Rearrangements of Hydroxylamines, Oximes and Hydroxamic Acids

Pereira, M. Manuela A.; Santos, Pedro P.

doi:10.1002/9780470682531.pat0461

Cited by 16 publications

(31 citation statements)

References 409 publications

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“…Based on the findings of the current study, earlier research on Lossen rearrangement17212223, the fact that N -hydroxy phthalimide anion is a particularly effective nucleophile, and the involvement of water, we proposed a unique TCBQ-activated and water-assisted Lossen rearrangement mechanism for the isomerization of NHPI to IA (Fig. 6).…”

Section: Resultssupporting

confidence: 55%

“…This leads to the following question, “In what way could the transient product o -carboxyl benzyl isocyanate be formed from NHPI?” It has been shown that one typical way could be through the Lossen rearrangement, a well-known reaction describing the conversion of an O -activated hydroxamic acid (R-C(O)-NH-OX) into the corresponding isocyanate2122. The rate-limiting step of this reaction is the activation of the hydroxamic acid by a variety of activating agents (i.e., sulfonyl and benzoyl chloride, etc.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that the rate-limiting step in the Lossen rearrangement is the activation of the hydroxamic acid and that the rate of the rearrangement is directly proportional to the relative acidity of the conjugate acid of the anionic leaving group2122. Due to the strong acidity of TrCBQ-OH (pK a : 1.10) and DDBQ (pK a1 : 0.58; pK a2 : 2.72)18303132, the conjugate acids of the anionic leaving groups in the present study, it is expected that the rate of rearrangement of the postulated reaction intermediate (IN1) should be very fast.…”

Section: Resultsmentioning

confidence: 99%

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An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

Huang

Xie

et al. 2016

Sci Rep

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N-hydroxyphthalimide (NHPI), which is best known as an organocatalyst for efficient C-H activation, has been found to be oxidized by quinoid compounds to its corresponding catalytically active nitroxide-radical. Here, we found that NHPI can be isomerized into isatoic anhydride by an unusually facile two-step method using tetrachloro-1,4-benzoquinone (TCBQ, p-chloranil), accompanied by a two-step hydrolytic dechlorination of highly toxic TCBQ into the much less toxic dihydroxylation product, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid). Interestingly, through the complementary application of oxygen-18 isotope-labeling, HPLC combined with electrospray ionization quadrupole time-of-flight and high resolution Fourier transform ion cyclotron resonance mass spectrometric studies, we determined that water was the source and origin of oxygen for isatoic anhydride. Based on these data, we proposed that nucleophilic attack with a subsequent water-assisted Lossen rearrangement coupled with rapid intramolecular addition and cyclization in two consecutive steps was responsible for this unusual structural isomerization of NHPI and concurrent hydroxylation/detoxication of TCBQ. This is the first report of an exceptionally facile double-isomerization of NHPI via an unprecedented water-assisted double-Lossen rearrangement under normal physiological conditions. Our findings may have broad implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, two important classes of compounds of major chemical and biological interest.

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

Huang

Xie

et al. 2016

Sci Rep

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“…The rate-limiting step in this variant of the Lossen rearrangement is the formation of an activated hydroxamate, and the rate of the reaction is directly proportional to the relative acidity of the conjugate acid of the anionic leaving group. [22] …”

Section: Mutagenicitymentioning

confidence: 99%

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

2015

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Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan-HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery.

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“…4, 5 The sulfur atom is, in this strategy, part of a reactive thiocarbonyl, a functional group which can modulate molecular reactivity, and has found ample use in synthesis. 6 We report here our results on a formal sigmatropic rearrangement to achieve this goal.…”

mentioning

confidence: 99%

Thermal rearrangement of an N-hydroxy-imidazole thiocarbamoyl derivative as a simple entry into the 4-thio-imidazole motif

Pinto

Justino

Vieira

et al. 2009

Arkivoc

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Rearrangements of Hydroxylamines, Oximes and Hydroxamic Acids

Abstract: Introduction The [3,3]‐Sigmatropic Rearrangements The [2,3]‐Sigmatropic Rearrangements The Dyotropic Rearrangements The B amberger Rearrangements The B eckmann Rearrangements The … Show more

Cited by 16 publications

References 409 publications

An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Thermal rearrangement of an N-hydroxy-imidazole thiocarbamoyl derivative as a simple entry into the 4-thio-imidazole motif

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