Conversion of oxadiazolo[3,4-b]pyrazines to imidazo[4,5-b]pyrazines via a tandem reduction-cyclization sequence generates new mitochondrial uncouplers.

[Display omitted] We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4- b ]pyrazines to 1 H -imidazo[4,5- b ]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N -methylation are crucial for mitochondrial uncoupling capacity. [ABSTRACT FROM AUTHOR]