Oxidative halogenations of nucleosides using tetrabutylammonium peroxydisulfate

Abstract

Tetrabutylammonium peroxydisulfate has been prepared from tetrabutylammonium hydrogen sulfate and potassium persulfate and shows strong oxidizing ability. This peroxide shows high solubility in organic solvents such as methylene chloride, chloroform, acetonitrile and acetone in contrast to the poor solubility of the known metal peroxydisulfates. Tetrabutylammonium peroxydisulfate has turned out to be a useful source of tetrabutylammonium sulfate radical which is relatively stable in organic solvents and can be used at higher temperature than 20℃. Expeditious and practical halogenations of pyrimidines and purine nucleosides have been achieved by using tetrabutylammonium peroxydisulfate in good to excellent yields. Chlorination has been achieved by using tetrabutylammonium peroxydisulfate with HCl in DMF under mild reaction conditions. Regioselective chlorination has been observed at C5 position of pyrimidines and C8 position of purine nucleosides. An alternative method for the chlorination using tetrabutylammonium peroxydisulfate with inorganic salts such as LiCl, NaCl and $NH_4Cl$ in MeCN was also achieved under mild reaction conditions with good yields. Regioselective bromination has been achieved with excellent yields using tetrabutylammonium peroxydisulfate in the presence of NBS in MeCN under mild reaction conditions. Furthermore, pyrimidine nucleosides reacted with tetrabutylammonium peroxydisulfate and iodine or LiI in MeCN to give the corresponding 5-iodo pyrimidine nucleosides in moderate to good yields. The oxidative halogenation procedures described herein can be undoubtedly useful and applicable for the synthesis of halogenated ribonucleosides and 2’deoxy ribonucleosides.