Abstract: The growing concerns of rapid population expansion, depletion of fossil fuels, climate change, and escalating environmental degradation pose significant challenges to the sustainable development of modern society. In response, the scientific community has increasingly focused on the development of green and sustainable chemical methodologies. Within this context, metal-free synthetic strategies have gained prominence due to their ability to eliminate the dependence on toxic, heavy, and non-renewable transition metals. These methodologies offer a cleaner alternative for the chemo-selective transformation of inexpensive starting materials into high-value products. Recent advances have led to the development of metal-free oxidation, reduction, hydrogenation, and condensation reactions that align with the principles of green chemistry. However, the replacement of transition-metal-catalyzed carbon–carbon (C–C) bond-forming reactions remains a critical challenge. Innovative approaches involving the nucleophilic addition of organometallic species to carbonyl or imine compounds, as well as radical-mediated C–C couplings in the presence of aryl halides, are paving the way for sustainable alternatives. This abstract highlights the recent progress and ongoing efforts toward achieving environmentally benign synthetic methodologies, emphasizing the pivotal role of metal-free reactions in shaping a greener chemical future.

Abstract: The intramolecular Diels-Alder (IMDA) reactions of four substituted deca-1,3,9-trienes and one N-methyleneocta-5,7-dien-1-aminium with different electrophilic/nucleophilic activations have been studied within the Molecular Electron Density Theory (MEDT) and compared to their intermolecular processes. The topology analysis of the electron density and DFT-based reactivity indices reveal that substitution does not modify neither the electronic structure nor the reactivity of the reagents relative to those involved in the intermolecular processes. The analysis of the relative energies establishes that the accelerations found in the polar IMDA reactions follow the same trend as those found in the intermolecular processes. The geometries and the electronic structures of the five transition state structures involved in the IMDA reactions are highly similar to those found in the intermolecular processes. A relative interacting atomic energy (RIAE) analysis of Diels-Alder and IMDA reactions allows for the establishment of the substituent effects on the activation energies. Although the nucleophilic frameworks are destabilized, the electrophilic frameworks are further stabilized, resulting in a reduction in the activation energies. The present MEDT study demonstrates the remarkable electronic and energetic similarity between the intermolecular and intramolecular Diels-Alder reactions. Only the lower, unfavorable activation entropy associated with the latter renders it 104 times faster than the former.

Abstract: When using chalcones as therapeutic agents, a potential drawback is their susceptibil-ity in solution to light-induced isomerisation around the double bond of their α,β-unsaturated carbonyl moiety giving rise to a mixture of cis- and trans-isomers. This photoisomerisation can be circumvented by transforming chalcones into indanones thus creating a conformationally constrained frame incorporating a five membered ring whilst retaining the structural key features of the parent compound. Herein, we have synthesised indanone DMU5401, i.e. 3-(benzo[d][1,3]dioxol-5-yl)-4,5,6-trimethoxy-2,3-dihydro-1H-inden-1-one, starting from chalcone DMU135, i.e. (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, via Nazarov cyclisation reaction using a green solvent, i.e. 4-methyltetrahydropyran (4-MeTHP). Although the yield was lower compared to that of previously reported methods, the green solvent procedure we adopted here did not include harmful sol-vents or hazardous chemicals, and significantly shortened the work-up stage of the Nazarov cyclisation reaction making this process more sustainable.

Abstract: A series of p-substituted pyridinium catalysts were investigated as sustainable organic catalysts for carbon dioxide utilization under ambient conditions. Dimethylaminopyridine hydroiodide (DMAP·HI) was found to be a superior catalyst for cyclic carbonate synthesis from epoxide and CO2 without solvents or additives. Mechanistic studies indicated that DMAP played a pivotal role as a nucleophile toward carbon dioxide during the cyclic carbonate formation. The organic catalyst could be recycled without any significant loss of catalytic activity, and was successfully applied for the multigram-scale synthesis of cyclic carbonate at mild temperature under atmospheric carbon dioxide.

Abstract: This study investigates the use of peptide-based hydrogels as scaffolds for the encapsula-tion and delivery of Peptide Nucleic Acids (PNAs) in drug delivery applications. Ultra-short aromatic peptide-based hydrogels (HGs), such as Fmoc-FF (Nα-fluorenyl methox-ycarbonyl-diphenylalanine), provide an ideal platform for encapsulating biomolecules due to their biocompatibility, self-assembling nature, and ability to form stable, nanostructured networks. The functionalization of these hydrogels with Fmoc-FFX tripep-tides—where X is cysteine (C) or lysine (K)—enhances their ability to interact with PNA sequences. Model four-bases PNA, functionalized with cysteine (C) or glutamic acid (E) residues at the C-terminus, facilitate covalent or electrostatic interactions with the hydro-gel matrix, improving encapsulation efficiency and stabilizing the PNAs. We systemati-cally optimized the composition and ratios of hydrogel components and PNAs to enhance encapsulation efficiency, structural stability, and controlled release profiles. The resulting hydrogels were thoroughly characterized using High-Performance Liquid Chromatog-raphy (HPLC), Electrospray Ionization Mass Spectrometry (ESI-MS), Circular Dichroism (CD), rheology, Fourier-Transform Infrared (FT-IR) spectroscopy, Scanning Electron Mi-croscopy (SEM), Proton Nuclear Magnetic Resonance (¹H-NMR), as well as optical and fluorescence microscopy. Our results demonstrate the potential of these hydrogels as highly effective platforms for stabilizing and delivering PNAs, offering promising pro-spects for the development of innovative nucleic acid-based therapies.

Abstract: The crystal structures of naphthalene dicarboxamides, namely 1,4-naphthalene dicarboxamide (1,4-NDA), 2,6-naphthalene dicarboxamide (2,6-NDA), and 2,7-naphthalene dicarboxamide (2,7-NDA), are presented for the first time along with an analysis of their supramolecular organization. The compounds, obtained in single-crystalline form via solvothermal crystallization from methanol, are stable in air to near 350 °C and have melting points above 300 °C. In their densely packed structures (r = 1.43-1.47 cm3g-1) the combination of C11(4) chains and R22(8) rings give one-dimensional hydrogen-bonded ladders with the additional R42(8) pattern. The amide groups and the naphthalene rings form dihedral angles between 22° and 40°. Neighboring H-bond ladders run parallel in 1,4-NDA and 2,6-NDA and are connected by means of the naphthalenedyil cores along, so that two-dimensional (2D) H bonded sheets are obtained Except for a weak intra-sheet π-π stacking in 1,4-NDA there are no π-π stacking and C–H⋯π interactions. The R22(8) rings act as four-connected nodes, leading to the formation of two-dimensional H-bonded planar sheets with sql topology for the nearly linear dicarboxamides 1,4-NDA and 2,6-NDA and cds topology for the angular 2,7-NDA. Hirshfeld surface analysis and NCI plots provide additional insight into the H-bonding interactions.

Abstract: As examples of “Click Chemistry”, the reaction of 1-(oxiran-2-ylmethyl)piperidine with several 1,2,4-triazoles derivatives was studied. According to as a result, the reaction shows that the oxirane ring opens regiospecifically, according to Krasusky’s rule, without using a catalyst. The basic nitrogen present in 1-(oxiran-2-ylmethyl)piperidine has a catalytic (anchimer) effect.

Abstract:

The 1,3 -dipolar cycloaddition reaction of nitrile oxides, prepared in situ from pyridine aldehyde oximes, with propargyloxy- or propargylaminocoumarins afforded the corresponding new 3,5-disubstituted isoxazoles in moderate to good yields. As oxidants for the formation of nitrile oxides utilized (diacetoxyiodo)benzene (PIDA) at room temperature or under microwave irradiation or tert-butyl nitrite (TBN) under reflux. Preliminary in vitro screening tests for some biological activities of the new compounds have been performed. Compounds 12b and 13a are potent LOX inhibitors with IC₅₀ 5 μΜ and 10 μΜ, respectively, while hybrids 12b and 13a exhibit moderate to low anticancer activities on Hela, HT-29, and H1437 cancer cells.

Abstract: A series of new 3-alkyl substituted cis- and trans-(±)-3,4-dihydro-6,7-dimethoxy-1-oxo-1H-isochromene-4-carboxylic acids (cis-/trans-1-3) was synthesized through the reaction of 6,7-dimethoxyhomophthalic anhydride with aliphatic aldehydes of varying chain lengths. Their structure and configuration were elucidated using spectral methods, including 1H-, 13C-, DEPT-135-NMR, and HRMS analyses. A deductive conformational analysis was performed for determining the preferred conformations in solution and to explain the observed vicinal coupling constants.

Abstract:

In this work, two pentacyanoferrate(II) complexes are synthesized and characterized, and their intense solvatochromic properties are examined in various solvents and solvent mixtures. These complexes feature ligands with flexible xylylene bridges and distinct heterocycles: one combining 4-dimethylaminopyridine (DMAP) with 4,4’-bipyridine, and the other isoquinoline with 4,4’-bipyridine. This structural diversity leads to intriguing solvatochromic behavior, enabling various intermolecular interactions and motifs in solution among the solvents and the complexes acting as solutes. The determined dipole moment changes between ground and excited states of both compounds highlight their sensitivity to small changes in dipolarity within polar media, such as water and polar organic solvents and mixtures thereof. Linear solvation energy relationships are employed to investigate their dependencies on solvent polarity and their responsiveness to different media. Additionally, the solvatochromic aptitude of the molecules examined is utilized to determine the polarity properties of aqueous solutions containing the bio-based molecule urea, a major player in bio-based resins and adhesives and other imminent applications.

Abstract:

3,3-Dialkoxy-2-oxindoles are prevent in natural product family and exhibit unique biological activities. Among them, acyclic alkoxy analogues shows instability toward acidic conditions, making the access to acyclic isatin ketals highly challenging. Conventional methods for the synthesis of 3,3-dialkoxy-2-oxindoles usually require strong acid and harsh reaction conditions, resulting in low overall efficiency. Herein, we report the acid- and metal-free protocol for the synthesis of 3,3-dialkoxy-2-oxindoles from isatins through an iodine-catalyzed ketalization. This protocol does not require the use of any specific reagents including metal-catalysts. Furthermore, the total synthesis of the unprecedented 2-oxindole alkaloid bearing 3,3-dimethoxy moiety has been achieved.

Abstract: Spirocalcaridines A and B are among the most challenging members of the marine invertebrate derived Leucetta alkaloids. Approaches for construction and elaboration of the highly compact spirocyclic core are described. Synthesis of tricyclic guanidine via a tandem oxidative amination dearomatizing spirocyclization (TOADS) using hypervalent iodine set the stage for total synthesis via migration of the C4/C8 double bond to C4/C5 position followed by oxidation. The undesired but not surprising propensity of the spirocyclic cyclohexadienone to undergo rearrangement to the phenol hindered the desired olefin migration. Furthermore, initial efforts to install the oxidation sequentially first, at C5 followed by C4 of the complete carbon skeleton were fraught with unforeseen challenges and unusual outcomes. In addition, the scope, and limitations of hypervalent iodine mediated tandem oxidative dearomatizing spirocyclization on various substrates were explored. Urethanes and thiourethanes undergo spirocyclization in excellent yield whereas, the reaction with allylic substrates and species lacking the p-methoxy substituent does not proceed. Attempts to prepare other guanidine precursors are briefly discussed.

Abstract:

In this study, we examined the oxidation of (E)-2-hydroxy-1-naphthaldehyde oxime with lead tetraacetate in tetrahydrofuran that produced novel (E)-7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazin-12-one oxime and 1-(pyrrolidin-1-yl)naphtho[1,2-d]isoxazole, and, known 7a,8,9,10-tetrahydro-12H-naphtho[1,2-e]pyrrolo-[2,1-b][1,3]oxazin-12-one, in 15, 18 and 10% yields, respectively. The oxime is readily hydrolysed to its corresponding ketone. Modifying the oxidants and reaction conditions did not improve the product yields. Based on previous studies in our laboratory, we proposed that the reactions proceed via the formation of an o-naphthoquinone nitrosomethide intermediate. 1H and 13C NMR, HRMS, IR, and UV-VIS spectra provided information that supported the structure of the products.

Abstract:

The word opium derives from ancient Greek word ὄπιον (ópion) for the juice of any plant, but today means the air-dried seed capsule latex of Papaver somniferum. Alkaloid chemistry began with the isolation of morphine from crude opium by Friedrich Wilhelm Adam Sertürner in 1804. More than a century later, the Hungarian pharmacist János Kabay opened new perspectives for the direct isolation of morphine from dry poppy heads and straw without the labor-intensive harvesting of opium. In 2015, Kabay’s life and achievements obtained official recognition as constituting a «Hungarikum», thereby entering the national repository of matters of unique cultural value. To this day, the study of Papaver alkaloids is a focus of medicinal chemistry, which the (perhaps unstated) aspiration to obtain an opioid with lesser abuse potential and side effects, while retaining good analgesic properties. We begin this review with a brief account of opiate biosynthesis, followed by a detailed presentation of semisynthetic opioids, emphasizing efforts of the Alkaloida Chemical Company, founded in 1927 by János Kabay, and the morphine alkaloid group of the University of Debrecen.

Abstract:

4-Aminoquinoline derivatives were synthesized on a small scale using a novel microwave-assisted method, and scaled up in sealed tubes. The synthesis adhered to green chemistry principles, employing a solvent-free approach for both the reaction and purification. The purification was achieved through simple washing, no need for column chromatography. All reactions were conducted at temperatures between 90–150 ºC within 90–120 minutes, achieving yields of up to 95%. The products were characterized using FT-IR, 1H- and 13C-NMR spectroscopy, and HR-MS spectrometry. Antibacterial and antifungal activity testing revealed that four compounds exhibited moderate antibacterial activity. Compound 6-chlorocyclopentaquinolinamine demonstrated a strong MIC of 0.125 mM against MRSA, while compound 2-fluorocycloheptaquinolinamine showed a MIC of 0.25 mM against S. pyogenes. A Structure-Activity Relationship (SAR) docking study was conducted within the Penicillin Binding Protein (PBP) binding site. Docking analysis of anti-MRSA com-pounds 7-chlorophenylquinolinamine, 6-chlorocyclopentaquinolinamine, and 2-fluorocycloheptaquinolinamine in the MRSA PBP2a binding pocket (PDB: 4DK1) revealed that 6-chlorocyclopentaquinolinamine and 7-chlorophenylquinolinamine interacted via hydrophobic (ALA601, ILE614), hydrogen bonding (GLN521), and halogen interactions (TYR519, THR399). Compound 6-chlorocyclopentaquinolinamine exhibited superior MRSA inhibition (20 mm inhibition zone vs. 12.5 mm for 7-chlorophenylquinolinamine), attributed to additional π-alkyl interactions and favorable docking parameters, including higher Ligscore2 (4.03), PLP1 (59.15), and Dock Score (34.31). In contrast, compound 2-fluorocycloheptaquinolinamine exhibited weaker activity due to its bulky structure, limited interactions, and less favorable docking scores.

Abstract: The aerial parts of Smilax canariensis Brouss., an endemic plant species of the Canary Islands and Madeira, were chemically investigated, resulting in the isolation of multiple known and novel compounds. These include three known flavonol glycosides: quercetin-3-O-rutinoside, rutin (7), quercetin-3-O-rutinoside decaacetate (7a), kaempferol-3-O-rutinoside nonaacetate, nicotiflorin acetate (8), 1-O-p-coumaroylglycerol triacetate (10) and trans-resveratrol (9). Additionally, a new sterol, 24,24- dimethy-5α-cholesta-7, 25-dien-3-one (1), and two novel dammarane–type triterpenes, 24-hydroxy-24-methyl-dammara-20,25-dien-3-one (2) and 3-acetyl-25-methyl-dammara-20,24-diene (3), were identified. In addition, stigmasterol, sitosterol and stigmast-4-en-3-one (4) were obtained. The structural elucidation of these compounds was achieved via 1D and 2D NMR spectroscopy, mass spectrometry, and comparison with literature data. This study provides the first phytochemical profile of S. canariensis and highlights its potential as a source of bioactive compounds for pharmacological applications.

Abstract:

We hereby report a simple and efficient method for the preparation of (E)-3-aryl-2-styryl-2,3-dihydroquinazolin-4-(1H)-ones, from isatoic anhydride, anilines and cin-namaldehydes in the presence of 20 mol% citric acid in methanol at 60 °C for 2 h. The styryl-dihydroquinazolin-4-(1H)-one products were obtained in moderate and good yields (30-80 %) through the three-component condensation reaction, under an environment-friendly protocol. The latter were easily transformed into styrylquinazolin-4-(3H)-one derivatives with 57-91 % yields using a mild oxidation with I2/DMSO system for less than 60 min.

Abstract: Considering the importance of organic functionalization of MOFs, we here report a simple, tunable and efficient one-step post-modification procedure for introducing amino and carboxylic groups into the mesoporous metal-organic framework Al- and Cr-MIL-101-NH2 based on its reaction with alkyl bromides. This procedure allows also access to polyfunctionnalized MIL-101 decorated with both carboxylic and primary amino groups. Other chemical functions, such as alcohols and alkynes, were also successfully introduced by this method.

Abstract: In this work, we present fully π-conjugated diradical(oid)s and tetraradical(oid)s with five-membered non-alternant cyclopentadienyl and quasi-alternant thiophene rings, latter of which is used as a source of aromatic stabilization. By controlling the topology of the π-systems, we can restrict the lower-bound number of unpaired electrons. Aromaticity and/or anti-aromaticity in the different configurations of the compounds can be used to design conjugated compounds with high open-shell characters. We also designed the diradical(oid) based only on the five-membered rings, without any terminal radical groups. This work exemplifies the application of our theory of rational design of polyradicals with the heteroatomic and non/quasi-alternant organic systems. The ability to create polyradicals with different classes of organic compounds offers possibilities to create multifunctional organic materials with tunable magnetic properties.

Abstract: The common alkaloid theophylline (Tph) is known to exist in five polymorphic forms. The structures of its 8-halo analogues were previously unreported. Here we report three polymorphs for 8-chlorotheophylline (8-Cl-Tph) and an additional distinct one for 8-bromotheophylline (8-Tph). Whilst polymorphs for theophylline are dominated by NH---N inter-molecular hydrogen bonds, the halo compounds exclusively exhibit NH---O interactions. 8-Cl-Tph has two related structures with chains N(7)-H(7)---O(2), one is also the stable form for 8-Br-Tph. Polymorphs with a dimeric R22(10) ring structure using N(7)-H---O(6) H-bonds exist for all three compounds, though each with distinct 3D packing. DFT calculations indicate the alkaloid ring nitrogen N(9) is a weaker base in 8-halo compounds, disfavoring NH---N interactions in their polymorphic forms.