From Cyanopyrazines

The preparation of acetylpyrazines from cyanopyrazines and Grignard reagents proceeded in the usual manner. 2-Cyanopyrazine with methylmagnesium bromide in ether followed by treatment with dilute hydrochloric acid gave 2-acetylpyrazine (138, 1447). In a similar way the following pyrazines were prepared 2-acetyl-5-methyl (1327) 2-acetyl-6-methyl (1327) 5-acetyl-23-diphenyl (866) 2-acetyl-3,5,6-trimethyl (886) and 2-benzoyl (1447). 

2-(l-Bromoethyl)-3-methylpyrazine was oxidized to 2-acetyl-3-methylpyrazine by sodium 2-propanenitronate (from 2-nitropropane and sodium ethoxide in ethanol) at reflux (66.5% yield) and by pyridine 1-oxide in acetonitrile at reflux (25% yield) (691), and 2-(l-bromoethyl)-3-ethylpyrazine similarly oxidized with 

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Thioamides have been prepared from cyanopyrazines with hydrogen sulfide in the presence of base. In this way the following thiocarbamoylpyrazines have been prepared (conditions of reactions) 2-thiocarbamoyl [EtsN/EtOH/HjS (1409) EtjN-pyridine/HjS/lOO (1419) NHj/EtOH/HjS (138)) 2-thiocarbamoylmethyl and its I -ethyl or 1 -phenyl derivatives (Et3N-pyridine/20° or 100°/H2S) (1420,... 

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

The isonipecotinoyl analogues of FA and AP, (592) and (593) respectively, were prepared from 2-amino-5-bromomethyl-3-cyanopyrazine (16b) by an extension of the strategy first developed by Taylor, as depicted in Scheme 3.123 [2491. 

The synthesis of 2-amino-5-chloromethyl-3-cyanopyrazine 1-oxide (529) from aminomalononitrile and chloromethyl hydroxyiminomethyl ketone, and of 2-amino-6-chloromethyl(and chloroalkyl)-3-cyanopyrazine 1-oxide (534) from aminomalononitrile and -chloro-a-hydroxyiminopropionaldehyde (prepared from the addition of nitrosyl chloride to acrolein) has been described in Section III.l. 

Cyano-6-methylaminopyrazine was also prepared from the chloro compound with methylamine hydrochloride and sodium hydroxide in aqueous dioxane (945) and 2-cyano-6-(2, 2 -dimethylhydrazino)pyrazine was prepared similarly (945). 2-Chloro-6-cyanopyrazine with methanol (and similarly with ethanol) and triethylamine gave 2-methoxy-6-(C-methoxyformidoyl)pyrazine (32) [see Section 5D(2)], and 2-chloro-6-carbamoylpyrazine with concentrated aqueous ammonia at 170-175° gave 2 -amino-b-carboxypyrazine (744). 2-Chloro-3-cyano-5,6-diphenylpyrazine with ammonium hydroxide and potassium iodide formed 2-amino-3-carbamoyl-5,6-diphenylpyrazine, but on fusion with ammonium acetate it gave 2-amino-3-cyano-5,6-diphenylpyrazine (848). 

Displacement of the chloro substituent from pyrazines by the cyano group has not been satisfactorily accomplished (866), but many cyanopyrazines have been prepared from the bromo analogues. Karmas and Spoerri (866) prepared 11 cyanopyrazines with mono-, di-, or trialkyl or phenyl substituents from the corresponding bromo compounds and cuprous cyanide in refluxing dry 4-picoline, but the procedure was not suitable for the preparation of 2-cyanopyrazine (866). It was prepared in 29% yield when the reaction was performed in pyridine (866). Another preparation of 2-cyano-3-phenylpyrazine from the bromo analogue has also been reported (1024). 

Chloro-3-dichloromethylpyrazine with sodium methanethiolate has been claimed to give a mixture of products analogous to those obtained from its reaction with sodium methoxide (688). 2-Amino-5-chloromethyl-3-cyanopyrazine with... 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide with triphenylphosphine in dimethylformamide at 80-90° gave 2-amino-3-cyano-5-(triphenylphosphonio)-methylpyrazine 1-oxide chloride (97) (520) and the 5-bromomethyl analogue reacted similarly with triphenylphosphine in propan-2-ol (542). Compound (97) on hydrolysis with 30% aqueous ethanol containing a small amount of triethylamine gave 2-amino-3-cyano-5-methylpyrazine 1-oxide and thus enabled removal of the chloro substituent from the chloromethylpyrazine (529) compound (97) with triethylamine and acetaldehyde (and other aldehydes) in chloroform at room temperature gave 2-amino-3-cyano-5-(prop-l -enyl)pyrazine 1-oxide (and other alkenyl analogues) (529). 

An analogous series of reactions was observed from 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide and the 2-amino-3-cyano-6-(triphenylphosphonio)-methylpyrazine 1-oxide chloride with aqueous sodium bicarbonate gave the betaine (98) (534). 

Amino-2prepared from 2-amino-3-cyanopyrazine 1-oxide by reflux with acetic acid-acetic anhydride followed by ready deacetylation by refluxing in methanol (538), and in a similar manner 3-amino-2-ethoxycarbonyl-5-hydroxypyrazine has been prepared from 2-amino-3-ethoxycarbonylpyrazine 1 -oxide through 3-acetamido-2-ethoxycarbonyl-5 ydroxy-pyrazine (538), and 2-amino-3-carbamoyl-6-hydroxy-5-methylpyrazine from 2-amino-3-cyano-5-methylpyrazine 1-oxide (538). The preparation of 24 ydroxy-6-methoxycarbonylpyrazine (10) has been claimed from 3-methoxycarbonylpyrazine 1-oxide with acetic anhydride followed by hydrolysis (1057) [cf. Nov Cek et al. (839), who claim it to be the 5-isomer, and Foks (744)]. 

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). 

C-imino-C-methylthiomethyl)pyrazine refluxed in N hydrochloric acid gave 2-amino-3-(methylthio)carbonylpyrazine (1075) and 2-methoxy-6-(C-imino-C-methoxymethyOpyrazine (from 2sodium methoxide) acidified with hydrochloric acid gave 2-methoxy-6-methoxycarbonylpyrazine (986). 

The preparation of cyanopyrazines by primary synthesis has been described in Section II.IH (286-288) and Section 11.2 (353-360). Further data have been recorded on the condensation of diaminomaleonitrile with glyoxal (1434, 1435), with a variety of 1,2-dicarbonyl compounds (1435, 1436), and Bredereck and Schmotzer (1044) have described the preparation from the tetramer of hydrocyanic acid with /J,p -dibromobenzil and p,p -diphenoxybenzil of 2,3-bis(p-bromo-phenyl)-5,6-dicyanopyrazine and 2,3-dicyano-5,6-bis(p-phenoxyphenyl)pyrazine, and with phosgene in dioxane of 2,3-dicyano-5,6-dihydropyrazine. Other preparations are described in Section II.3 (158, 383-387), with further data given in references 1050, 1154 and 1180, Section 11.5 (454) and Section 11.7 (484-486, 488-490). 

Preparations of cyanopyrazines from halogenopyrazines have been described in Section V.5I. 

The dipole moment of 2-chloro-3-cyanopyrazine has been determined as 3.44D in dioxane (749). Polymers have been prepared from 2,3-diamino-5,6-dicyano-... 

Iminoethers were also prepared from 2-amino-3-cyanopyrazine with ethanolic hydrogen chloride (792, 1218) [the product with guanidine and sodium methoxide in methanol formed 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878, 1218)] from 2,6-diamino-3-chloro-5-cyanopyrazine with ethanolic hydrogen chloride at 0 (the product heated with ethanol gave 2,6-diamino-3-chloro-5-triethoxymethyl-pyrazine) (1432) from 2-amino-5-chloro-3-cyanopyrazine the product with... 

A -(2 -imidazolin-2 -yl)amidino]pyrazine (59) (877)) and from 2,6-diamino-3-chloro-5-cyanopyrazine [the product heated with dimethylamine in ethanol at 40° gave 2,6-diamino-3-chloro-5-(A(,A -dimethylamidino)pyrazine] (1361). 2-Chloro-... 

Iminothioethers have similarly been prepared from nitriles. 2-Amino-3-cyano-pyrazine with sodium methanethiolate (other alkanethiolates reached similarly) in ethanol gave 2-amino-3-(Cimino-C-methylthiomethyl)pyrazine (60) (792, 878, 1075) [which with guanidine hydrochloride and sodium methoxide in methanol gave 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878)] 2-amino-5-chloro-3-cyanopyrazine with methanethiol and sodium hydroxide in methanol gave 2-amino-5-chloro-3-(C-imino-C-methylthiomethyl)pyrazine (877, 1218) [which with... 

Cyanopyrazine with concentrated aqueous ammonia was converted through 2-[A(-(C-imino-C-pyrazin-2-ylinethyl)amidino]pyrazine (43) to 2-carbamoylpyrazine (985), and 2-chloro-6-cyanopyrazine reacted similarly (985). 2-Ethoxy-6-(C-ethoxy-C-iminomethyl)pyrazine was found to be a by-product of the reaction of 2-chloro-6-cyanopyrazine with concentrated ethanolic ammonia and 2-ethoxy(or methoxy)-6-[C-ethoxy(or methoxy)-C-iminomethyl]pyrazine was obtained from 2-chloro-6-cyanopyrazine by the action of ethanol (or methanol) in the presence of triethylamine (985). 2-Cyanopyrazine treated in water with hydroxylamine hydrochloride and sodium carbonate at 70-75° gave 2-(C-amino-C-hydroxyiminomethyl)-pyrazine (62), and 2aluminum chloride at 140-220° gave 2-(C-anilino-C-iminomethyl)pyrazine (and similar preparations were carried out with other aromatic amines) (1334,1410). 

Cyanopyrazine A -oxides have been prepared from a-amino nitriles and a-hydroxyimino carbonyl compounds as summarized in Section III. 1 (528-530, 532-534, 537, 540, 542). Oxidation of 2-cyanopyrazine with perhydrol gave 3-cyanopyrazine 1-oxide (575), 2-cyano-5-ethoxy-3,6-dimethylpyrazine with 30% hydrogen peroxide in acetic acid at 55° gave 2-cyano-5-ethoxy-3,6-dimethylpyrazine iV-oxide (288), and the oxidations of 2-amino-3-cyanopyrazine 1-oxide (538) and... 

Preparation of thieno[2,3-b]pyrazines involves appropriate substituted pyrazines as intermediates. Possible alternative routes starting from thiophenes were not attempted as 2,3-diaminothiophene is only accessible with difficulty. Reaction of 2-chloro-3-cyanopyrazine (3) with a-mercaptocarbonyl compounds in the presence of sodium carbonate gave high yields of the 7-amino derivatives 4 and 5. 

However, some ring systems have posed difficulties. 4-Aminopteridine could not be obtained from 2-amino-3-cyanopyrazine (see 9), and 2-amino-... 

Miscellaneous Fused Systems.—The reaction of 2-vinylthiophen with azodicar-boxylates gave a mixture of tetra- and dihydro-thienopyridazine diesters upon dicarbethoxylation with TFA followed by oxidation, these gave thieno[2,3-c]pyridazine. ° Thieno[2,3-6]pyrazine has been synthesized from 2-chloro-3-cyanopyrazine by reaction with ethyl thioglycollate and condensation with base... 

Figure 11.8 Reaction sequence analogies of 3-cyanopyridine 1 degradation and 2-cyanopyrazine 4 transformation (through nicotinic acid 2 and 6-hydroxy-nicotinic acid 3 or pyrazinecarboxylic acid 5 and 5-hydroxypyrazine-2-carboxylic acid 6 respectively). Figure reproduced from [49] with kind permission from Springer Science and Business media.

Hong, C. and Li, Y. 2-Cyanopyrazine Prepared from 2-methylpyrazine by catalytic ammoxidation on Mo VPO catalyst. Chinese J Chem Eng 14, 670-675 (2006). 

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