Development of N‑Substituted Hydroxamic Acids with Pyrazolone Leaving Groups as Nitrosocarbonyl Precursors

A novel
class of nitrosocarbonyl precursors, N-substituted hydroxamic
acids with pyrazolone leaving groups (NHPY), has been synthesized.
Under physiological conditions, these compounds generate nitrosocarbonyl
intermediates, which upon hydrolysis release nitroxyl (azanone, HNO)
in excellent yields. The amount and rate of nitrosocarbonyl generation
are dependent on the nature of the pyrazolone leaving groups and significantly
on the structural properties of the NHPY donors. Pyrazolones have
been found to be efficient nitrosocarbonyl traps, undergoing an N-selective
nitrosocarbonyl aldol reaction. This trapping reaction has been used
to confirm the involvement of nitrosocarbonyl intermediates in NHPY
aqueous decomposition. In addition, NHPY compounds are shown to generate
nitrosocarbonyls efficiently under mild basic conditions in organic
solvent and may therefore also enjoy synthetic utility.