Letters in Organic Chemistry - Volume 22, Issue 5, 2025

In pharmaceutical research and drug design, five-membered heteroaromatic ring-fused pyridine derivatives are becoming more common. The pyridine moiety is prone to ring fusion and substitution because it is basic, soluble in water, stable, and able to establish hydrogen bonds. Because of their diverse variety of biological actions, pyridine and thiadiazole have become intriguing possibilities in medicinal chemistry. The water solubility of pharmaceutically promising compounds is often improved by pyridine scaffolds with low basicity, which has also contributed to the development of several broad-spectrum medicinal medicines. Considering these, this manuscript offers a thorough investigation of the synthesis and variety of biological activities displayed by derivatives of pyridine thiadiazole derivatives. The manuscript summarizes different synthetic approaches utilized in the synthesis of these fused compounds and provides insight into their possible pharmacological uses by conducting a comprehensive assessment of recent literature. The complex relationship between biological significance and chemical synthesis provides novel treatment approaches and medication development opportunities.

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.

We present a protocol for the synthesis of 3-aminopyrazoles through an eco-friendly cyclocondensation reaction of α-oxo ketene-N, S-acetals with hydrazine hydrates. The reaction runs by using H2O as a solvent to give access to a library of 3-aminopyrazole derivatives (25 examples) under mild and operationally simple conditions. In this study, the green synthesis method showed various fascinating advantages, such as good scale-up performance, good Eco-scale value (89 points), and reusable aqueous medium. 3-aminopyrazoles were further confirmed by X-ray crystallographic analysis, and a reasonable reaction mechanism was proposed.

Metal ion sensing properties of thiophene based hydrazone (TH) have been studied using UV-Vis and DFT studies. In comparison to heavy transition metal ions, TH especially binds to Cu²⁺ and Fe³⁺ ions. The lower limit of detection (LOD) of the compound is 6 μM and 9 μM for Cu²⁺ and Fe³⁺ ions respectively. The binding constant for the compound: Cu²⁺ and compound: Fe³⁺ complexes are obtained as 3 x 10⁴ M^-1 and 4.5 x 10³ M^-1 respectively using the Benesi-Hildebrand plot. The stoichiometry ratio for compound: Cu²⁺ complex 2:1 is obtained using Job's plot. The complex is more stable than the free compound and is validated through computation of HOMO-LUMO orbital energy and band gap of compound and complex using density functional theory. TH exhibits antioxidant properties against the DPPH radical with IC50: 23 μM. The possible mechanism of quenching of radical is suggested through single electron transfer followed by a proton transfer mechanism. From the above studies, it can be concluded that the hydrazone TH detects both Cu²⁺ and Fe³⁺ ions up to micromolar concentration and quenches the DPPH radical with IC50 comparable to vitamin E.

The allylation reaction of Morita-Baylis-Hillman carbonates is an effective method for constructing C-C bonds. Yang's group has utilized azomethine ylides, which are generated in situ from 2-aminomalonate and ortho-amino benzaldehydes, to engage in allylation reactions with MBH carbonates. Despite the initial substrate specificity that confined the reaction to ortho-amino benzaldehydes, rendering benzaldehyde and salicylaldehyde ineffective for producing the desired adducts, our group has made a significant advancement. By employing diethyl amino malonate hydrochloride as the substrate, we have successfully integrated benzaldehyde and salicylaldehyde into this reaction framework, thereby broadening the versatility of the process. This strategy demonstrates excellent substrate tolerance and provides the corresponding adducts with yields up to 99%. The gram-scale synthesis and subsequent product derivatization highlight the significant applicability of this method.

The reduction of ketones to secondary alcohols is an essential reaction in organic chemistry and various reagents are utilized for this purpose. Herein, we have reported the reduction of ketone using decaborane in conventional as well as microwave-assisted methods in aqueous solution. Different types of aromatic ketones containing distinct functional groups were analyzed. We observed that ketones having an electron-withdrawing group showed a faster reaction rate with higher yield as compared to the ketones with electron-donating groups. Additionally, a comparison between microwave-assisted and conventional synthesis was done by evaluating the total reaction time and percentage yield. The results indicate that microwave-assisted synthesis lead to higher yields within very short reaction times.

A facile, three-component one-pot synthesis of a combinatorial library of pyrido[2,3-d]pyrimidines by condensation of easily accessible β-oxodithioesters with 1,3-dimethyl-6-amino uracil and aldehydes under deep eutectic solvent medium is achieved. The yields of the desired products are good to excellent, irrespective of the steric and electronic nature of the substituents. The advantages of operational simplicity, economic viability, generality, and atom economy, together with its ecologically benign nature, make this protocol a very efficient alternative to literature methods. These compounds contain reactive functionalities for further ring annulation reactions and thus can be utilized as building blocks for complex natural products.