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2000
Volume 22, Issue 5
  • ISSN: 1570-1786
  • E-ISSN: 1875-6255

Abstract

5-amino-3-hydroxy-1-phenyl-1-pyrazol and 3-amino-5-hydroxy-1-phenyl-1-pyrazol are widely used as synthons in organic and pharmaceutical chemistry. We developed a high-yield synthesis method for 5-amino-3-hydroxy-1-phenyl-1-pyrazol using high-pressure and base catalysis, achieving up to 80% yield. This method significantly outperforms existing techniques, which yield no more than 39%. The synthesis was performed at pressures up to 10 katm, both in solvent-free conditions and in the presence of solvents, such as methanol, ethanol, toluene, -butyl methyl ether, and 1,4-dioxane. Thermodynamic parameters of possible paths were calculated using the SMD-M06-2X/MG3S method. Applying high pressure (7 katm) enables the solvent-free and catalyst-free synthesis of 2-cyano-N'-phenylacetohydrazide with a yield of 96%. This compound can subsequently be converted into 5-amino-3-hydroxy-1-phenyl-1-pyrazol with yields of up to 90% using base catalysis. Additionally, the reaction pathways of phenylhydrazine with ethyl cyanoacetate and its anion have been explored. These pathways are discussed in terms of thermodynamic potentials calculated using the SMD-M06-2X/MG3S method. High pressure significantly accelerates the reaction between phenylhydrazine and ethyl cyanoacetate, leading to the formation of 2-cyano-'-phenylacetohydrazide. This intermediate can then be easily converted into 5-amino-3-hydroxy-1-phenyl-1-pyrazol. Under neutral conditions, the most favorable reaction pathway involves the attack of the terminal nitrogen of phenylhydrazine on the carbonyl group. In the case of the ethyl cyanoacetate anion, the attack also targets the carbonyl group, but occurs the phenyl-substituted nitrogen.

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2025-01-03
2025-10-29

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High-Pressure Pathway in the Two-Stage Synthesis of 5-Amino-3-Hydroxy-1-Phenyl-1H-Pyrazole
Lett. Org. Chem. 22, 372 (2025); https://doi.org/10.2174/0115701786331865241120043030
/content/journals/loc/10.2174/0115701786331865241120043030
/content/journals/loc/10.2174/0115701786331865241120043030
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Supplements

Supplementary material is available on the publisher’s website along with the published article. It contains NMR and IR spectra of 3-amino-1-phenyl-5-pyrazolone, 5-amino-1-phenyl-1H-pyrazol-3-ol, Z- and E-isomers of 2-cyano-N'-phenylacetohydrazide.

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  • Article Type:     Research Article
Keyword(s): cyclocondensation; DFT; high pressure; N-phenylpyrazoles; phenylhydrazine; pyrazole ring

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