Search Results (799)

A novel Ag(I) coordination polymer, [Ag₂(bipy)(btca)]_n, (SCP 1) was synthesized using 4,4′-bipyridyl (bipy) and 1,2,4,5-benzene-tetracarboxylic acid (H₄BTC). Characterization by FT-IR, ¹H/¹³C NMR, and single-crystal X-ray diffraction confirmed its 3D network structure. The structure of SCP 1 consists of two chains arranged in …ABAB… fashion. Chain A is one-dimensional, containing [Ag(4,4′-bipy)]_n chain, while chain B is free, containing uncoordinated 1,2,4,5-benzene tetracarboxylate and water molecules. The stacking and argentophilic interactions extend the chain A of [Ag(4,4′-bipy)]_n into a two-dimensional layer. In contrast, chain B of uncoordinated 1,2,4,5-benzene tetracarboxylate and water molecules form a 1-D chain through extensive hydrogen bonds between water molecules and BTC ions and between water molecules themselves. Chains A and B are connected through extensive hydrogen bonds, generating a three-dimensional network structure. This Silver I supramolecular coordination polymer (SCP 1) demonstrated high catalytic activity as a recyclable heterogeneous catalyst for the synthesis of 5-substituted 1H-tetrazoles via [3+2] cycloaddition of NaN₃ and terminal nitriles under solvent-free conditions in a Q-tube pressure reactor (yields: 94–99%). A mechanistic proposal involving cooperative Lewis acidic Ag(I) sites and Brønsted acidic -COOH groups facilitates the cycloaddition and protonation steps. SCP 1 catalyst exhibits reusability up to 4 cycles without significant loss of activity. The structural stability of the SCP 1 catalyst was assessed based on PXRD and FTIR analyses of the catalyst after usage, confirming its integrity during the recycling process. Full article

Azomethine ylides (AMYs) have a nitrogen–carbon double bond and an electron lone pair on the nitrogen atom. They are essential 1,3-dipoles for [3+2] cycloadditions in the synthesis of pyrrolidine-containing heterocycles. Significant progress in 1,3-diplolar cycloadditions has been made in the construction of novel heterocyclic scaffolds, with efforts to broaden substrate scope, enhance stereoselectivity, and integrate green chemistry principles. This article summarizes double cycloadditions of AMYs derived from amino esters and amino acids for the synthesis of novel polyheterocycles. The design of double cycloadditions through the pot, atom, and step economic (PASE) method to increase the reaction efficiency is discussed. The examples presented in this paper may be applied to the synthesis of biologically active molecules. Full article

Two series of imidazole-2(3H)-thiones inspired by naturally occurring lepidiline alkaloids, bearing either one or two benzyl-type substituents located at the N(1)/N(3) atoms, respectively, were prepared and examined in reactions with in situ generated C-trifluoromethyl-N-aryl nitrile imines. N,N-Dibenzylated imidazole-2-thiones served exclusively as C=S dipolarophiles to afford hitherto unknown CF₃-functionalized spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives formed through the (3+2)-cycloaddition pathway. In contrast, the enolizable N-monobenzylated imidazole-2-thiones provided acyclic products, i.e., hydrazonothioates, resulting from nucleophilic addition of the respective en(thio)late onto the C-termini of the 1,3-dipole. The presented results extend the scope of both fluorinated products available via trapping of the in situ generated CF₃-nitrile imines as well as synthetic analogues of lepidilines. In addition, spectroscopic analysis of the obtained products and the known related systems revealed ¹³C NMR chemical shifts attributed to the C-(CF₃) atom as useful probes to differentiate the open-chain hydrazonothioates (δ = 112–120), 2,2-diaryl/dialkyl-2,3-dihydro-1,3,4-thiadiazoles (δ = 130–145), and more strained spiro-1,3,4-thiadiazole derivatives (δ = 166–170) reported herein. Full article

The relative reactivity of the nitrovinyl molecular segment characterized by the “cis” orientation of nitro group and the aryl ring was evaluated based on the experimental and Density Functional Theory quantum chemical data. It was found that, on the contrary to E-R-nitroethenes, the Z-2-Ar-1-EWG-1-nitroethene molecular segment is not planar. This fact reduces the possibility of the conjugation of π-electron systems, and as a consequence, decreases the global reactivity. Due to these conditions, the reaction of the model ethyl 4,β-dinitrocinnamate and 2-methylenecyclopentane is realized as a very difficult process; however, with full regioselectivity, it leads to the expected (4 + 2) hetero Diels–Alder cycloadduct. Bonding Evolution Theory studies show that the first new C4-C5 single bond is formed in Phase VIII by merging two pseudoradical centers. In turn, the second C6-O1 single bond is formed in last phase of the reaction, by the depopulation of V(C6), V(O1) and V’(O1) monosynaptic basins. According to this, the title reaction was classified as a process carried out according to a “one-step two-stage” mechanism. Full article

Donor–acceptor (D–A) cyclopropanes are important precursors in the synthesis of complex molecules due to their bidentate character and high reactivity. Among them, cyclopropane-1,1-dicarbonitriles are less commonly reported in modern literature, primarily because of the high reactivity of the nitrile groups and their limited compatibility with metal-catalyzed processes, which is caused by the geometrical constraints imposed by the linear cyano substituents. While the cyano groups can be seen as a limitation, they also offer synthetic versatility by serving as handles for further functionalization. In this work, we performed a cycloaddition reaction with mercaptoacetaldehyde, leading to a new class of DA cyclopropanes bearing a thiazole moiety. This one-pot, two-step transformation requires only a single purification step. The resulting thiazolyl-substituted cyclopropanes were subjected to ring strain-release reactions, showing reactivity comparable to the parent cyclopropane-1,1-dicarbonitriles. Full article

Quinazoline is a privileged heterocyclic scaffold commonly found in numerous pharmaceuticals and bioactive natural products, known for its diverse biological activities. The pursuit of efficient and versatile synthetic methods to produce quinazoline derivatives remains a central focus for organic and medicinal chemists, owing to the therapeutic potential of these compounds. This paper reviews the innovative use of 2-azidobenzaldehyde-enabled annulation strategies for the synthesis of quinazoline derivatives, including quinazolin-4(3H)-one, 2,3-dihydroquinazolin-4(1H)-one, 3,4-dihydroquinazoline, 3,4-dihydroquinazoline-2(1H)-thione, and 1,2,3,4-tetrahydroquinazoline. Emphasizing both the mechanistic insights and practical advantages, this review highlights the efficacy and applicability of these methods in the domain of heterocyclic chemistry, providing an invaluable framework for future drug discovery and development efforts. Full article

Sulfur-containing heterocyclic structures play an important role in modern biotechnology. Their synthesis is made possible by means of the hetero Diels–Alder reaction involving unsaturated sulfur compounds. In the framework of this paper, the molecular mechanism of the cycloaddition reactions between tioanalogs of the butadiene generated in situ with the participation of the Lawesson reagent and the E-2-phenyl-1-nitroethene was evaluated on the basis of the DFT quantum chemical calculations. It was found that the most favored reaction path is realized according to a stepwise mechanism with the participation of the zwitterionic intermediate. To study this further, the molecular mechanism of the deamination process of the primary cycloadducts was also analyzed. It was found that this mechanism is substantially different to the case of other known β-elimination processes and is achieved via a stepwise scheme. In addition to these investigations, the LA catalysis of the deamination process was also explored. Full article

In this article, the 1,3-dipolar cycloaddition (1,3-DC) reactions between 4-acyl-1H-pyrrole-2,3-diones fused at the [e]-side with a heterocyclic moiety (FPDs) and diphenylnitrone are studied using Molecular Electron Density Theory (MEDT) at different computational levels. An analysis of the global reactivity descriptors has determined the role of the reagents. FPDs will act as electrophiles, while diphenylnitrone will be a nucleophile. It was found that the reactions proceed according to a one-step but asynchronous mechanism. Additionally, based on the Bonding Evolution Theory (BET) analysis of the model 1,3-DC reaction between FPDs 1b and diphenylnitrone 2, we can distinguish eight different phases. The formation of the first C1-O5 single bond takes place in phase VII through the disappearance of the V(C1) monosynaptic basin and the depopulation of the V″(O5) monosynaptic basin, while the formation of the second C2-C3 single bond begins at the last phase of the reaction through the connection of two V(C2) and V(C3) monosynaptic basins. Based on this, we can classify this reaction as a “one-step two-stage” process. Furthermore, molecular dynamics (MD) simulation analysis up to 100 ns demonstrated the stability of both the 2P3B–Ligand1 and 2P3B–Zidovudine complexes. An enhancer of shape compression was generated for ligand1, whereas Zidovudine generated a more packed and stable hydrogen bond network that would allow a better occupancy of the active site. Full article

Click chemistry has become a powerful and flexible approach for designing hydrogels used in tissue engineering thanks to its high specificity, fast reaction rates, and compatibility with biological systems. In this review, we introduce the core principles of click chemistry, including efficiency, orthogonality, and modularity, and highlight the main types of reactions commonly used in hydrogel formation, such as azide-alkyne c-cloadditions, thiol-ene/yne reactions, Diels–Alder cycloadditions, and tetrazine–norbornene couplings. These chemistries allow researchers to create covalently crosslinked hydrogels that are injectable, responsive to environmental stimuli, biodegradable, or multifunctional. We also explore strategies to enhance bioactivity, such as incorporating peptides, growth factors, or extracellular matrix components, and enabling precise spatial and temporal control over biological cues. Click-based hydrogels have shown promise across a wide range of tissue engineering applications, from cartilage and skin repair to neural regeneration, corneal healing, and cardiovascular scaffolds, as well as in 3D bioprinting technologies. Despite the many advantages of click chemistry such as mild reaction conditions and customizable material properties, some challenges remain, including concerns around copper toxicity, the cost of specialized reagents, and scalability. Finally, we discuss the status of clinical translation, regulatory considerations, and future directions, including integration with advanced bio fabrication methods, the design of dual-click systems, and the emerging role of in vivo click chemistry in creating next-generation biomaterials. Full article

Nitrile imines and nitrile oxides are capable of undergoing (3+2)-cycloaddition reactions at double and triple carbon–carbon, carbon-heteroatom, or heteroatom–heteroatom bonds of various dipolarophiles, forming five-membered heterocyclic compounds. When cyclic dipolarophiles bearing an exocyclic carbon–nitrogen double bond (exo-C=N) are introduced into the reaction with these dipoles, spiro-fused 1,2,4-triazoline or 1,2,4-oxadiazoline cycles are formed. Such reactions can provide efficient synthetic approaches to spiro-heterocyclic compounds with enhanced biological activity. This review comprehensively summarizes the literature data on the 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides to exo-C=N bonds for spiro compound synthesis. The research area covers reactions of both saturated and unsaturated dipolarophiles, monocyclic and polycyclic molecules, as well as compounds containing one to three heteroatoms, with special emphasis on systems containing biologically significant heterocyclic pharmacophores. Recent advances in reaction techniques, such as microwave and ultrasonic activation, as well as one-pot and diffusion protocols, are also mentioned. Full article

An unprecedented nickel-catalyzed [2 + 2 + 2] cycloaddition that enables efficient construction of fused pyridine frameworks with allyl boronate was reported. This transformation is proposed to occur through a mechanism involving aza-nickelacyclopentadiene intermediates, wherein the boryl group of the allyl boronate plays a critical role in enabling the following cyclization via the control experiments. This work not only expands the structural diversity accessible via transition-metal-catalyzed [2 + 2 + 2] cycloadditions but also showcases the untapped potential of unsaturated substrates in cycloaddition reactions. Full article

Three new series of indolizines (5a–f, 6a–f and 7a–g), functionalized with bromine or ethyl ester substituents on the pyridine ring, were designed and synthesized as promising anticancer agents. The synthesis of indolizine derivatives was carried out using the 1,3-dipolar cycloaddition of pyridinium N-ylides to ethyl propiolate as a key step. Spectral characterization (using NMR, FT-IR, HRMS and X-ray diffraction) showed that two types of cycloadducts 5a–f and 6a–f were obtained when the ylides generated by the 3-bromopyridinium salts were used as 1,3-dipoles in Huisgen cycloaddition reactions to ethyl propiolate. The anticancer effect of selected compounds was in vitro assessed against the National Cancer Institute (NCI) panel of 60 human tumor cells, at 10 μM concentration, with three compounds (5c, 6c and 7g) showing promising inhibitory activity on the growth of several cell lines including lung, brain, renal cancer and melanoma, as well as a cytotoxic effect against HOP-62 non-small cell lung cells (34% for compound 5c and 15% for compound 7g) and SNB-75 glioblastoma cells (15% for compound 5c and 14% for derivative 7c). Molecular docking revealed favorable binding affinities for 5c, 6c and 7g (–9.22 to –9.88 kcal/mol) at the colchicine-binding site of tubulin with key interactions involving βASN-258, βALA-317, and βLYS-352 residues for 5c, βASN-258 in case of 6c, and αVAL-181 and βLYS-254 for derivative 7g. According to the in silico ADMET analysis, the active compounds are predicted to exhibit good oral bioavailability, promising drug-like qualities and low toxicity risks. Full article

The 1,3-dipolar cycloaddition reaction was applied to 9α-hydroxyparthenolide, an important sesquiterpene component of Anvillea radiata that was extracted directly from plant material collected in Morocco. Several new spiro-isoxazolidine derivatives were generated on the B-ring of 9α-hydroxyparthenolide (α-methylene-γ-butyrolactone (1)) by 1,3-dipolar cycloaddition of its exocyclic double bond with various nitrones. These compounds were fully characterized by spectroscopic methods. Full article

A one-pot synthetic methodology that combines an Ugi-Zhu three-component reaction (UZ-3CR) with a cascade sequence (intermolecular aza Diels–Alder cycloaddition/intramolecular N-acylation/decarboxylation/dehydration) using microwave-heating conditions, ytterbium (III) triflate (Yb(OTf)₃) as the catalyst, and chlorobenzene (for the first time in a multi-component reaction (MCR)) as the solvent, was developed to synthesize twelve new fluorinated-pyrrolo[3,4-b]pyridin-5-ones containing a 4-amino-7-chloroquinoline moiety, yielding 50–77% in 95 min per product, with associated atom economies around 88%, also per product. Additionally, by in vitro tests, compounds 19d and 19i were found to effectively stop early SARS-CoV-2 replication, IC₅₀ = 6.74 µM and 5.29 µM, at 0 h and 1 h respectively, while cell viability remained above 90% relative to the control vehicle at 10 µM. Additional computer-based studies revealed that the most active compounds formed strong favorable interactions with important viral proteins (M_pro, NTDα and NTDo) of coronavirus, supporting a two-pronged approach that affects both how the virus infects the cells and how it replicates its genetic material. Finally, quantum chemistry analyses of non-covalent interactions were performed from Density-Functional Theory (DFT) to better understand how the active compounds hit the virus. Full article