Introduction:
Pyrazine derivatives are widely recognized as important building blocks in heterocyclic and medicinal chemistry, with numerous applications in pharmaceuticals, agrochemicals, and advanced materials. Among them, 2-chloropyrazine is a synthetically versatile substrate due to the electron-withdrawing chlorine substituent, which directs lithiation to the 3-position. Although selective monolithiation at this site is well documented, achieving multiple metalations on the pyrazine ring has remained a significant synthetic challenge because of its electron-deficient nature and the instability of potential poly-lithiated intermediates.

Methods:
In this study, we developed a new strategy for the regioselective 3,6-dilithiation of 2-chloropyrazine by employing lithium 2,2,6,6-tetramethylpiperidide (LiTMP) as a strong, hindered base. Careful control of stoichiometry and reaction temperature was essential to generate the dilithiated intermediate efficiently, which was then trapped in situ with ethyl benzoate to introduce carbonyl functionality.

Results:
Under optimized conditions, the reaction provided the novel symmetrical 3,6-dicarbonyl derivative in good isolated yield. The structure was confirmed by a subsequent Sonogashira coupling with 1-hexyne, followed by detailed ¹H and ¹³C NMR spectroscopy, which unambiguously established substitution at both the 3- and 6-positions of the pyrazine core.

Conclusions:
These findings demonstrate for the first time that regioselective 3,6-dilithiation of 2-chloropyrazine is feasible under mild, practical conditions. This approach provides a straightforward and scalable route to novel polyfunctionalized pyrazine frameworks, expanding the scope of directed ortho-lithiation strategies for nitrogen-containing heterocycles with promising potential in synthetic and medicinal chemistry.

Heteroarylketenes have recently attracted considerable attention as reactive intermediates in the synthesis of β-lactams due to their structural diversity and relevance in pharmaceutical chemistry (Chen et al., J. Am. Chem. Soc. 2021; Mann et al., SynOpen 2024; Alcaide & Almendros, Curr. Med. Chem. 2004).

In this work, stereoselective synthesis of novel β-lactams via in situ generation of a highly destabilized and nonconjugated pyrrolylketene intermediate from N-pyrrolylpropanoic acid was reported. Unlike typical aryl ketenes, this system lacks resonance stabilization, which enhances its reactivity toward aromatic imines under mild conditions.

The [2+2] cycloaddition proceeded efficiently, affording β-lactams predominantly as single trans-isomers. The stereochemistry of the products was confirmed via ¹H NMR, ¹³C NMR, and IR analysis. NOE experiments were employed to elucidate the relative stereochemistry of the trans-β-lactams. The observed selectivity supports a zwitterionic intermediate mechanism, allowing precise control over stereochemical outcome. Importantly, the approach tolerates various imine substrates and may serve as a basis for rapid access to azetidinone scaffolds of potential biological interest.

These findings broaden the scope of synthetic approaches to β-lactam synthesis and highlight the unique reactivity profile of destabilized heteroarylketenes as privileged intermediates.

This abstract is based on a previously published study (Synlett 2013, 24, 1937–1940) with emphasis on its stereoselective features and synthetic utility in β-lactam synthesis. Co-authors (Dr. M.R. Islami and Dr. M. Kalantari) of the original publication have been fully acknowledged.

Introduction

Biological activity of hydrazones and thiasemicarbazones is well-described: thiosemicarbazide moiety is present in the structure of thioacetazone, isoniazid-derived hydrazones demonstrate a high activity against Mycobacterium spp., whereas 5-nitrofuran-derived hydrazones prove effective in the treatment of urinary tract infections. Such compounds are also known to readily form Cu(II) complexes with a high antibacterial activity attributed to ROS generation and subsequent apoptotic cell death. Antifungal properties of thiosemicarbazone ligands and their Cu(II) complexes have been linked to alteration of ergosterol biosynthesis and membrane damage.

Methods

4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde-derived hydrazones, thiosemicarbazones and their Cu(II) complexes have been synthesized and characterized by NMR, ESR, FT-IR, UV-visible absorption spectroscopy, mass spectrometry, and elemental, XRD powder diffraction and thermogravimetric analysis studies.

Results

The obtained binuclear Cu(II) complexes have been found to possess the coordination polyhedron of [Cu₂L₂], HL being the formula of the corresponding ligand. Microbiological screening of the synthesized compounds against Gram-positive (Bacillus subtilis, Staphylococcus saprophyticus) and Gram-negative (Escherichia coli, Pseudomonas putida) bacteria has demonstrated a markedly enhanced antibacterial activity of hydrazone and thiosemicarbazone derivatives upon their complexation with the Cu(II) ion. Interestingly, antifungal activity of the 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde-derived hydrazones and thiosemicarbazones against Phytophthora spp. has been found to slightly decrease upon Cu(II) complexation.

Conclusions

Due to tautomerism and metal chelation via anionic or neutral forms, biological activity of hydrazone and thiosemicarbazone derivatives can be controllably tuned by the formation of Cu(II) complexes of various coordination cores and nuclearities, rendering them promising basic structures for further modification.

Heterocyclic compounds with privileged scaffolds are central to the development of novel bioactive molecules due to their ability to interact selectively with biological targets. Among them, flavenes stand out for their structural versatility. This work describes the stereoselective synthesis of 2H-flavenes using the ApDOS strategy (Aminocatalytic privileged Diversity-Oriented Synthesis). The key transformation involves an oxa-Michael cyclization between salicylaldehydes and an iminium ion intermediate formed in situ from cinnamaldehyde (or its derivatives) and the Hayashi–Jørgensen catalyst.

A systematic study of additives (PhCOOH, p-NO₂PhCOOH and NaOAc), solvents (toluene, acetonitrile, chloroform and dioxane) and temperatures (25 and 40 °C) was performed. Optimal conditions (PhCOOH, toluene, 40 °C, 18 h) afforded flavenes in up to 81% yield and 90% ee. The synthesized compounds were fully characterized by NMR, High-Resolution Mass Spectrometry (HRMS), and single-crystal X-ray analysis.

Subsequent functionalization of the flavenes with ethyl cyanoacetate under mild basic conditions resulted in Knoevenagel-type adducts rather than the expected Michael addition products. This unexpected chemoselectivity is attributed to the extended conjugation of the flavene core, HSAB (hard and soft acids and bases) principles, and both kinetic and thermodynamic factors. The resulting polycyclic products exhibit promising electronic features and may serve as valuable dienophiles in Diels–Alder-type pericyclic reactions, thus broadening the structural diversity of this class of compounds and paving the way for future bioactive molecule development.

Introduction

Benzimidazole derivatives have a wide range of biological activity, including plant growth regulating activity. The study of the structure-activity relationship (SAR) in a number of benzimidazole derivatives is important for the development of new effective plant growth regulators. The design of new effective plant growth regulators based on these derivatives is an important scientific direction, as it is relevant for the development of agriculture, taking into account modern stringent environmental requirements.

Experimental

The reaction was monitored and the identification of the obtained compounds was determined by TLC, FTIR, NMR and XRD. The ¹H,¹³C NMR (400 MHz, 100 MHz, respectively), HMBC, HSQC, COSY spectra were obtained using a Varian 400 spectrometer. XRD of the single crystal of 2a was performed on an Xcalibur Ruby diffractometer.

Results and Discussion

A series of benzimidazole derivatives was synthesized (1-3a-c). The biological activity of the obtained compounds was carried out on wheat seeds. The results of studying the growth regulating activity of benzimidazole derivatives 1-3a-c showed that phenyl-substituted tricyclic benzopyrroloimidazolone 1a demonstrated the greatest effectiveness compared with the control (water) and the reference drug, indole-3-acetic acid (IAA).

It was found that the effectiveness of the compounds depends both on the structure of the molecule (cyclic or non-cyclic form) and on the steric volume of the side substituent and the volume of the molecule as a whole (the propionated molecule is sterically more voluminous than the original non-propionated one).

The development of new hybrid molecules that combine privileged heterocyclic structures remains a central challenge in medicinal chemistry. In this work, we report an efficient synthetic strategy for accessing novel 1,4-disubstituted-1,2,3-triazole-1,3-oxazole hybrids. The synthesis involves a two-step, three-sequence approach: a multicomponent reaction, subsequent oxidation, and the Van Leusen reaction. This operationally simple protocol proceeds under mild conditions and allows the rapid assembly of structurally diverse heterocyclic systems.
Three new hybrid molecules were synthesized and structurally characterized. To investigate their biological potential, we performed bioactivity prediction studies using cheminformatics tools. Polo-like kinase 3 (PLK3), a serine/threonine-protein kinase involved in cell cycle regulation and apoptosis, was identified as a potential molecular target. PLK3 is overexpressed in several types of cancer and is considered a promising target for the development of anticancer therapies.
Molecular docking simulations revealed that the synthesized compounds exhibit favorable interactions within the PLK3 binding site, including hydrogen bonding, π–π stacking, and hydrophobic contacts. The binding affinities and interaction profiles suggest a strong potential for these molecules as PLK3 inhibitors. These findings support further in vitro studies to evaluate their antiproliferative activity and validate their mechanism of action. Overall, this work highlights the potential of triazole–oxazole hybrids in the design of novel anticancer agents.

The present study focuses on the kinetics of the Knoevenagel condensation reaction between 7-methoxy-1-tetralone and glyoxylic acid, catalysed by potassium tert-butoxide in tert-butanol as a solvent, using a batch-type system under nitrogen atmosphere. The objective of this study was to synthesize the product (E)-2-(7-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene) acetic acid. The reaction was conducted under controlled temperature conditions (65 °C, 75 °C and 85 °C), considering five-time intervals to monitor its progress by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The kinetic data obtained were analysed through three different mathematical methods: the integral, the differential, and the nonlinear regression method, in order to determine the most suitable kinetic model. Applying the power law, the findings indicated that the pseudo-second order model, which was estimated via nonlinear regression, showed the best fit with the experimental data, characterised by minimal discrepancy between the calculated and observed values. The kinetic constants (k) obtained at temperatures of 65 °C, 75 °C and 85 °C were 0.0078, 0.0196 and 0.0321 mL mmol^-1 min^-1, respectively. The pre-exponential factor (A) was calculated to be 1.194×106 mL mmol^-1 min^-1, and the activation energy (Ea) was determined to be 42.20 kJ mol^-1. The product yield at these temperatures was 17.00%, 81.40% and 72.59%, respectively. The final product was characterised by GC-MS, FTIR, and UV-Vis. In conclusion, the kinetic study of the reaction was able to determine the optimal Knoevenagel condensation reaction conditions between 7-methoxy-1-tetralone and glyoxylic acid catalysed by potassium tert-butoxide, and to facilitate understanding of the mechanism involved.

Given the biological significance of β-amino ketone compounds and the synthetic challenges in obtaining enantiomerically pure forms, a new series of Mannich-type β-amino ketone derivatives was successfully synthesized, with exclusive formation of the anti-enantiomer. These compounds were fully characterized and extensively evaluated for their biological activities. Antioxidant properties were assessed using the DPPH radical scavenging assay, and the results demonstrated excellent antioxidant activity for the synthesized molecules.

In addition, molecular docking simulations were conducted to investigate the interaction of the compounds with key biological targets, particularly acetylcholinesterase and tubulin. The anti-enantiomers exhibited strong binding affinities, suggesting potential anti-Alzheimer’s and anticancer activities. The docking analysis revealed multiple hydrogen bonding and hydrophobic interactions with critical amino acid residues in the active sites, supporting their strong inhibitory potential.

Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling showed that the compounds possess favorable drug-likeness properties. Specifically, they were predicted to cross the blood–brain barrier and to comply with Lipinski’s Rule of Five, indicating potential oral bioavailability and activity within the central nervous system.

In conclusion, these newly synthesized Mannich-type β-amino ketone derivatives exhibit promising pharmacological profiles and represent valuable candidates for further development as therapeutic agents targeting oxidative stress, neurodegenerative diseases, and cancer. The synthesized anti-β-amino ketone derivatives show great potential as lead compounds for future drug development.

This work presents the progress in the semi-synthetic transformation of 6β-acetoxyvouacapane, a cassane-type diterpene isolated from Coulteria platyloba, using an organocatalytic strategy based on trienamine activation. C. platyloba is a plant of ethnopharmacological interest, with several traditional medicinal uses and a rich content of biologically relevant diterpenes.

The methodology involved the maceration of 1 Kg of dried leaves, yielding 77 g of dichloromethane extract. From this, 8.13 g of 6β-acetoxyvouacapane were successfully isolated through silica gel column chromatography. The semi-synthetic strategy includes: an oxidative aromatization of ring C to obtain an aromatic derivative, furan ring opening to generate a salicylaldehyde fragment, and then the formation of a coumarin core through a Knoevenagel condensation with diethyl malonate. From this intermediate, a nucleophilic substitution with a primary amine will be performed to obtain an amide derivative. Subsequently, this amide will undergo an organocatalytic cascade with various α,β,γ,δ-unsaturated aldehydes under trienamine activation.

As part of the preliminary studies, a Diels–Alder cycloaddition with dienals was successfully performed using the coumarin intermediate, confirming the feasibility of this step under trienamine catalysis, albeit outside of a cascade sequence. All compounds have been fully characterized by NMR and MS spectroscopy.

The first three transformations have been successfully achieved with good yields and purity. These results establish the viability of the proposed methodology for future cascade reactions aimed at generating novel scaffolds through efficient, sustainable, and stereocontrolled approaches aligned with Diversity-Oriented Synthesis (DOS) and ApDOS principles.

Heterocycles, particularly those containing nitrogen, play a central role in medicinal and pharmaceutical chemistry due to their widespread presence in bioactive molecules. They also occupy a key place in agrochemistry, materials science, and modern drug design. Among them, oxadiazoles, as N,N-heterocycles, are of particular interest due to their promising biological activities such as antimicrobial, anti-inflammatory, anticancer, and antifungal properties.

In this work, we focus on the synthesis of oxadiazole derivatives from functionalised intermediates derived from terephthalic acid, a versatile and readily available aromatic precursor widely used in the construction of nitrogen-containing heterocycles and advanced organic frameworks. Several synthetic approaches have been explored, taking advantage of the symmetry, rigidity, and reactivity inherent in this molecule to generate suitable intermediates for heterocycle formation.

Our preliminary results demonstrate that the terephthalic nucleus offers interesting structural flexibility, enabling the efficient construction of oxadiazole-based systems under mild and easily achievable conditions. In addition to classical synthetic routes, alternative strategies are also being investigated to broaden the accessible chemical space around these heterocycles.

This synthesis strategy, relying on a widely available starting material and adaptable steps, paves the way for the development of new heterocyclic compounds with potential applications in pharmaceutical, agrochemical, and materials fields.