Dimetalation of pyrazines.: A one-pot synthesis of multisubstituted pyrazine C-nucleosides

As a part of our efforts to pursue direct, convergent, and concise methodologies for the synthesis of pyrazine C-nucleosides, we have successfully established a sequential dilithiation - addition method, which allows one to introduce two different functional groups to a pyrazine ring in a one-pot fashion. 2,6-Dichloropyrazine was dilithiated at -100 degreesC and then allowed to react with an electrophile, such as bromine, iodine, or disulfides, followed by a reaction with a protected ribonolactone to afford C-nucleosides. After reduction and deprotection, tetrasubstituted pyrazine C-nucleosides, including 2,6-dichloro-3-iodo-5-(beta -D-ribofuranosyl and 2-bromo-3,5-dichloro-6-(beta -D-ribofuranosyl)pyrazine, were obtained. A tandem reaction sequence occurred when disulfides were used, resulting in the formation of 5,6-bis-methylthio- 2-chloro-3-(beta -D-ribofuranosyl)pyrazine and 6-(beta -D-ribofuranosyl)-2,3,5-tris-phenylthiopyrazine.