2-Chloro-6-cyanopyrazine

Oxidation of one of the nitrogen atoms of 2-chloro-3-cyanopyrazine to form a mono-iV-oxide allows for an identical sequence of reactions to generate the corresponding W-oxide 484 <1999W09957122, 2000JME1586>. 

A direct and versatile synthesis of the thieno[2,3-6 ]pyrazine ring system was found by Schneller and coworkers and consists of the reaction of 2-chloro-3-cyanopyrazine (361) with ethyl a-mercaptoacetate in the presence of sodium carbonate (Scheme 106) (75JHC513, 76JHC273 cf. 79MI31703). The conversion of (362) to thieno[2,3- >]pyrazine (363) is accomplished by straightforward methods. The compound (363) forms colorless crystals with m.p. 44 °C. 

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-... 

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. 

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... 

Miscellaneous Fused Systems.— Ethyl 3-aminothieno[2,3- ]pyrazine-2-carboxyIate has been prepared from 2-chloro-3-cyanopyrazine and ethyl a-mercaptoacetate, and then converted into (269) by reaction with formamide. Other derivatives of (269) were subsequently prepared. Fused thieno[3,2-c/]-y/c-triazin-4-ones... 

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>. 

Reaction of cyanopyrazine and its 6-chloro derivative with hydrazine gives the corresponding amidrazones, these compounds have been prepared for testing as antitubercular agents.262b... 

Amino-2-carbamoyl-5-hydroxypyrazine in dimethylformamide with phosphoryl chloride gave 3-amino-5-chloro-2-cyanopyrazine (538). 

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. 

Chloro-6-cyanopyrazine with anhydrous methylamine (940), diethylamine, and other amines in refluxing benzene (941,942), thiomorpholine, and A -methyl-... 

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 on treatment with potassium acetate in propan-2-ol at 80-90° gave 5-acetoxymethyl-2-amino-3-cyanopyrazine(542),and 2-amino-6-chIoro-5-chloromethyl-3-cyanopyrazine with anhydrous sodium acetate in dimethylformamide gave 2-acetoxymethyl-5-amino-3-chloro-6-cyanopyrazine (874). 

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). 

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). 

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). 

Chloro-6-cyanopyrazine with aqueous methylamine at 0° gave 2-chloro-6-(A -methylamidino)pyrazine (940), and 2-cyano-6-dimethylaminopyrazine with dimethylamine in the presence of anhydrous aluminum chloride gave 2-dimethyl-amino-6-(C-dimethylamino-C-iminomethyl)pyrazine and similar reactions were observed with other secondary amines (1424). 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature gave 2-cyano-5-ethoxy-3,6-dimethylpyrazine and 2-cyano-5-hydroxy-3,6-dimethylpyrazine (288). Reactions of 2-chloro-6-cyanopyrazine with sodium methoxide have been described in Sections 1 A(2)(c). 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

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