3- Carboxy-2-hydroxy pyrazine

Ultraviolet spectra of numerous pyrazines have been recorded, but in many cases without regard to the effects of ionization, and in various solvents. All pyrazines are basic and thus have both neutral (e.g., 5) and cationic (e.g., 6) forms. Pyrazines with a substituent containing an ionizable hydrogen, such as a carboxy, hydroxy, or mercapto group, may also exist in the anionic form (e.g., 7), the tautomeric neutral form (e.g., 2, R = H), a potentially zwitterionic form (8, R = H) or an isomeric cationic form (e.g., 9, R = H). Many published spectra are in fact of mixed ionic species to determine the spectrum of each ionic form it is necessary to measure its spectrum in a solution buffered at least two units above or below the pAa value (or values) of the substance. In nonaqueous solvents, the neutral (uncharged) species are favored. The ultraviolet spectra of pure species may then serve to characterize the pyrazine, may permit the correlation of spectra with structure, and may be used in quantitative determinations. 

Pyrido 2,3-b pyrazin 7-Carboxy-2-methyl-8-oxo-5-(2-propinyl)-5,8-dihydro- E9c, 243 (NH - N-R) Quinazolin 2-(Cyan-tnethoxycarbo-nyl-methyl)-4-hydroxy- E9h/2, 29 [2-NH2-Ar-COOH/ (NC)2CH-COOR]... 

H2, 3-Dimethylphenyl)-4-hydroxy-2-oxo-l,2-dihydropteridine with sodium hydroxide in refluxing ethanol gave 2-carboxy-3-(2, 3 -dimethylphenylamino)pyrazine (Laboratories Hermes,... 

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). 

Diacetyl-3,6-dibenzylpiperazine-2,5-dione (15) reacted with sulfur in dimethyl-formamide and triethylamine to form, after hydrolytic removal of the acetyl groups, 3-benzyl-6-benzylidenepiperazine-2,5-dione (16) (1068). 2-Chloro-5-hydroxy-3,6-dimethylpyrazine heated with solid potassium hydroxide gave 3-hydroxy-2,5-dimethylpyrazine (312), and 2-chloro-6-hydroxy-3,5-diphenylpyrazine with an excess of methanolic sodium methoxide at 150° formed 2-hydroxy-3,5-diphenylpyrazine (873). Decarboxylation of 2-carboxy-3-hydroxypyrazine gave 2-hydroxypyrazine (420) and in this way 24iydroxy[2- C]pyrazine (823) and 2-hydroxy[l- N]pyrazine (822) have been prepared. 

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). 

Amino-3-cyano-5-methylpyrazine 1,4-dioxide (91) refluxed for several minutes with acetic anhydride formed 3-acetamido-2-cyano-5-hydroxy-6-methylpyrazine 1-oxide (92) (24%) (532) and 2-acetoxymethyl-5-methylpyrazine 1,4-dioxide refluxed with acetic anhydride afforded a mixture of2,5-di(acetoxymethyl)pyrazine 1-oxide, with some 2,5-diacetoxymethylpyrazine and a monoxide of 2-acetoxy-methyl-5-methylpyrazine (625). 2-Formylpyrazine hydrate 1,4-dioxide with aqueous sodium hydroxide or bicarbonate at < 37° in an unusual reaction gave 3-carboxy-pyrazine 1-oxide mixed with 5 [Pg.188]

The preparation of 2-amino-3-carboxy-5-methylthio(and 5-benzylthio)pyrazines by saponification of 4-hydroxy-6-methylthio(and 6-benzylthio)pteridine with 5% sodium hydroxide has been described in Chapter II.5 (432,432a). Some additional references also describe these preparations (778, 780,783,786, 858). 2-Acetamido-... 

Renilla (sea pansy) luciferin (and certain of its synthetic analogues) produces a brilliant blue chemiluminescence when dissolved in organic solvents such as dimethylformamide and involves the anion of 2-acetamido-3-benzyl-5-(p-hydroxy-phenyl)pyrazine (21) (1191). 5-Hydrazino-2-hydrazinocarbonylpyrazine is effective against mycobacterium tuberculosis and m. kansasii in vitro (1098). Aminonitro-pyrazines have been claimed as useful yellow dyes for wool (1180) and tetraamino-pyrazine (1180) and A -substituted amides of 2-carboxy-3,5-bismethylamino-6-(A -methylcarbamoyl)pyrazines (1192) as fluorescent brighteners (or optical bleaching agents) for textiles. 

The preparation of arylazo derivatives from hydroxypyrazines has been described in Section VI.6E and from l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahydro-pyrazine to give l,4,6-trimethyl-2-oxo-3-phenykzomethylene-l,23,4-tetrahydro-pyrazine in Section VI.9B. In addition to these reactions Princivalle (1122) reports that 2reacted with benzenediazonium chloride and p-toluenediazonium chloride by elimination of the carboxy group para to the hydroxy group and coupling to form 2-hydroxy-3,6-dimethyl-5-phenyl-azo(and p-tolueneazo)pyrazines, respectively (1122), identical to those prepared from 3-hydroxy-2,5 -dimethylpyrazine. 

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 following nitriles have been used to prepare carboxypyrazines 2-cyano-3-phenyl [NaOH/ethylene glycol/reflux (1274) or heated with H2S04/NaN02 (1024)] 3-cyano-2,5-dimethyl (NaOH/EtOH/reflux) (1015) 3-cyano-2,5-diphenyl (NaOH) (286) 2,3-dicyano [NaOH/EtOH (354) aq. KOH/EtOH (353) NajOj (357)] 2,6-dicyano (5% NaOH/10072h)(865) 23-dicyano-5,6-dimethyl(Na202) (357) 2-cyano-6-ethylthio(propylthio or phenylthio) (NaOH/EtOH/reflux) (992) 2hydrochloric acid to 2-(3 -carboxy-3 -phenylpropyl)pyrazine (731). 

When heated with aqueous potassium hydroxide, 2,5-dicyano-3,6-dimethyl(and diphenyOpyrazine gave 2-carboxy-5-hydroxy-3,6-dimethyl(and diphenyl)pyrazine (286-288) and the diethyl analogue was prepared similarly (287). 2-ChIoro-6-cyanopyrazine refluxed with three equivalents of sodium methoxide for 2 hours gave 2-carboxy-6-methoxypyrazine, also obtained from 2-chloro-6-cyanopyrazine with one equivalent of sodium methoxide through 2-(C-imino-C-methoxymethyl)-6-methoxypyrazine (2), which, refluxed with 15% sodium hydroxide, gave 2-carboxy-6-methoxypyrazine (986). 

Amino-5-carboxypyrazine in anhydrous dimethylformamide with triethyl-amine and ethyl chloroformate and then diethyl glutamate and stirred at room temperature gave 2-amino-5-(l, 3 -diethoxycarbonylpropyl)carbamoylpyrazine (24) (1244). Similarly a mixture of 2-carboxypyrazine and triethylamine in methylene dichloride with ethyl chloroformate and morpholine gave 2-( -morpholinocarbonyl)-pyrazine (1351). 2-Carboxy-3-hydroxypyrazine refluxed with phosphorus tris(A-methylanilide) in toluene gave 2-hydroxy-3-(A-methyl-A-phenyIcarbamoyl)pyrazine (1055), and 2-hydroxy-3-(A -methyl-A -p-tolylcarbamoyl)pyrazine was prepared similarly (1055). Tetracarboxypyrazine heated with sulfur tetrafluoride (SF4) at 150° gave tetra(trifluoromethyl)pyrazine (899). 

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). 

Carboxypyrazine A -oxides have been prepared by hydrolysis of carbamoyl- and alkoxycarbonylpyrazine A(-oxides as follows (reagent and conditions) 2-carbamoyl-pyrazine 1-oxide (10% NaOH/reflux/12h) (838) 3-carbamoylpyrazine 1-oxide (10% NaOH/reflux/30 min) (1266, cf. 838) 3-A(-acetylcarbamoylpyrazine 1-oxide (10% NaOH/heat) (1057) 3-morpholinocarbonylpyrazine 1-oxide (18% HQ/reflux/ 8h) (870) 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/20-25°/ 20min) (739) 3-hydroxy-5-methoxycarbonylpyrazine 1-oxide (KOH/22 /2h gave 3-carboxy-5-hydroxypyrazine 1-oxide, which interfered with the growth of Streptococcus faecium Escherichia coli at 6 x lO and 4 x 10" M, respectively) (1035) 2-amino-3-benzyloxycarbonyl-5-methyIpyrazine 1-oxide 2N NaOH/reflux/ 30min) (365c) and 2-amino-5-chloro-3-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/heat) (876,1222). 

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