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

Abstract

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.

Nitrosocarbonyl release from O-substituted hydroxamic acids with pyrazolone leaving groups

“…OHPY is very small, observed half-lives should correlate with donor pKa and the pyrazolone leaving group 19,20. Pyrazolone 2a (R 1 = Ph, R 2 = (C(=NOMe)Me, pKa = 6) is a better leaving group than pyrazolone 2b (R 1 = Ph, R 2 = Me, pKa = 7.6),19 consistent with the much shorter half-life for OHPY 1a (t1/2 = 25 min) compared with 1b (stable).Exchanging the R 1 group from phenyl to methyl(OHPY 1c vs. 1d)increases the half-life by a factor of two, consistent with that previously reported for analagous HAPY and NHPY donors 19,47. A comparison of the known pKa values of the related compounds,…”

“…We have recently found that pyrazolones are efficient traps for nitrosocarbonyl intermediates to generate N-substituted hydroxamic acid derivatives with pyrazolone leaving groups (NHPY) in a reversible manner. 47 In the current work, we observe OHPY decomposition to generate nitrosocarbonyls which further react with pyrazolones to produce isomeric NHPY compounds (Scheme 1). We have synthesized and studied NHPY compounds independently, and have recently demonstrated the efficient formation of nitrosocarbonyl intermediates upon decomposition of these compounds.…”

“…19,20 Pyrazolone 2, NHPY 3, and carboxylic acid 4 are cleanly formed as the only observable organic products. Because NHPY compounds 3a, 3c, and 3d all have half-lives on the order of days, 47 Path C in Scheme 3 does not contribute to the observed chemistry for OHPY donors 1a, 1c, and 1d. Thus, the relative yields of pyrazolone 2 and carboxylic acid 4 compared with that for NHPY compound 3 in Table 1 reflect the competition between Path A and Path B for these donors.…”

“…In the case of NHYP donors, the dissociation barrier was found to be strongly dependent on the R 3 group. 47 The origin and impact of the R 3 group on OHPY dissociation requires further investigation.…”

“…-hydroxy-N-(4-(acetyl-O-methoxyoxime)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-N-acetamide (NHPY 3a), N-hydroxy-N-(4-(acetyl-O-methoxyoxime)-3methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-N-methylcarbamate (NHPY 3c), N-hydroxy-N-(4-(acetyl-O-methoxyoxime)-1,3-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-N-methylcarbamate (NHPY 3d),47 4-(acetyl-O-methoxyoxime)-3-methyl-1-phenylpyrazolone 2a, 3,4-dimethyl-1-phenyl-pyrazolone 2b, 4-(acetyl-O-methoxyoxime)-1,3dimethylpyrazolone 2c,19 4-(acetyl-O-methoxyoxime)-4-bromo-3-methyl-1-phenylpyrazolone , 4-bromo-3,4-dimethyl-1-phenyl-pyrazolone, 4-(acetyl-O-methoxyoxime)-4bromo-1,3-dimethyl-pyrazolone,18 C-methoxycarbohydroxamic acid, and tertbutylhydroxycarbamate 50 were prepared according to literature procedures.Acetohydroxamic acid was purchased and used without further purification. NMR spectra were obtained on a 400 MHz FT-NMR spectrometer.…”