Cycloaddition Research Articles

Insulated π-Conjugated Azido Scaffolds for Stepwise Functionalization via Huisgen Cycloaddition on Metal Oxide Surfaces.

In organic-inorganic hybrid devices, fine interfacial controls by organic components directly affect the device performance. However, fabrication of uniformed interfaces using π-conjugated molecules remains challenging due to facile aggregation by their strong π-π interaction. In this report, a π-conjugated scaffold insulated by covalently linked permethylated α-cyclodextrin moiety with an azido group is synthesized for surface Huisgen cycloaddition on metal oxides. Fourier-transformed infrared (FT-IR) spectroscopy and X-ray photoelectron spectroscopy confirm the successful immobilization of the insulated azido scaffold on ZnO nanowire array surfaces. Owing to the highly independent immobilization, the scaffold allows rapid and complete conversion of the surface azido group in Huisgen cycloaddition reactions with ethynyl-terminated molecules, as confirmed by FT-IR spectroscopy monitoring. Cyclic voltammetry analysis of modified indium tin oxide substrates shows the positive effects of cyclic insulation toward suppression of intermolecular interaction between molecules introduced by the surface Huisgen cycloaddition reactions. The utility of the scaffold for heterogeneous catalysis is demonstrated in electrocatalytic selective O2 reduction to H2O2 with cobalt(II) chlorin modified fluorine doped tin oxide electrode and photocatalytic H2 generation with iridium(III) dye-sensitized Pt-loadedTiO2 nanoparticle. These results highlight the potential of the insulated azido scaffold for a stepwise functionalization process, enabling precise and well-defined hybrid interfaces.

Thorium Cluster Synthesized by a Solvent-Free Flux Approach: The Richest Coordination Diversity and Application Exploration.

The renaissance of research interests in actinide oxo clusters in the past decade arises from both the concerns of radioactive contamination and their potential utility as nanoscale materials. Compared to the uranium cluster, the thorium (Th) cluster shows less coordination variation. Herein, we presented a unique Th cluster (ThC-1) that exhibits the most diverse coordination chemistry found within a single Th cluster via a solvent-free flux synthesis approach. The melt triazole not only offers a unique solvation environment that may be responsible for the coordination diversity in ThC-1 but also represents the first nitrogen-donor capping ligand in Th clusters. The potential utility of ThC-1 as a heterogeneous catalyst was also explored for a classical CO2 cycloaddition reaction. This work offers a novel approach in synthesizing Th clusters, broadening the realm of the structural diversity of Th.

Multitargeted Molecular Docking and Dynamics Simulation Studies of 1,3,4-Thiadiazoles Synthesised from (R)-Carvone against Specific Tumour Protein Markers: An In-silico Study of Two Diastereoisomers

In the present work, we describe the synthesis of new 1,3,4-thiadiazole derivatives from natural (R)-carvone in three steps including, dichloro-cyclopropanation, a condensation with thiosemicarbazide and then a 1,3-dipolar cycloaddition reaction with various nitrilimines. the targeted compounds were structurally identified by 1H &13C NMR and HRMS analyses. The cytotoxic assay demonstrated that some synthesized novel compounds were potent on certain cancer cell lines. Molecular modeling studies were undertaken to rationalize the wet lab study results. Furthermore, molecular docking was performed to unveil the binding potential of the most active derivatives, 3a and 6c, to caspase-3 and COX-2. The stabilities of the protein-compound complexes obtained from the docking were evaluated using MD simulation. Furthermore, FMO and related parameters of the active compounds and their stereoisomers were examined through DFT studies. The docking study showed compound 6c had a higher binding potential than caspase-3. However, the binding strength of 6c was found to be less than that of the standard drug, doxorubicin, as it formed lower conventional hydrogen bonds. On the other hand, compound 3a had a higher binding potential to COX-2. However, the binding potential 3a was much lower than that of the standard COX-2 inhibitor, celecoxib. The MD simulation demonstrated that the caspase-3-6c complex was less stable than the caspase-3-doxorubicin complex. In contrast, the COX-2-3a complex was stable, and 3a was anticipated to remain inside the protein's binding pocket. The DFT study showed that 3a had higher chemical stability than 6c. The electron exchange capacity, chemical stability, and molecular orbital distributions of the stereoisomers of the active compounds were also found to be alike.

Intermolecular Formal [2π + 2σ] Cycloaddition of Enol Silyl Ethers with Bicyclo[1.1.0]butanes Promoted by Lewis Acids.

Silyl enol ethers react with bicyclo[1.1.0]butanes (BCBs) through Yb(OTf)3-promoted formal [2π + 2σ] cycloaddition reactions to furnish bicyclo[2.1.1]hexanes (BCHs). This new reaction tolerated a wide range of enol silyl ethers and BCBs. Furthermore, the amplification experiments and synthetic transformations of the cycloaddition compounds further highlighted their practicality.

Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights.

Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.

Synthesis of 1‐azabicyclo[2.1.1]hexanes via formal single electron reduction of azabicyclo[1.1.0]butanes under photochemical conditions

C(sp3)‐rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen‐containing heterocycles are in high demand. Herein, we report a general synthesis of 1‐azabicyclo[2.1.1]hexanes (1‐aza‐BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar‐radical‐polar relay strategy that leverages a fast acid‐mediated ring‐opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB‐ketones and we demonstrate the 1‐aza‐BCH products can be further functionalised to access larger saturated, conformationally rigid heterocycles.

Synthesis of 1-azabicyclo[2.1.1]hexanes via formal single electron reduction of azabicyclo[1.1.0]butanes under photochemical conditions.

C(sp3)-rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen-containing heterocycles are in high demand. Herein, we report a general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar-radical-polar relay strategy that leverages a fast acid-mediated ring-opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB-ketones and we demonstrate the 1-aza-BCH products can be further functionalised to access larger saturated, conformationally rigid heterocycles.

Synthesis of diarylpyrrole pseudo-natural products: Cyanide-mediated nitrile-to-nitrile cyclocondensation and C-H acidity-guided regioselectivity

"Pseudo-natural products (pseudo-NPs)", the chemically re-engineered molecular skeletons generated by deconstruction of NPs into fragments and their newly recombination, have gained immense attention in recent time owing to their ability to occupy a significant portion of the medicinally-relevant NP-based molecular space, possess novel bioactivities, and address chemical and biological challenges. In this study, the fragments of Combretastatin, Steganacin, Podophyllotoxin, Colchicine other natural product and drug molecules, and their newly assembly by a cis-lock fusion-edge combination led to generation of diarylpyrrole pseudo-natural product functionalized skeleton, “Combretapyrrole”. These Combretapyrroles with excellent substrate scope were synthesized in good yields by a new method of cyanide-mediated nitrile-to-nitrile cycloaddition reaction of vic-dinitrile with TMG-mediated desilylative cleavage of TMSCN and in-situ generation of cyanide. The differential acidity of benzylic C-Hs of the vic-dinitrile intermediate was found to influence regioselectivity in the mechanistic pathway and provided different products. Cheminformatic analysis showed that the Combretapyrroles occupy a unique drug-relevant chemical space that is rarely covered by NPs. Combretapyrroles also were found to possess drug-like physicochemical properties.

Synthesis and Antimicrobial Evaluation of 1H-1,2,3-Triazole-Linked Quinoline-Phenolic Natural Product Conjugates

A new library of quinoline–natural product conjugates bearing 1,2,3-triazole moiety as a linker has been synthesized using the copper(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) methodology. The structure characterization of the synthesized compounds was achieved using NMR and HRMS analysis. The compounds were subsequently screened for their antimicrobial efficacies against methicillin resistant Staphylococcus aureus (MRSA), MDR Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The studied compounds generally displayed stronger inhibition of microbial cell growth compared to their parent phenolic natural products. Eugenol, thymol, guaiacol, and o-vanillin based 1H-1,2,3-triazole compounds exhibited the best antimicrobial profiles while the pathogen, A. baumannii showed the highest susceptibility to the hybrids. Precisely, hybrids 19a, 20b, and 25b derived from eugenol, thymol, and o-vanillin, respectively, exhibited over 50% growth inhibition of the pathogen. K. pneumoniae was however strongly resistant to the compound series. In silico docking studies of the representative compounds further explored the characteristic binding orientations of these compounds in the active sites of the bacterial and fungal proteins. Overall, we perceive that rational scaffold hopping of these compounds holds promise to offer novel antimicrobial agents with enhanced potency.

Interception and Synthetic Application of Diradical and Diene Forms of Dual-Nature Azabicyclic o-Quinodimethanes Generated by 6p-Azaelectrocyclization.

We demonstrate that 2-alkenylarylaldimines and ketimines undergo thermal 6p-azaelectrocyclization to generate a wide range of azabicyclic o-quinodimethanes (o-QDMs). These o-QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H-atom donor, 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o-QDMs by H-atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4 + 2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o-QDMs can be generated for [4 + 2] cycloaddition from a wide range of electronically and sterically varied 2-alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc-amine.

Synthesis of Difluoromethyl Chromono[3,2-c]pyrazolines/pyrazoles by [3+2] Cycloaddition Reaction of Difluoroacetohydrazonoyl Bromides with 3-EWG-Chromones

Synthesis of Difluoromethyl Chromono[3,2-c]pyrazolines/pyrazoles by [3+2] Cycloaddition Reaction of Difluoroacetohydrazonoyl Bromides with 3-EWG-Chromones

Azidodifluoromethanide (N3CF2-): In Situ Generation and Nucleophilic Addition to Aldehydes.

A facile one-pot approach for the azidodifluoromethylation of aldehydes via in situ-generated azidodifluoromethenide (N3CF2-) utilizing commercially available TMSCF2Br and NaN3 is disclosed. The formed O-silyl ether products are obtained in yields of up to 91% in short reaction times at ambient temperature. Examples of both inter- and intramolecular [3 + 2] azide-alkyne cycloaddition reactions of the installed azidodifluoromethyl handles are also presented, demonstrating the prospective synthetic and biochemical functionality and utility.

Covalent surface modification of single-layer graphene-like BC6N nanosheets with reactive nitrenes for selective ammonia sensing via DFT modeling.

Novel graphene-like nanomaterials with a non-zero bandgap are important for the design of gas sensors. The selectivity toward specific targets can be tuned by introducing appropriate functional groups on their surfaces. In this study, we use first-principles simulations to investigate the covalent functionalization of single-layer graphitized BC6N with azides to yield aziridine-functionalized adducts and explore their possible use to realize ammonia sensors. First, we determine the most favorable sites for physical adsorption and chemical reaction of methylnitrene, arising from the decomposition of methylazide, onto a BC6N monolayer. Then, we examine the thermodynamics of the [1+2]-cycloaddition reaction of various phenylnitrenes and perfluorinated phenylnitrenes para-substituted with (R = CO2H, SO3H) groups, demonstrating a favorable energetics. We also monitor the effect of the functionalization on the electronic properties of the nanosheets via density of states (DOS) and band structure analyses. Finally, we test four dBC6N to gBC6N substrates in the sensing of ammonia. We show that, thanks to their hydrogen bonding capabilities, the functionalized BC6N can selectively detect ammonia, with interaction energies varying from -0.541 eV to -1.371 eV, even in presence of competing gas such as CO2 and H2O, as also confirmed by analyzing the change in the electronic properties and the values of recovery times near ambient temperature. Importantly, we model the conductance of a selected substrate alone and in presence of NH3 to determine its effect on the integrated current, showing that humidity and coverage conditions should be properly tuned to use HO3S-functionalized BC6N-based nanomaterials to develop selective gas sensors for ammonia.&#xD.

Theoretical insights into enantioselective [2 + 1] cyclopropanation reactions of diazo compounds with electron-deficient olefins.

The cyclopropane skeleton plays a significant role in bioactive molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations. The findings indicate that these [2 + 1] cycloaddition reactions proceed in two stages, where the first step is not only the rate-determining step but also critically dictates the stereoselectivity of the product. The calculated diastereomeric ratios are in agreement with the experimental results. Furthermore, by utilizing non-covalent interaction (NCI) analysis and energy decomposition analysis based on molecular force fields (EDA-FF), we elucidated that the electrostatic interactions between reactant fragments in the transition state TS1s for the first step are the predominant factors determining the stereoselectivity, as opposed to the experimentally hypothesized steric hindrance and π-π stacking interactions. The geometrical structures of all minima and transition states on the potential energy surface (PES) in solvents water and toluene were fully optimized using the DFT method at the M06-2X(D3)/SMD/6-31 + G(d,p) level of theory. Single-point energy calculations were carried out based on the optimized geometries in the solution at the M06-2X(D3)/6-311 + G(d,p) level. All the DFT calculations were performed using the Gaussian 09 software. The optimized molecular structures were visualized using CYLview software. NCI analysis was performed using the Multiwfn and VMD softwares. The Multiwfn program was also used for CDFT and EDA-FF analyses.

Rh-catalysed enantioselective [2+2+1] cycloaddition reactions using three different 2π-components

Rh-catalysed enantioselective [2+2+1] cycloaddition reactions using three different 2π-components

Type of Tetrahydronaphthalene-Fused 1,5-Dipoles and Their Application in Polycyclic Compounds Synthesis.

Palladium-catalyzed dipolar cycloaddition reactions represent an efficient strategy for the construction of cyclic compounds, with the development of novel dipolar precursors being a key focus. In this study, a new type of dipolar precursor was synthesized through the assembly of the vinylethylene carbonate unit and the tetrahydronaphthalene skeleton. This dipolar precursor can undergo [3 + 2], [5 + 4], and [5 + 2] cycloaddition reactions, leading to the construction of tetrahydronaphthalene-fused oxazolidin-2-ones, 1,5-oxazonines, and tetrahydrooxepines. In general, all of these reactions exhibited good reaction efficiency and functional group tolerance.

Supramolecular Catalysis of a Halogen-Bonded Co-crystal that Undergoes a [2 + 2] Cycloaddition Reaction Formed via Dry Vortex Grinding

Supramolecular Catalysis of a Halogen-Bonded Co-crystal that Undergoes a [2 + 2] Cycloaddition Reaction Formed via Dry Vortex Grinding

Cu-alginate hydrogels in microfluidic systems: a sustainable catalytic approach for click chemistry

This work explores the innovative use of copper-alginate (Cu-alginate) hydrogels within microfluidic systems to catalyze dipolar cycloaddition reactions, emphasizing green chemistry principles and process intensification. Utilizing naturally occurring biopolymers, such as alginates, provides an environmentally friendly alternative to conventional catalyst supports due to their biocompatibility, biodegradability, and effective metal ion immobilization capabilities. The integration of these biopolymer-based catalysts into microfluidic devices allows for precise control over reaction conditions, leading to enhanced reaction kinetics and mass transfer efficiencies. Our results demonstrate that Cu-alginate hydrogels effectively catalyze the formation of 1,4-disubstituted 1,2,3-triazoles through [3 + 2] dipolar cycloaddition reactions with high regioselectivity and conversion. The microfluidic setup ensures rapid and efficient synthesis, surpassing traditional batch reaction methods in both reaction rate and environmental impact by reducing solvent usage and waste generation. Furthermore, the use of microfluidics contributes to the reproducibility and scalability of the synthesis process, important for industrial applications. The model-based design and its simulations have been employed to further understand and optimize the reaction system. Diffusion through the gel layer and catalytic reaction kinetics estimated from experimental data were included in the model, providing a theoretical foundation for a comprehensive process evaluation. This study not only advances the field of sustainable catalysis by demonstrating the practical utility of biopolymer-supported catalysts in microfluidic systems, but also sets the stage for further research into biopolymer applications in complex chemical syntheses.

Dicationic ionic liquid‐grafted UiO‐66 as efficient catalyst for CO2 conversion into cyclocarbonate under cocatalyst‐free and solventless conditions

CO2 chemical fixation offers a feasible approach for carbon mitigation and high‐value utilization, but it is still challenging to develop an efficient catalyst for CO2 conversion into cyclic carbonate. Herein, the triethylenediamine‐derived dicationic ionic liquids (DIL‐X, X = Cl, Br, and I) were grafted into UiO‐66 linkers through self‐assembly of Zr4+ ions and the mixed ligands of terephthalic acid and DIL‐bearing dicarboxylic acid, resulting in UiO‐66‐DIL‐Xn, (n designated as molar amount of the feeding DIL‐X). Their catalytic performance was evaluated by the epoxide cycloaddition reaction in the absence of solvent and cocatalyst. Among them, the UiO‐66‐DIL‐Cl0.4 catalyst exhibited outstanding performance, with a chloropropene carbonate yield of 92% and a high selectivity of 99% under 0.1 MPa CO2 at 110 °C for 16 h. Its high activity could be ascribed to the cooperativity among Lewis acidity of MOF nodes, the enhanced CO2 absorption, and the strong nucleophilicity offered by halogen ions of ionic liquid‐modified MOF. Moreover, UiO‐66‐DIL‐Cl0.4 presented excellent recyclability and substrate extension. A potential catalytic mechanism for the epoxide‐CO2 cycloaddition into cyclic carbonate has been proposed. This work will shed light on the rational design of functionalized MOFs‐based catalysts for CO₂ utilization.

Insight into the Mechanism of CO2 Chemical Fixation into Epoxides by Windmill-Shaped Polyoxovanadate and n-Bu4NX (X = Br, I).

Carbon dioxide (CO2) coupled with epoxide to generate cyclic carbonate stands out in carbon neutrality due to its 100% atom utilization. In this work, the mechanism of CO2 cycloaddition with propylene oxide (PO) cocatalyzed by windmill-shaped polyoxovanadate, [(C2N2H8)4(CH3O)4VIV4VV4O16]·4CH3OH (V8-1), and n-Bu4NX (X = Br, I) was thoroughly investigated using density functional theory (DFT) calculations. The ring-opening, CO2-insertion, and ring-closing steps of the process were extensively studied. Our work emphasizes the synergistic effect between V8-1 and n-Bu4NX (X = Br, I). Through the analysis of an independent gradient model based on Hirshfeld partition (IGMH), it was found that the attack of n-Bu4NX (X = Br, I) on Cβ of PO triggers a distinct attractive interaction between the active fragment and the surrounding framework, serving as the primary driving force for the ring opening of PO. Furthermore, the effect of different cocatalysts was explored, with n-Bu4NI being more favorable than n-Bu4NBr. Moreover, the role of V8-1 in the CO2 cycloaddition reaction was clarified as not only acting as Lewis acid active sites but also serving as "electron sponges". This work is expected to advance the development of novel catalysts for organic carbonate formation.