2-Cyano-6- pyrazine

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Li (6) prepared (5-cyano-pyrazin-2-yl)urea derivatives, (IV), that were effective as kinase inhibitors to treat hyperproliferative states such as cancer. 

Patents describe the preparation (by chlorination) of 2,3,5-trichloro-6-cyano-pyrazine (794,795) and the chlorination of 2-methoxy-3-methoxycarbonylpyrazine (product not stated) has been described (155). 

Pyrazine 1-oxide and 3-amino- and 3-chloropyrazine 1-oxide with tosyl chloride in the presence of pyridine gave 2-pyridiniopyrazine chloride (14) and 2-amino- or 2-chloro-3-pyridiniopyrazine chloride, respectively and 3-methoxycarbonyl(or morpholinocarbonyl or cyano)pyrazine 1 -oxide treated similarly gave 2-methoxy-... 

Methylpyrazine with ammonia and air over an alumina catalyst containing vanadium pentoxide and potassium sulfate at 350° for 10 hours gave 2-cyano-pyrazine (726), also obtained similarly under other conditions (1437). 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

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... 

Cyano-2,3-diphenylpyrazine heated with dry ammonium thiocyanate at ISO gave 5-amidino-2,3-diphenylpyrazine (866). 2-Cyano-5-phenylthiopyrazine heated in acetic acid with hydrogen peroxide for 3 hours gave 2-cyano-5-phenylsulfonyl-pyrazine and some 2-carbamoyl-5-phenylsulfonylpyrazine (840) and 2-cyano-pyrazine with hydrogen peroxide in aqueous alkali at 70° gave 2-carbamoylpyrazine... 

The oxidations of 2-amino-3-cyanopyrazine 1-oxides to the 1,4-dioxides are described in Section VIII.3A(4) and deoxygenations of some 2-amino-3-cyano-pyrazine 1-oxides and 1,4-dioxides with phosphorus trichloride or sodium dithionite in Section VIII.3C(4). Deoxygenation and chlorination of aminocyanopyrazine 1-oxides are reported in Section V.IG, and deoxygenation and acetoxylation or alkoxylation of 2-amino-3-cyano-5-methylpyrazine 1,4-dioxide in Section VIII.3C(5). Hydrolysis of cyanopyrazine Y-oxides to carbamoylpyrazine Af-oxides are given in Section 10A(3) and ring closure reactions of 2-amino-3-cyanopyrazine 1-oxides to pteridine 8-oxides in Section V11I.3C(3). 

Chemoselective cyanation in the C-3 position of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one has been described by Van der Eycken et al. [27]. The procedure is similar to that reported by Alterman and Hallberg. The only difference is that CuCN was selected as transmetal-lating agent instead of Zn(CN)2. When a mixture of 3,5-dichloro-N-(4-methoxybenzyl)-pyrazin-2(lH)-one and CuCN in DMF, using Pd(PPh3)4 as a catalyst, was irradiated for 15 min at 200 °C, the desired 5-chloro-3-cyano-N-(4-methoxybenzyl)pyrazin-2(lff)-one could be isolated with a 68% yield (Scheme 69). 

This bistability is favoured by structures, which will adopt n—stacked motifs, i.e. lamellar molecules. In addition the tendency to adopt the planar structure is enforced by the presence of electronegative heteroatoms (currently restricted to N), which lead to a propensity of in-plane electrostatic S- N contacts between rings. These may comprise heterocyclic S- N contacts or S- N contacts to other functional groups such as the pyrazine or cyano nitrogen atoms. 

Vercek and co-workers described an effective approach to some 3-cyano-4-amino[l,2,3]triazolo[l,5-tf]pyrazines starting from the N-substituted triazole derivatives 396 <2002H(56)353>. This compound when treated either with acetic acid or triethylamine gave rise to the ring-closed products 397 in acceptable yield (55-66%). 

Pd-catalyzed cyanation of 2-methylpyrido[3,4- ]pyrazine 95 with Zn(CN)2 in the presence of Pd2(dba)3 and dppf gave the 5-cyano derivative 96 (dba = dibenzylideneacetone). Amination, without using any base, with benzylamine converted 95 into adduct 97 in excellent yield. Hydrolysis of 95 in aqueous formic acid provided the 5-oxo derivative 98 (Scheme 4) <2003H(60)925>. 

The conversion of DAMN into 2,3-dicyanopyrazines substituted in the 5-and 6-positions with various combinations of amino, cyano, chloro, and hydroxyl groups will be described in this section along with transformations of these initially formed materials into a variety of other multifunctional and fused ring pyrazines. 

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