Reactions of glyoxals with hydrazones: a new route to 4-hydroxypyrazoles

Begtrup, Mikael; Nytoft, Hans Peter

doi:10.1039/p19850000081

Cited by 33 publications

(7 citation statements)

References 11 publications

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“…Upon cooling a precipitate corresponding to ~85% of 3 was confirmed by 1 H NMR and mass spectrometry analysis, and a negative Tollens test for aldehyde. In addition to supporting spectral data, selective hydrazone formation onto the aldehyde moiety under these conditions is well precedented from prior studies on glyoxal hydrazones of methylhydrazine 9,10. The ~15% co-crystallized impurity plus 5–10% additional material in the mother liquor corresponded to one of two possible cyclization products 4 or 5 by spectral analysis with a distinctive 1 H NMR methine proton (H 4 ) at δ 8.72 ppm in DMSO- d 6 .…”

supporting

confidence: 53%

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

Turbiak

Kampf

Showalter

2010

Tetrahedron Letters

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An improved synthesis of 3-(substituted)pyrimido [4,5-c]pyridazine-5,7(1H,6H)-diones, a known subclass of 4-deazatoxoflavins, is reported. The approach involves treatment of 3-methyl-6-(1-methylhydrazinyl) uracil with representative phenyl and alkyl glyoxal monohydrates, which in turn are obtained by selenium dioxide oxidation of the corresponding phenyl and alkyl methyl ketones. The first entry into 4-monosubstituted isomers is also reported. KeywordsPyrimido [4,5-c]pyridazine-57(1H6H)-dione; 4-Deazatoxoflavin; Phenylglyoxal; Cyclizations; 6-(1-Methylhydrazinyl)uracil 1,6-Dimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione, also known as 4-deazatoxoflavin, and its 3,4-disubstituted analogues have been shown to serve as biomimetics of flavin and 5-deazaflavin in their ability to oxidize amines to carbonyl compounds 1 and to abstract hydrogen equivalents from hydrogen donors under certain conditions (Fig. 1). 2 4-Deazatoxoflavin itself has also demonstrated both inhibitory activity against Pseudomonas and DNA-binding properties 3 while not displaying the generalized cytotoxicity that is characteristic of toxoflavin. 4 There are scattered reports of 3,4-disubstituted 3,5 and 3-mono-substituted 2,6 analogues of 4-deazatoxo flavin, but no reports of 4-monosubstituted analogues. The described syntheses of 3-monosubstitued analogues generally proceed in poor yields and via pathways that produce alternate products. Our goal was to develop an improved synthesis that would lead to clean products and possess generality for a wide range of analogues for biological testing.Our strategy is based on the known reaction of 6-(1-methylhydrazinyl) uracil with glyoxal and α-diketones to yield 3,4-unsubstituted-and 3,4-disubstituted-pyrimido[4,5-c]pyridazine-5,7 (1H,6H)-diones, respectively.3 Despite these prior examples, there are no reports of reaction between this or related 6-(hydrazinyl)uracils and unsymmetrical alkyl or aryl glyoxals. We imagined that reaction could occur by several manifolds. One could proceed via initial hydrazone formation onto either one or both of the aldehyde or ketone moieties, or as is often the case for 6-aminouracils, 7 by nucleophilic attack by the 5-position of the uracil onto either glyoxal carbonyl. Thus, we set out to evaluate a number of reaction conditions to determine if regiochemical preferences for the uracil and glyoxal reaction partners could be established. Initially, we treated 3-methyl-6-(1-methylhydrazinyl)uracil8 with phenylglyoxal monohydrate in refluxing ethanol or water and obtained the result shown in Scheme 1. Upon cooling a precipitate corresponding to ~85% of 3 was confirmed by 1 H NMR and mass spectrometry analysis, and a negative Tollens test for aldehyde. In addition to supporting spectral data, selective hydrazone formation onto the aldehyde moiety under these conditions is well precedented from prior studies on glyoxal hydrazones of methylhydrazine. 9,10 The ~15% cocrystallized impurity plus 5-10% additional material in the mother liquor corresponded to one of two...

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supporting

confidence: 53%

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

Turbiak

Kampf

Showalter

2010

Tetrahedron Letters

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“…20 Variation of the nitrogen substituent on the pyrazole was easily accomplished by choosing the appropriately substituted hydrazine to derivatize the 1-position. The adjacent position could be modified by choice of an appropriate 2-oxoaldehyde substrate.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Following literature precedent, 4-hydroxy-3-acetyl pyrazoles were prepared in one or two synthetic steps in a straightforward manner. 20 Variation of the nitrogen substituent on the pyrazole was easily accomplished by choosing the appropriately substituted hydrazine to derivatize the 1-position. The adjacent position could be modified by choice of an appropriate 2-oxoaldehyde substrate.…”

Section: ■ Introductionmentioning

confidence: 99%

Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

et al. 2012

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This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

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“…Elemental analyses were performed at the Microanalytical Center of Cairo University, Egypt. The hydrazonoyl halides 1 [17][18][19] and pyruvaldehyde hydrazones 3 and 5 [20] were prepared according to literature procedures. Pyruvaldehyde, tetrahydrofuran (THF), and triethylamine were purchased from Avocado Research Chemicals, England, and used without further purification.…”

Section: Methodsmentioning

confidence: 99%

Reaction of Nitrilimines with Pyruvaldehyde Hydrazones: Synthesis and Antimicrobial Evaluation of Some New 1,2,4-Triazole Derivatives

Dalloul

2015

Journal of Chemistry

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A new series of 1,3,4,5,5-pentasubstituted-1,2,4-triazoles (4a–j,6a–j) have been synthesized by the 1,3-dipolar cycloaddition of suitable nitrilimines2to pyruvaldehyde (2-oxopropanal) hydrazones having (COPh, COOMe, COOEt, Me/Me, and Me/Ph) groups3and5. Both analytical and spectroscopical data of all the synthesized compounds are in full agreement with the proposed structures. The microbial features of the synthesized compounds were studied by a known method.

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Reactions of glyoxals with hydrazones: a new route to 4-hydroxypyrazoles

Cited by 33 publications

References 11 publications

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

Reaction of Nitrilimines with Pyruvaldehyde Hydrazones: Synthesis and Antimicrobial Evaluation of Some New 1,2,4-Triazole Derivatives

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