Substituted hydroxyureas have potential uses as more selective treatments for sickle cell anemia and cancer.   A facile, high-yielding route to N-alkyl-N'-hydroxyureas has been optimized from the air- and water-stable phosgene synthetic equivalent S,S'-dimethyldithiocarbonate (DMDTC).  First, N-alkyl-S-methylthiocarbamates were prepared from primary alkyl amines by a method modified from Fochi, et al. The amines were added as neat liquids to a suspension of DMDTC on water at 0 �C and then stirred at 23 �C for 1-5 h.  The desired products were furnished in 64-99% yield from unbranched and a- or �-monobranched amines.  From the N-alkyl-S-methylthiocarbamates, the synthesis of their corresponding N-alkyl-N'-hydroxyureas was achieved by gently heating them to 60 �C for 18-24 h in a mixture of tert-butanol and aqueous hydroxylamine. The N-alkyl-N'-hydroxyurea products (70-98%) were obtained in high purity after simple vacuum concentration to remove the volatile solvents and methanethiol byproduct� a distinct advantage over previously reported methods utilizing N-alkyl-O-phenylcarbamates.

Hydroxyureas with ease: Optimized synthesis of N-alkyl-N′-hydroxyureas from the phosgene synthetic equivalent S,S′-dimethyldithiocarbonate

243rd National Meeting (2012)

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