Chloromethylpyrazines

AP (protected by acetylation at N-10, (650)) was prepared in an unequivocal fashion by a different strategy starting with 2-amino-3-cyano-6-formylpyra-zine (647), which was itself prepared by two independent procedures Scheme 3.141) [261], In the first, 2-amino-3-cyano-6-chloromethylpyrazine (645) was converted to (647) via (646) by the KrOhnke procedure in excellent overall yield. In the second, the 1-oxide (644) was treated with w-propylamine,... 

The 7-isomer of 10-thiaAP (653) was prepared by taking advantage of the Taylor unequivocal synthesis of 2-amino-3-cyano-6-chloromethylpyrazine (645). Thus, condensation of the latter with the anion of diethyl p-mercaptoben-zoylglutamate (40) [53], followed by guanidine cyclization and saponification, gave (653) (Scheme 3.143) [263]. 

Methylpyrazine gave 2-chloromethylpyrazine (272) ((V-chlorosuccinimide, Bz202, A, CC14, reflux, 24 h 89% after purification by TLC).205 cf428 674938 ... 

Chloromethylpyrazine (250) gave 2-(isothiouroniomethyl)pyrazine chloride (251) [S=C(NH2)2, MeOH, 1 h crude solid), and thence 2-(mercap-tomethyl)pyrazine (252) (1.3 M NaOH, reflux, N2, 1 h >20% overall) 674 2-bromomethyl- gave 2-mercaptomethyl-3,5,6-trimethylpyrazine (85%) in a similar way.1551... 

Vapor phase bromination of bromopyrazine (feed ratios 1 1) at 425-625° with water as a diluent gave dibromopyrazines, and increased feed ratios favored formation of tribromopyrazine (768). The reaction of2-bromopyrazine (0.10 mol) and bromine (0.11 mol) with a trace of phosphorus tribromide and ferrous bromide at 95° formed 2,3-dibromopyrazine (797). Bromination of 2-bromo-3-chloromethylpyrazine in carbon tetrachloride has been claimed to give 2,5-dibromo-3-chloromethylpyrazine, 2,6-dibromo-3-chloromethylpyrazine, and 2,5,6-tribromo-3-chloromethylpyrazine (688). 

Deoxygenation of 2-amino-3-cyano-6-chloromethylpyrazine 1-oxide with phosphorus trichloride in tetrahydrofuran has been shown to give 3-amino-2-cyano-5-chloromethylpyrazine (534). 

The halogenopyrazines are liquids but the polyhalogeno compounds are usually low melting solids (Table V.3 contains representative literature values). 2-Chloro-pyrazine is a strong smelling liquid and 2-chloromethylpyrazine a lacrimatory oil (679). 

Hydrolysis of 2-chloromethyl-3-ethoxy-5-methylpyrazine with aqueous potassium hydroxide gave 3-ethoxy-2-hydroxymethyl-5-methylpyrazine (872), but attempted acid hydrolysis of 2-chloromethyl-3-ethoxy-5-methylpyrazine (and 3-ethoxy-2-ethoxymethyl-5-methylpyrazine) was unsuccessful (872). Attempts to convert 2-chloromethylpyrazine to 2-hydroxymethylpyrazine were also unsuccessful (679). 

Chloromethylpyrazine with sodium azide in refluxing aqueous acetonitrile gave 2-azidomethylpyrazine (690), and 2-amino-5-bromomethyl-3-cyanopyrazine with sodium cyanide in dimethyl sulfoxide at 40° gave 2-amino-3-cyano-5-cyano-methylpy razine (1031). 

Certain a-chloromethylpyrazine A -oxides have been deoxygenated with phosphorus trichloride. Treatment of 2-amino-5-chloromethyl-3-cyanopyrazine 1-oxide (and 2-amino-3-cyano-5-methoxymethylpyrazine 1-oxide) with phosphorus trichloride at room temperature in tetrahydrofuran resulted in smooth deoxygenation to 2-amino-5-chloromethyl-3-cyanopyrazine (and 2-amino-3-cyano-5-methoxy-methylpyrazine) (529), whereas 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide was best deoxygenated to 3-amino-5-chloromethyl-2-cyanopyrazine by phosphorus trichloride in refluxing tetrahydrofuran (534). The more vigorous conditions necessary for the last reaction may be a reflection of increased steric hindrance at the fV-oxide grouping (529). Use of solvents like chloroform or dioxane led to slow reactions which were accompanied by the formation of numerous unidentified by-products (534). 

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). 

Some preparations of extranuclear aminopyrazines from extranuclear halogenopyrazines and amines have been described in Section V.6B (542, 679, 932,1029-1031). 2-Chloromethylpyrazine also reacted with sodium azide and gave 2-azidomethylpyrazine, which was hydrogenated in 95% ethanol over Adams catalyst to 2-aminomethylpyrazine (690). 

Aluminum bromide, 10,42,140 Aluminum chloride, 10-15,140,357 Aluminum cyclohexoxide, 15 Aluminum hydride, 357 AluminumOII) iodide, 106 Aluminum isopropoxide, 15-16 Amberlite-15, 266 Amberiite IR 120, 267 Amide acetals, 527-528 Amides, 424,456 Amidines, bicyclic, 16-18 Amine oxides, 270 p-Aminoacetophenone, 18 Amino adds, 252, 273, 368 Aminoalkenylation, 95 4-Aminobenzoic add, 45 2-Amino-3-cyano-5-chloromethylpyrazine 1-oxide, 459... 

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