Studies on pyrazines. Part 22. Lewis acid-mediated cyanation of pyrazine N-oxides with trimethylsilyl cyanide: new route to 2-substituted 3-cyanopyrazines

Abstract

Reaction of 3-substituted pyrazine 1-oxides with trimethylsilyl cyanide in the presence of triethylamine in acetonitrile gave the corresponding cyanopyrazines, yields of which depended remarkably on the substituent. Electron-donating groups enhanced the cyanation with high regioselectivity to 2-substituted 3-cyanopyrazines, while a chloro substituent suppressed the conversion. Addition of zinc halide to the reaction mixture, in most cases, increased the reactivity and improved the regioselectivity. On the other hand, the N-oxides carrying an electron-withdrawing methoxycarbonyl or N-butylcarbamoyl group underwent the cyanation, without need for the Lewis acid, to provide a mixture of nearly equal amounts of 2-substituted 3- and 5-cyanopyrazines. The latter compound was exclusively obtained when 3-methoxycarbonyl- or 3-cyanopyrazine 1 -oxide was treated with diethoxyphosphoryl cyanide.