High-Pressure Pathway in the Two-Stage Synthesis of 5-Amino-3-Hydroxy-1-Phenyl-1H-Pyrazole

Title:High-Pressure Pathway in the Two-Stage Synthesis of 5-Amino-3-Hydroxy-1-Phenyl-1H-Pyrazole

Volume: 22

Author(s): Stanislav A. Grabovskii*, Nadezhda M. Andriyashina, Alexandr N. Lobov and Rustam L. Safiullin

Affiliation:

• Ufa Institute of Chemistry, UFRC RAS, Prospect Oktyabrya, 71, 450054, Ufa, Russia

Keywords: N-phenylpyrazoles, synthesis, phenylhydrazine, cyclocondensation, high pressure, DFT.

Abstract: 5-amino-3-hydroxy-1-phenyl-1H-pyrazol and 3-amino-5-hydroxy-1-phenyl-1H-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-1H-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, tert-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-1H-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-N'-phenylacetohydrazide. This intermediate can then be easily converted into 5-amino-3-hydroxy-1-phenyl-1H-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 via the phenyl-substituted nitrogen.

Cite this article as:

Grabovskii A. Stanislav*, Andriyashina M. Nadezhda, Lobov N. Alexandr and Safiullin L. Rustam, High-Pressure Pathway in the Two-Stage Synthesis of 5-Amino-3-Hydroxy-1-Phenyl-1H-Pyrazole, Letters in Organic Chemistry 2025; 22 () . https://dx.doi.org/10.2174/0115701786331865241120043030