2-Cyano-6- pyrazine hydrolysis

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). 

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>. 

An unequivocal synthesis of (637), protected as its A-2 -acetyl derivative (643), was successfully accomplished as shown in Scheme 3.140 [40]. Pyruval-dehyde dimethylacetal was first converted into its enamine (108). Condensation of (108) with the O-tosyl derivative of oximinomalononitrile gave the azadiene (638), which was converted to 2-amino-3-cyano-6-dimethoxymethyl-pyrazine (639) with ammonia. This latter compound was condensed with guanidine and the product (640) hydrolyzed first with base (to remove the 4-amino group) and then with acid to give pterin-7-carboxaldehyde (641). Acetylation of (641) followed by condensation with di-t-butyl p-aminobenzoyl-glutamate (235), reduction and hydrolysis gave (643). 

Pyrazinecarbaldehydes can of course be recovered from their derivatives for example, the acetal, methyl 6-amino-5-cyano-3-diethoxymethyl- (249), gave methyl 6-amino-5-cyano-3-formyl-2-pyrazinecarboxylate (250) in 85% yield by selective hydrolysis in dilute hydrochloric acid at 20°C during 12 h 773 likewise, the extranu-clear acetal, 2-(3,3-diethoxypropyl)-3-ethoxycarbonylmethylpyrazine, gave 2-ethoxycarbonylmethyl-3-(2-formylethyl)pyrazine in 92% yield on hydrolysis in aqueous alcoholic hydrochloric acid at 35°C during 2 h.1249... 

Gastaldi (286) first described this synthesis, in which an a-hydroxyimino ketone was treated with aqueous sodium bisulfite saturated with sulfur dioxide, and the bisulfite compound treated with potassium cyanide followed by hydrolysis with hydrochloric acid. By this procedure, Gastaldi prepared 2,5-dicyano-3,6-dimethyl-pyrazine from hydroxyiminoacetone, and 2,5-dicyano-3,6-diphenylpyrazine and some 3-cyano-2,5-diphenylpyrazine from hydroxyiminoacetophenone. He proposed a reaction mechanism involving the intermediate compounds (21) and (22). Sharp and Spring (287) used the same procedure to prepare 2,5-dicyano-3,6-diethyl-pyrazine from ethyl hydroxyiminomethyl ketone. 

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). 

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)]. 

In the synthesis of (III. 15) and (III.16) by Rosowsky and Chen [21], which was an application of the regioselective Taylor pteridine synthesis [22-24], 2-amino-5-chloromethyl-3-cyano-6-methylpyrazine A-oxide was condensed with diethyl A-[4-(A-methylamino)benzoyl]-L-glutamate, the A-oxide group was removed with triethyl phosphite in DMF at 125 °C, and the resultant pyrazine amino nitrile was condensed with gujmidine. Brief hydrolysis (15 min, 1 M NaOH in refluxing EtOH) led to (III. 15), and chlorination of (III.15) at 5 °C afforded the 3, 5 -dichloro derivative (III.16). Ultraviolet absorption spectra of (III. 15) and (III. 16) in 0.1 M NaOH were consistent with those reported in the literature for MTX and DCM, except for small... 

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