Alkylation of hydroxypyrazines

3-Khydroxypyrazine (which was converted into its jV -dimethyl derivative by treatment with dimethyl sulfate and alkali) gave, on reaction with an excess of ethereal diazomethane a mixture of its N,N-, 0,N-, and 0,0-dimethyl derivatives (58-60) (832). 2-Hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenylpyrazine with ethereal diazomethane gave predominantly 2,5-dimethoxy-3,6-diphenyl-pyrazine and only minor amounts of A -methylated products (832). Methylation of 2-hydroxy-6-methoxypyrazine with ethereal diazomethane produced a mixture of 0- and A -methyl derivatives in which the 0-methyl derivative predominated but the corresponding reaction of 2-benzyloxy-6-hydroxypyrazine gave almost exclusively the 0-methyl derivative (832) [the results of these methylations were correlated with the carbonyl stretching frequency (1103) in the parent lactam (832)]. 

Other methylations with diazomethane are as follows 2,6-dihydroxy-3,5-diphenylpyrazine formed a mixture of products from which only 2,6-dimethoxy- 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

3-Hydroxy-2,5-diphenylpyrazine, methyl iodide, and methanol and some potassium hydroxide heated in a sealed tube at 100° for 10 hours formed the methiodide of 1 -methyl-3,6-diphenyl-2-oxo-l, 2-dihydropyrazine (1104) [3-hydroxy- 

5-dimethylpyrazine reacted similarly (1104), and this in aqueous solution reacted with potassium hydroxide to give a product claimed to be l,4,5-trimethyl-2-methylene-3-oxo-l, 2,3,4-tetrahydropyrazine (1105)]. 

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The preparation of alkoxypyrazines by alkylation of hydroxypyrazines with several reagents is discussed in detail in Section 6D. Many such alkylations give rise to both N- and 0-alkyl derivatives. 

Alkylation of hydroxypyrazines to give N- or 0-alkyl derivatives (and mixtures of both formed particularly from methylations with diazomethane) have been described in Section 6D. 

The alkylation of hydroxypyrazine A oxides to C- and A-alkoxypyrazine N-oxides has been described in Section 11C. 

Most alkoxy- or aryloxypyrazines have been made by primary synthesis (see Chapters 1 and 2), by addition of alcohols to alkynylpyrazines (see Section 3.2.4.9), by alcoholysis or phenolysis of halogenopyrazines (see Sections 4.2.3 and 4.4), by O-alkylation of tautomeric pyrazinones or extranuclear hydroxypyrazines (see Sections 5.1.2.2 and 5.2.2), or by epoxidation of alkenylpyrazines (see Section 3.2.4.1). Some of the few remaining routes (presently of minor preparative value) are illustrated briefly in the following recent examples ... 

The antibiotic emimycin was first isolated (107) from Streptomyces No. 2021-1 and subsequent work (108) showed it to be 3-hydroxypyrazine 1-oxide which from infrared evidence (Nujol) was assigned the pyrazine structure (99, R = H) [alkyl derivatives have been assigned similar structures (978)]. It had an acidic pAi, 6.2 (108) and was a stronger acid than 2-hydroxypyrazine [acidic pA 8.23 (1082)]. Emimycin did not form acetyl derivatives under a variety of conditions acetic anhydride and pyridine, acetyl chloride and pyridine, or acetic anhydride and sulfuric acid (108). 

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