2-Carboxy-5-methoxy pyrazine

Replacement of the chloro substituent by methoxide has been observed in the following pyrazines 2-chloro-3-methoxycarbonyl (at <5°) (867) 2-chloro-6-methoxycarbonyl (870) 2-chloro-3-methoxycarbonyl-5,6-diphenyl (371, 837) 2-carboxy-6-chloro (869, 871) 2-carbamoyl-5( )-chloro (839) 2-carbamoyl-6-chloro (805, 839) 2-chloro-6-(4 -morpholinocarbonyl) (870) 2-chloro-3-cyano (810, 811) 5-chloro-3-cyano-2-methoxy (reflux 14h) (881) 2-chloro-5-methoxy-3,6-dimethyl (844) 2-chloro-5-isopropyl-6-methoxy-3-methyl (50, 844) 2-chloro-5-methoxy-3,6-diphenyl (1.1 equivalents of 20% methanolic sodium methoxide at 135° for 20h) (797) 2-benzyloxy-6-chloro(at reflux) (832, cf. 883) 2-chloro-3-pyridinio(pyrazine)chloride (or tosylate) (to give 2,3-dimethoxypyrazine) (765) ... 

The first lithiopyrazine derivative was prepared by Hirschberg et al. (1015) from 3-iodo-2,5-dimethylpyrazine and butyllithium in ether subsequent reaction with (a) carbon dioxide gave 3-carboxy-2,5-dimethylpyrazine, and (b) several aromatic aldehydes gave the carbinols (62, R = H, p-methoxy, m-nitro) (1015). Similar reactions were observed when 2-formylpyridine and 2-acetylpyridine (1016) were used as the carbonyl compounds, but with acetaldehyde attempted reactions were unsuccessful (1015). A patent also describes the preparation of many carbinols from 2,5-disubstituted 3-iodopyrazines (164). The lithio reagent derived from 3-iodo-2,5-dimethylpyrazine (with butyllithium in hexane) with 2-nitrobenzaldehyde gave 2,5-dimethyl-3[ 1 -hydroxy-1 (2"-nitrophenyl)methyl] pyrazine (1017). 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

Chloro-3-methoxycarbonyl-5,6-diphenylpyrazine refluxed with sodium methoxide gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (371) and the attempted Schmidt reaction of 2,5-dimethoxycarbonylpyrazine, in concentrated sulfuric acid with trichloroacetic acid at 60° with subsequent addition of sodium azide, gave 2,5-dicarboxypyrazine (1176). 2-Methoxy-3-methoxycarbonyl-5,6-diphenylpyrazine, when refluxed with cuprous chloride in dry dimethylformamide, gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (10%) 2-hydroxy-3-methoxycarbonyl-5,6-diphenyl-pyrazine similarly treated gave 5-hydroxy-2,3-diphenylpyrazine (30%) (837). 

The amino group of hydrazides react with aldehydes and ketones. For example, 2-hydrazinocarbonylpyrazine refluxed with acetone-ethanol gave 2-isopropylidene-hydrazinocarbonylpyrazine (51) [which was reduced in methanol over palladium-charcoal to 2-(2 -isopropylhydrazinocarbonyI)pyrazine] (1366,1428,1429). Other references to similar reactions include the following reactions 2-hydrazinocarbonylpyrazine with p-acetamidobenzaldehyde (138) 4-hydroxy-, 4-hydroxy-3-methoxy-and 2-carboxy-3,4-dimethoxybenzaldehydes (1319) furfural (1201) and pyruvic acid (1201) 2-amino-3-hydrazinocarbonylpyrazine with acetone and benzaldehyde (1214) and 2-hydrazinocarbonyl-5,6-dimethyl-3-methylaminopyrazine with acetone (428). 

There is a separate table for each class of pyrazine with one type of substituent, a table for each combination containing two types of substituents, and appropriate tables for three and four types of substituents. Thus, for example, 2-amino-3-ethoxypyrazine is listed in Table A. 12 (amino oxypyrazines), 3-amino-2-methoxy-carbonyl-5-methylsulfinylpyrazine in Table A. 16 (amino carboxy sulfonylpyra-zines), and 2-amino-5-chloro-6-ethoxy-3-ethoxycarbonylpyrazine in Table A.20 (amino carboxy halogenopyrazines with other functional groups). 

---