Highly regio- and diastereoselective synthesis of spiropyrrolidine-fused pyrrolo[2,1-a]isoquinolines through dearomative (3 + 2) cycloaddition reactions

The [3+2] cycloaddition of a chiral acridine-derived alkene with 2,4,6-trimethylbenzonitrile N-oxide yields two regioisomeric isoxazoline cycloadducts, each formed as a pair of diastereomers. Single-crystal X-ray diffraction analysis of (1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl (4S,5S)-5-(acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-1,2-oxazole-4-carboxylate (6b) and (1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl (4R,5R)-4-(acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (7a) cycloadducts, both C36H40N2O3, unambiguously establishes the regiochemistry of the cycloaddition and the relative configuration at the newly formed stereogenic centres. The molecular structures reveal a rigid acridine framework linked to a slightly puckered isoxazoline ring, with the ester substituent adopting distinct orientations depending on the regiochemical outcome. In the solid state, the molecules are stabilized by weak C-H...O contacts involving the isoxazoline and ester functionalities, and by weak C-H...π interactions. These crystallographic results provide reliable structural benchmarks for acridine-based isoxazoline derivatives obtained via 1,3-dipolar cycloaddition reactions.

Understanding the spatiotemporal dynamics of protein synthesis and degradation is important for establishing how cells maintain protein homeostasis. Conventional methods for detecting newly synthesized proteins include metabolic labeling with radioactive [35S]methionine (Met) or the incorporation of l-azidohomoalanine (AHA) or l-homopropargylglycine followed by fluorescent labeling via copper(I)-catalyzed click chemistry. However, these methods typically require cell fixation, making them unsuitable for live-cell imaging. Here, we describe a fluorescence imaging technique to monitor newly synthesized proteins in living cells by utilizing a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction, in which l-AHA-containing proteins are labeled with fluorescent dyes conjugated to dibenzocyclooctyne (DBCO). We synthesized orange-emitting tetramethylrhodamine (TAMRA)-DBCO and far-red-emitting silicon rhodamine (SiR)-DBCO. TAMRA-DBCO enabled the visualization of newly synthesized proteins and their time-dependent degradation throughout the entire cell. SiR-DBCO was similarly effective, but was mainly distributed to the cytoplasm. The time-dependent decrease of TAMRA-DBCO fluorescence intensity in living cells was suppressed by lysosomal enzyme inhibitors and a proteasome inhibitor, suggesting that newly synthesized proteins are degraded via both pathways. Moreover, imaging of drug-induced senescent cells with TAMRA-DBCO suggested that senescent cells have a lower protein degradation ability than nonsenescent cells. These methods should be useful for investigating protein homeostasis in living cells.

Constructing mixed matrix membranes (MMMs) with excellent interfacial compatibility and superior anti-plasticization performance is still a challenge. Herein, we prepared a zeolitic imidazolate framework filler modified with maleimide (MI) cross-linking site (termed as ZIF-8-MI). Subsequently, this filler was blended into the polyimide (PI) matrix that also contains MI cross-linking site (termed as PMI), in order to construct a series of MMM. When the MMM was thermally treated at 350 °C, the ZIF-PMI interfacial cross-linking reaction took place, which was derived from the radical cycloaddition between ZIF-8-MI and PMI, thus promoting the interfacial compatibility between the fillers and the PMI matrix. Concurrently, the in situ cross-linking of the PMI matrix was also formed due to the similar MI-induced radical cycloaddition reaction. As a result, thanks to this dual cross-linking effect, the gas separation performance and the anti-plasticization ability of MMM were highly enhanced. The optimized MMM, termed as cPI-ZIF-8-SI-20%, achieved a CO2 permeability of 1028 Barrer, while maintaining a CO2/CH4 selectivity of 39.2, and its overall separation performance surpassed the Robeson 2008 Upperbound. Moreover, its CO2/CH4 (50:50) mixed gas separation performance continuously exceeds the 2018 performance upper limit across the 2-25 bar pressure range. In addition, it also exhibited exceptional plasticization resistance with a critical plasticization pressure of 44 bar. We believe that this dual cross-linking method provides an important reference for the development of MMMs with good interfacial compatibility and decent antiplasticization performance.

Photostability of organic dyes is a critical challenge in the field of organic photovoltaics, as prevalent exposure to light and air can lead to degradation of the active ingredient. In our study, a series of novel 2,1,3-benzothiadiazole-based extended tetrathiafulvalenes was synthesized and assessed for their photophysical properties. Extended tetrathiafulvalenes are promising candidates for dyes in organic photovoltaics, yet the role that dithiafulvene plays in singlet molecular oxygen sensitization remains unclear. Photophysical analyses show a clear link between dithiafulvene units and a decreased generation of molecular singlet oxygen, which further results in a [2 + 2] cycloaddition reaction and cleavage of the said unit.

The catalytic cycloaddition of CO2 to epoxides for the synthesis of cyclic carbonates represents a cornerstone of CO2 utilization within the green chemistry paradigm. This review comprehensively summarizes recent advances in the application of inorganic catalysts, including metal oxides, boron-based materials, and graphitic carbon nitride, with elaborated mechanistic insights into their unique activation pathways. Key material engineering strategies such as heteroatom doping, defect engineering, and crystal facet tuning are highlighted for their role in enhancing catalytic performance. Despite progress, significant challenges remain, particularly in developing co-catalyst-free systems that operate under mild conditions. This review critically discusses these challenges and outlines future research directions, emphasizing the rational design of intrinsic bifunctional catalysts, the adoption of greener reaction media, and the development of scalable synthesis methods to bridge the gap between laboratory innovation and industrial application.

Given that polycyclic indolines are widely recognized as essential structural motifs in numerous alkaloid natural products and biologically active compounds, the development of innovative synthetic approaches for these molecules has attracted significant attention in the scientific community. Herein, we present the development of a Pd-catalyzed tandem reaction pathway, which proceeds through a Sonogashira coupling step and a propargylic Alder-ene reaction to generate the reactive indenone-allene intermediate, followed by an intramolecular indole-participated dearomative [4 + 2] cycloaddition. This method exhibits remarkable tolerance toward a variety of functional groups and facilitates the synthesis of a broad spectrum of polycyclic indolines in moderate to high yields.

A cyanoacrylate derivative crystal exhibits an unusual combination of one-dimensional elasticity, plasticity, and reversible hand-held twisting. Twisting induces a reversible single crystal to polycrystal transition. It also displays photobending via a cycloaddition reaction under 365 nm irradiation and thermally recovers its original state, retaining functionality in the twisted state, indicating potential applications in soft robotics and smart actuators.

The idea of (3 + 2)-construction of pyrrolidines is realized based on a common natural substrate modified at a single position by functional groups with opposite electronic effects. Their role in switching the diastereoselectivity mode of cycloaddition is shown for the first time. In this work, Lewis-acid-complex-catalyzed (3 + 2)-cycloaddition reactions involving donor-acceptor cyclopropanes (DACs) and newly obtained citral imines were investigated and optimized. Based on the results obtained, a method for the diastereoselective synthesis of substituted 2,5-cis- and trans-pyrrolidines was developed. Our approach demonstrates broad substrate scope and significant synthetic utility, as evidenced by the directed product derivatization. This work expands the applicability of the known method to a wider range of aliphatic substrates due to the decisive participation of Yb(NTf2)3/PyBOX as a catalyst.

This study presents a theoretical investigation of the mechanistic pathways for H-H bond cleavage and [1 + 2] cycloaddition with ethylene mediated by triplet monomeric pnictinidenes ([G15]3; G15 = Group 15 element). Our results demonstrate that sterically congested singlet dipnictenes ([G15]12) can thermally dissociate into two triplet [G15]3 monomers, with the dissociation energy decreasing systematically from N to Bi. M06-2X-D3 calculations indicate that triplet [G15]3 activates H2 via a transition state on the triplet surface, followed by intersystem crossing to form singlet products, with the reactivity decreasing as the atomic number of G15 increases. Similarly, triplet [G15]3 undergoes [1 + 2] cycloaddition with ethylene through a triplet transition state, ultimately producing singlet three-membered heterocycles after intersystem crossing. Activation strain model (ASM) analyses reveal that the atomic radius of the central G15 atom provides a consistent explanation for the origins of the activation barriers in both H-H bond cleavage and [1 + 2] cycloaddition reactions. This study offers qualitative rationalization based on the activation barrier and assesses the feasibility of the proposed experimental observations.

Titanocene‐phosphinidene and diphosphanediide (or diphosphene) complexes Cp 2 Ti(PMe 3 )P Mes Ter and Cp 2 Ti(P 2 Ar 2 ) (Ar=Tipp, Dipp) undergo formal [2 + 2] or [3 + 2] cycloaddition reactions with terminal alkynes, respectively, to give the corresponding 4‐ and 5‐membered phosphatitanacycles. Cp 2 Ti(PMe 3 )P Mes Ter is shown to react selectively with aryl‐substituted and aliphatic terminal alkynes to give stable phosphatitanacyclobutene species, while the reactivity of Cp 2 Ti(P 2 Ar 2 ) is restricted to aryl‐substituted terminal alkynes featuring strong electron‐withdrawing substituents in para ‐position. These metallacycles were investigated spectroscopically and crystallographically.

This study explores the reactivity and pharmaceutical potential of a novel anticancer compound, 1,2,4-oxadiazolidine, synthesized through the [3 + 2] cycloaddition (32CA) reaction between nitrone (1a) and carbodiimide (2a). The mechanism, investigated using Density Functional Theory (DFT) with the B3LYP-D3 functional and the 6-311 + + G(2d,2p) basis set, reveals a polar, regioselective process involving two transition states (TS1 and TS2), with a thermodynamic preference for the ortho isomer, consistent with experimental findings. Molecular docking studies with the EGFR protein (PDB: 4HJO) indicate that compound P1 binds with a higher affinity (-8.8kcal/mol) compared to the reference drug Erlotinib. Furthermore, molecular dynamics (MD) simulations over 100 ns demonstrate that the P1-EGFR complex exhibits greater stability and lower fluctuation, further supporting its promising interactions with the target protein. In silico ADMET analysis reveals excellent oral absorption, low toxicity, and a favorable pharmacokinetic profile. These findings comprehensively validate P1's reactivity, affinity, and stability, positioning it as a promising anticancer drug candidate.

A novel visible-light-driven [3 + 2] cycloaddition reaction of nitrones with alkynyl esters, catalyzed by 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz), has been investigated. This reaction effectively synthesizes unstable 2,3-dihydroisoxazole derivatives with yields reaching up to 97%, attaining high selectivity under mild conditions and within a short reaction time. Furthermore, the methodology demonstrates a broad substrate scope, accommodating a wide variety of aromatic and aliphatic nitrones, thereby presenting a novel strategy for the efficient construction of multi - substituted five - membered heterocyclic structures. Based on a series of validation experiments, this paper proposes a plausible hybrid mechanism involving free radicals and synergistic reactions.

The first catalytic enantioselective formal (3 + 3) cycloaddition of pyridinium 1,4-zwitterionic thiolates with indol-2-ones, generated in situ from 3-halooxindoles and serving as C-C-O three-atom reaction components, was successfully developed. A series of optically pure indolenine-fused 2H-1,4-oxathiines were obtained in moderate to good yields with high enantioselectivities using a catalyst system comprising a chiral tridentate Pybox ligand and Ni(acac)2. The products could be further converted to chiral 3-sulfenyl-3,3'-disubstituted oxindoles with stereoretention. This work also represents the first report on a catalytic asymmetric cycloaddition reaction involving pyridinium 1,4-zwitterionic thiolates.

This study presents an efficient transition-metal-free method for the synthesis of aminomethyl-decorated 1,2,3-triazole-fused bicyclic heterocycles via a tandem azide-alkyne cycloaddition and azetidine ring-opening reaction. The tandem process proceeds with broad functional group compatibility and high atom economy. Mechanistic studies indicate that the transformation involves an initial [3 + 2] cycloaddition followed by intramolecular triazole-mediated azetidine ring opening. The resulting aminomethyl motif provides a versatile handle for further functionalization, enabling the synthesis of structurally complex, biologically relevant heterocycles including bioactive conjugates.

The [3+2] cycloaddition reactions of a square-planar Cu(II) azido complex with alkynes and coordinating nitriles were investigated.

An effective methodology for the targeted synthesis of a new hybrid heterocyclic compound that combines 2-methyl-5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one and 1H-tetrazole heterocycles linked via a methylene bridge within a single molecule was developed in the present study. The key synthetic stages include an N-alkylation reaction between the activated salt form of the 2-methyl-5-nitro-2,4-dihydro-3H-1,2,4-triazole-3-one synthon and chloroacetonitrile, followed by a catalyzed [3+2] cycloaddition reaction between the cyanomethyl derivative of methylnitrotriazolone and sodium azide, leading to the formation of a tetrazole moiety. The structure of the target compound was reliably confirmed by spectral analytical methods (1Н, 13С NMR and IR spectroscopies). In silico prediction of the possible biological activity range, pharmacokinetic properties and toxicity of the resulting hybrid compound was performed using specialized web tools (PASS Online, ADMETlab 3.0, and ProTox 3.0). The combination of two pharmacophore blocks: the methylnitrotriazolone framework with the tetrazole heterocycle imparts high bioavailability to the final molecule; chemosensitization, anti-inflammatory and antihypertensive activities are predictable with a fairly high probability. The calculated physicochemical parameters fully meet the criteria for drug similarity (Lipinski, Pfizer, GSK, Golden Triangle). The pharmacokinetic profile indicates good predictable permeability, low clearance, and no inhibition of the main cytochrome P450 isoenzymes. The developed hybrid is predicted to be a low-toxicity compound with a low probability of organ toxicity. A comparative analysis of the key predictable parameters with the commercially available antihypertensive agent, losartan, revealed significant benefits of the synthesized hybrid, including higher bioavailability, considerably lower plasma protein binding, no inhibition of cytochrome isoenzymes, and a more favorable toxicity profile. The obtained findings demonstrate high potential of the new hybrid compound as a promising candidate for further in vitro experimental studies to validate its predicted level of biological activity. For citation: Bosov K.K., Krupnova I.A., Pivovarova E.V., Sukhanov G.T., Sukhanova A.G., Filippova Yu.V. Synthesis and in silico evaluation of biological activity, pharmacokinetic properties and toxicity of a new hybrid compound based on methylnitrotriazolone and tetrazole. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2026. V. 69. N 6. P. 107-117. DOI: 10.6060/ivkkt.20266906.6847.

In recent years, a photoredox catalysis strategy has emerged as a powerful platform for generating open-shell intermediates under mild conditions, enabling the development of novel radical-based transformations that are difficult to achieve via traditional ionic pathways. Among these, radical-mediated cyclization reactions allow for the rapid and modular assembly of complex molecular scaffolds. Herein, we report a visible-light-driven formal [3 + 2] cycloaddition reaction of electron-deficient 1,3-conjugated enynes and α-silylamines. This reaction provides a practical route to highly functionalized 2,3-dihydropyrroles under mild and redox-neutral conditions with operational simplicity and a broad substrate scope.

ABSTRACT Organic synthesis has pushed for more nature‐friendly synthetic techniques toward the development of interesting compounds. Green synthesis lowers or gets rid of harmful chemicals through the use of recyclable or renewable materials. In this context, magnetic nanoparticles have gained popularity in green synthesis over the decade due to their various eco‐friendly features and successful implementation for the development of organic molecules. Tetrazoles are preferred organic compounds employed in the identification of lead structures of many reputed marketed drugs. Medicinal and organic chemists have developed various highly valuable derivatives of tetrazole by using magnetic nanoparticles as green catalysts in [3 + 2] cycloaddition reactions. This methodology has several additional features like high yields, short reaction times, and reusability of the catalyst. This is the first report that summarizes studies on using green magnetic nanoparticles to synthesize a class of tetrazole and its derivatives by the application of [3 + 2] cycloaddition reactions.

BF3-Mediated Stereoselective [3+2] Cycloaddition Reaction Between O-silyloxime with Styrene: A DFT Study