilamido-plasma half-life, 1, 162 Pyrazine, methyl-chlorination, 3, 168 oxidation, 3, 168 reactions... 

Pyrido[2,3-b]pyrazine, 2,3-dihydroxy-chlorination, 3, 251 Pyrido[2,3-b]pyrazine, 6-hydroxy-formation, 3, 251 Pyrido[2,3-b]pyrazine, 8-hydroxy-tautomerism, 3, 250 Pyrido[2,3-b]pyrazine, methyl-acylation, 3, 253 Pyrido[2,3-b]pyrazine, 2-oxo-oxidation, 3, 250-251... 

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). 

A tetrahydropyrido[3,4-/)]pyrazine nucleus was constructed from 2,3-dimethylpyrazine 687 by chlorination with A-chlorosuccinimide (NCS) to give 2,3-bis(chloromethyl)pyrazine 688, followed by cyclization with diethyl acet-amidomalonate to pyridopyrazine 689. Hydrolysis and decarboxylation of 689 in hydrochloric acid, then esterification by action of thionyl chloride in methanol gave methyl 5,6,7,8-tetrahydropyrido[3,4-. ]pyrazine-7-carboxylate hydrochloride 690 (Scheme 32) <2003BMC433>. 

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. 

Imidazo[4,5-6]pyrazine, 2-methyl-synthesis, 5, 645 I midazo[ 1,2-a]pyrazines reaaions, 5, 624 sjmthesis, 5, 642-643 Imidazo[l,5-a]pyrazines chlorination, 5, 625 reactions, 5, 625-626 synthesis, 5, 644-645 Imidazo[4,5- 6]pyrazines reactivity, 5, 626-627 synthesis, 5, 645-646... 

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>. 

Hydrolyses of carbamoylpyrazine A -oxides to carboxypyrazine IV-oxides have been described in Section 8A(2), deoxygenation and chlorination of carbamoylpyrazine A -oxides (A -unsubstituted carbamoyl compounds gave the nitrile) in Section V.IG, and deoxygenation of carbamoylpyrazine A -oxides (which also contained amino groups) in Section VIII.3C(4). In addition, 4-methyl-2-A -methyl-A -phenylcarbamoyl-3-oxo-3,4-dihydropyrazine 1-oxide refluxed with aqueous ethanolic sodium dithionite gave 4-methyl-2-Af-methyl-Af-phenylcarbamoyl-3-oxo-3,4-dihydropyrazine (1137), and 3,5-bis(methylamino)-3-A -methylcarbamoyl-pyrazine 1-oxide was deoxygenated by heating at 190-200° and 0.25 mm (462). 

The title compounds are stable tautomers of the corresponding 2-hydroxypyrazine 1-oxides, and in fact l-acetoxy-2(lH)-pyrazinones, not 2-acetoxypyrazine A -oxides, are obtained on treatment with acetyl chloride in the presence of pyridine at room temperature <87JHC187>. Nevertheless, these compounds resemble the N-oxides in most of their reactions. Representative examples are deoxidative acetoxylation and chlorination. Treatment of l-hydroxy-3,5-diphenyl-2(l//)-pyr-azinone (100) with a refluxing mixture of acetic anhydride and acetic acid affords 2,6-diacetoxy-3,5-diphenylpyrazine (101), which is deacetylated with potassium hydrogen carbonate to give 2,6-dihydroxy-3,5-diphenylpyrazine (102) (or tautomer) (Scheme 23) <7UCS(C)2977>, Acetoxylation of a methyl substituent occurs exclusively and then that of the pyrazine ring is suppressed completely. 

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