Cycloaddition Research Articles

Facile synthesis and in silico studies of benzothiazole-linked hydroxypyrazolones targeting α-amylase and α-glucosidase.

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M − HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33−80 μM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 μM), demonstrated good activity (IC50 = 17 μM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 μM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.

Novel 10,11-dihydro-5H-dibenzo[b,f]azepine triazoles hybrids: Synthesis, in vitro antioxidant activity and xanthine oxidase inhibition and computational study

The study reports the synthesis and antioxidant capability of six novel 10,11-dihydro-5H-dibenzo[b,f]azepine linked 1,2,3-triazoles 6(a–f), synthesized in good yield using copper (II)-catalyzed azide-alkyne 1,3- dipolar cycloaddition reaction (Click Chemistry) under ultrasonication. The alkyne of 10,11-dihydro-5H-dibenzo[b,f]azepine has been prepared and confirmed to have monoclinic geometry using single crystal XRD. All the synthesized compounds are fully characterized using 1H and 13CNMR , IR, and HRMS. The new compounds 6(a-f) were studied for in vitro DPPH and FRAP antioxidant assay, as well as their ability to inhibit xanthine oxidase enzyme. Compound 6d showed minimum IC50 values of 3.58 ± 1.5 µg/ml and 58.66 ± 3 µM for DPPH and FRAP inhibitory effect respectively. The HAT (hydrogen atom transfer) mechanism for DPPH activity and SET (single electron transfer) mechanism for FRAP activity of compound 6d, has been studied through a DFT study on B3LYP hybrid functional at 6–31+G(d,p) basis set. The bond dissociation enthalpy and ionization potential of 6d are 77.01 kcal/mol and 162.59 kcal/mol respectively, proving it to be an excellent antioxidant. Being the best antioxidant 6d has been further used for in vitro inhibition study on xanthine oxidase enzyme isolated from buttermilk. 6d derivative has an IC50 value of 4.93±2 µg/ml much lesser than the standard drug Allopurinol, having an IC50 value of 10.29 ± 1 µg/ml. The molecular docking study is performed on 6(a-f) for XO protein PDBID:1FIQ. All compounds showed effective binding with XO enzyme and the best lead 6d showed a maximum binding energy value of -10.0 kcal/mol. A molecular dynamic simulation study of 100 ns further proved the stability of enzyme 6d complex in the biological system.

Indole as a Versatile Building Block in Cycloaddition Reactions: Synthesis of Diverse Heterocyclic Frameworks.

Indole, a ubiquitous and structurally versatile aromatic compound, has emerged as a key player in the synthesis of diverse heterocyclic frameworks via cycloaddition reactions. These reactions are completely atom-economical and, hence, are considered as green reactions. This review article provides a comprehensive overview of the pivotal role played by indole in the construction of complex and biologically relevant heterocyclic compounds. Here we explore the chemistry of indole-based cycloadditions, highlighting their synthetic utility in accessing a wide array of heterocyclic architectures, including cyclohepta[b]indoles, tetrahydrocarbazoles, tetrahydroindolo[3,2-c]quinoline, and indolines, among others. Additionally, we discuss the mechanistic insights that underpin these transformations, emphasizing the strategic importance of indole as a building block. The content of this article will certainly encourage the readers to explore more work in this area.

Structural diversity of decalin forming Diels-Alderase.

The Diels-Alder (DA) reaction, specifically referring to the [4 + 2] cycloaddition reaction in pericyclic reactions, is a process that forms two carbon-carbon covalent bonds in a single step via an electron ring transition state. Among the secondary metabolites produced by microorganisms, numerous compounds are biosynthesized through DA reactions, most of which are enzymatic. Our research group has discovered an enzyme named Diels-Alderase (DAase) that catalyzes the DA reaction in filamentous fungi, and we have been investigating its catalytic mechanism. This review describes the reported microbial DAase enzymes, with a particular focus on those involved in the construction of the decalin ring.

A step closer to sustainable CO2 conversion: Limonene carbonate production driven by ionic liquids

This work aims to advance the biocarbonate concept by developing the first process to produce limonene carbonate based on ionic liquids (ILs). Conventional petroleum-derived cyclic carbonates are recognized products partially composed of CO2 with the main drawback of the high energy consumption that imposes epoxide production. In contrast, natural epoxidable compounds, such as terpenes, stand out in the literature as a more sustainable open research line to enable CO2 conversion processes with better sustainable indicators. Limonene, an abundant natural compound, is identified as a key terpene in the aforementioned discussion. Ammonium-based ILs are experimentally selected and optimized, after covering massive anion and cation substituent tuning, achieving high selectivity and competitive yields to limonene carbonate. The reaction-extraction platform concept, which recovers the catalyst by liquid-liquid extraction, is envisioned and developed using a rational experimental-computational approach. The work concludes with a novel process to effectively produce limonene carbonate by using an IL catalyst and water as an extracting solvent. Ultimately, taking advance of the process simulation, a CO2 emissions assessment was conducted. Using renewable raw materials enhances the sustainability of CO2 conversion to cyclic carbonate, reducing global warming impact compared to fossil-based epoxides. However, limonene extraction and epoxidation have a tangible impact on the overall result of CO2 balance, turning efforts outside battery limits of the CO2 conversion process in the search of a limonene carbonate production line with negative neat CO2 emissions that may change the paradigm in the fixation of CO2 through cycloaddition reactions.

A new nickel-based δ-isomer Anderson-type polyoxometalates: Synthesis, crystal structure and catalytic activity in 1,2,3-triazoles production

In this study, we present a novel organic hybrid Ni-based δ-isomer of Anderson-type polyoxometalates (POMs), namely, δ-[C6H12Mo6N2NiO24]4− (1), as an efficient catalyst for the cycloaddition reaction between alkynes, halides, and sodium azide. Synthesis of the catalyst was performed using a facile one-pot method followed by characterization using single crystal, powder XRD, SEM, and FT-IR techniques. After optimizing reaction conditions for a model reaction (T = 80 °C, time = 6 h, and solvent = 2 mL H2O), the catalytic activity of this compound was examined for the preparation of diversely substituted 1,2,3-triazoles under ambient atmospheric and additive-free conditions, achieving moderate to good yields. Catalyst 1 could reuse up to four sequential cycles without significant loss in its catalytic activity. Additionally, the true heterogeneity of the catalyst was determined by the hot-filtration test.

Cycloaddition reaction of methylidyne radical with dipyrromethanol: quantum chemical insights into the formation of di(pyridin-2-yl)methanol

Density functional theory was employed to investigate methylidyne radical reaction on to the unsaturation of dipyrromethanol moiety through cycloaddition forming a six membered di(pyridin-2-yl)methanol followed by H-elimination via ring expansion. Time-dependent density functional theory (TD-DFT) simulations were performed to figure out the ultraviolet–visible spectrum of dipyrromethanol and di(pyridin-2-yl)methanol. Ultraviolet–visible spectrum of dipyrromethanol and di(pyridin-2-yl)methanol shows that two sharp absorption peaks were obtained at λ max = 161 nm and 206 nm for the reactant dipyrromethanol while a sharp peak was observed for the product di(pyridin-2-yl)methanol at shorter wavelength (λ max = 170 nm). The theoretical IR spectrum of dipyrromethanol and di(pyridin-2-yl)methanol shows that a significant red shift of 129 cm−1 was observed in the case of di(pyridin-2-yl)methanol due to presence of two strong intra-molecular hydrogen bonds, which indicates its higher stability than the dipyrromethanol. HOMO–LUMO energy gap calculations and natural bond orbital (NBO) analysis endorse the type of electronic transition for the desired product di(pyridin-2-yl)methanol is π–π*. The global reactivity analysis shows the electron donor and acceptor nature of dipyrromethanol and methylidyne radical, respectively. A potential energy surface is constructed via methylidyne radical addition, ring expansion, and hydrogen elimination transition states. Thermodynamics study and potential energy surface of the title reaction indicates its highly exothermicity and spontaneous in nature.

Unveiling the integrated function of metallo‐/ionic‐covalent organic polymers for boosting atmospheric CO2 conversion

Unveiling the integrated function of metallo‐/ionic‐covalent organic polymers for boosting atmospheric <scp>CO₂</scp> conversion

Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads

Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads

Facile synthesis of Al-g-C3N4/Bi2S3 with enhanced for CO2 cycloaddition reaction performance

In this paper, a high specific surface area lamellar heterogeneous composite catalyst (MCN) was synthesized for the cycloaddition reaction of CO2 and epoxides. MCN is doped aluminum with high catalytic activity in Bi2S3 and g-C3N4 with photocatalytic activity, and it was prepared by a facile one-step calcination method. This catalyst achieved 88 % and 97 % conversion and selectivity for the cycloaddition reaction of epichlorohydrin and CO2 with no change in yield after five cycles. In addition, the two compositions of Bi2S3 and g-C3N4 in MCN resulted in enhanced light absorption of the catalyst, thus providing some photothermal performance. This paper provides an idea for the design of bifunctional catalysts with Lewis acid-base.

Metallo-Glycodendrimeric Materials against Enterotoxigenic Escherichia coli.

Conjugation of carbohydrates to nanomaterials has been extensively studied and recognized as an alternative in the biomedical field. Dendrimers synthesized with mannose at the end group and with entrapped zero-valent copper/silver could be a potential candidate against bacterial proliferation. This study is aimed at investigating the bactericidal activity of metal-glycodendrimers. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used to synthesize a new mannosylated dendrimer containing 12 mannopyranoside residues in the periphery. The enterotoxigenic Escherichia coli fimbriae 4 (ETEC:F4) viability, measured at 600 nm, showed the half-inhibitory concentration (IC50) of metal-free glycodendrimers (D), copper-loaded glycodendrimers (D:Cu) and silver-loaded glycodendrimers (D:Ag) closed to 4.5 × 101, 3.5 × 101 and to 1.0 × 10-2 µg/mL, respectively, and minimum inhibitory concentration (MIC) of D, D:Cu and D:Ag of 2.0, 1.5 and 1.0 × 10-4 µg/mL, respectively. The release of bacteria contents onto broth and the inhibition of ETEC:F4 biofilm formation increased with the number of metallo-glycodendrimer materials, with a special interest in silver-containing nanomaterial, which had the highest activity, suggesting that glycodendrimer-based materials interfered with bacteria-bacteria or bacteria-polystyrene interactions, with bacteria metabolism and can disrupt bacteria cell walls. Our findings identify metal-mannose-dendrimers as potent bactericidal agents and emphasize the effect of entrapped zero-valent metal against ETEC:F4.

Ultrasmall Single-Chain Nanoparticles Derived from Amphiphilic Alternating Copolymers.

The collapse or folding of an individual polymer chain into a nanoscale particle gives rise to single-chain nanoparticles (SCNPs), which share a soft nature with biological protein particles. The precise control of their properties, including morphology, internal structure, size, and deformability, are a long-standing and challenging pursuit. Herein, a new strategy based on amphiphilic alternating copolymers for producing SCNPs with ultrasmall size and uniform structure is presented. SCNPs are obtained by folding the designed alternating copolymer in N,N-dimethylformamide (DMF) and fixing it through a photocatalyzed cycloaddition reaction of anthracene units. Molecular dynamics simulation confirms the solvophilic outer corona and solvophobic inner core structure of SCNPs. Furthermore, by adjusting the length of PEG units, precise control over the mean size of SCNPs is achieved within the range of 2.8 to 3.9nm. These findings highlight a new synthetic strategy that enables enhanced control over morphology and internal structure while achieving ultrasmall and uniform size for SCNPs.

Iodine promoted annulation reaction for selective construction of Spiro[indene-2,1′-pyrido[4,3-b]indole] and Benzo[5,6]pyrrolo[3′,2': 3,4]cyclohepta[1,2-b]indole

I2 promoted cycloaddition reaction of 2-hydroxy-2-(indol-3-yl)-indane-1,3-diones with the in situ generated β-enamino esters, which were generated from the reaction of arylamines and dialkyl but-2-ynedioates, showed very interesting molecular diversity. In the presence of 30 % mmol iodine, the reaction in acetonitrile at 80 °C resulted in the novel spiro [indene-2,1′-pyrido [4,3-b]indole] derivatives in good yields. On the other hand, in the presence of 80 % mmol iodine, the reaction in acetonitrile at 60 °C gave the ring-expanded benzo [5,6]pyrrolo [3′,2':3,4]cyclohepta [1,2-b]indole derivatives in moderate to good yields. Additionally, the similar iodine-promoted reaction of 2-(indol-2-yl)diarylmethanols and β-enamino esters gave the unique 1,1,2-triphenyl-2,9-dihydropyrido [3,4-b]indoles in satisfactory yields. A plausible domino annulation mechanism was rationally proposed for the formation of various polycyclic compounds.

A molecular electron density theory study on the [3 + 2] cycloaddition reaction of a 2,4-dienone and a nitrone: regioselectivity, diastereoselectivity, energetic aspects, and molecular mechanism

A molecular electron density theory study on the [3 + 2] cycloaddition reaction of a 2,4-dienone and a nitrone: regioselectivity, diastereoselectivity, energetic aspects, and molecular mechanism

Semisynthesis of new isoxazolines from (E)-α-atlantone: Antibacterial, antifungal activities, ADME-Tox, molecular docking, and molecular dynamics simulations investigations

In the present work, new isoxazolines were semisynthesized by 1,3-dipolar cycloaddition reactions of nitriloxides on (E)-α-atlantone, a sesquiterpene compound isolated from Cedrus atlantica essential oil. The reaction proceeds in a chemo- and periselective manner to lead to two cycloadducts 3 and 3′. The structures of the obtained cycloadducts were determined using infrared, nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and elemental analysis. In addition, the semisynthesized cycloadducts were screened for their antimicrobial antibacterial and antifungal activities which they show significant diameter of inhibition zones ranging from 9 to 41.5 mm against Staphylococcus aureus, Proteus mirabilis, and Candida albicans. Furthermore, in silico investigations were conducted employing molecular docking, molecular dynamics, and (absorption, distribution, metabolism, excretion, toxicity) tests as well as drug-likeness evaluation, to complement the experimental findings and enhance our understanding of the potential bioactivity of the compounds at the molecular level.

Co(II)-N4 Catalysts for the Coupling of CO2 with Epoxides into Cyclic Carbonates: Catalytic Activity, Computational and Kinetic Studies.

In this study, we synthesized and characterized a series of cobalt(II) complexes bearing linear tetradentate N4 ligands. These Co(II)-N4 complexes proved to be efficient catalysts for the cycloaddition reaction between carbon dioxide and epoxides even at room temperature and 1 bar pressure of carbon dioxide without the need for solvents or cocatalysts. Furthermore, when combined with (triphenylphosphoranylidene)ammonium chloride (PPNCl) as a cocatalyst, the Co-N4 catalysts exhibited an impressive turnover frequency of up to 41,000 h-1 for coupling of epichlorohydrin/CO2. These Co(II)-N4 catalysts were found to have excellent stability and reusability, retaining their catalytic activity after they were recycled seven times. Density functional theory (DFT) calculations provided a comprehensive mechanism for the cycloaddition reaction, indicating that the rate-determining step is the epoxide ring opening, in both the presence and absence of PPNCl. Further kinetic studies allow us to determine the activation parameters (ΔH‡, ΔS‡, and ΔG‡ at 25 °C) of the coupling reaction using the Eyring equation. The Gibbs free activation energy obtained from the kinetic studies was in close agreement with that of the DFT calculations. The substituent effect on the cycloaddition reaction of CO2 with various substituted styrene oxides was also examined for the first time.

Mechanistic Basis of the Cu(OAc)2 Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.

Two 2D Metal-Organic Frameworks Based on Purine Carboxylic Acid Ligands for Photocatalytic Oxidation of Sulfides and CO2 Chemical Fixation.

Two two-dimensional (2D) layered metal-organic frameworks (MOFs), namely, {[Yb(L)(H2O)2NO3]·2H2O}n (Yb-MOF) and [Er(L)(H2O)3Cl]n (Er-MOF) (H2L = 5-((6H-purin-6-yl)amino)isophthalic acid), were constructed by a solvothermal method and characterized. The catalytic performance study showed that the Yb-MOF could efficiently catalyze the oxidation of sulfides to sulfoxides under 15 W light-emitting diode (LED) blue light irradiation. Electron paramagnetic resonance spectroscopy and free-radical trapping experiments demonstrated that the photocatalytic reaction process involved •O2-, and the corresponding mechanism was proposed. Moreover, Er-MOF exhibited good catalytic efficiency and excellent substrate tolerance in the cycloaddition reaction of CO2, and the reaction conditions were mild. After 5 cycles, the catalytic activities of two MOFs did not significantly decrease, and the framework structures remained unchanged. Therefore, the Yb-MOF and Er-MOF were considered efficient and stable heterogeneous catalysts.

Cobalt/Photoredox Cooperative Catalysis‐Enabled Cycloaddition Reactions of 1,6‐Diynes and Related Compounds

AbstractCobalt catalysts have recently gained considerable attention as alternatives to catalysts based on precious transition metals such as Rh and Ir. Recently, Co/photoredox cooperative catalysis has emerged as a powerful tool that enables versatile transformations, including cycloaddition reactions of unsaturated compounds. In particular, 1,6‐diyne derivatives are fascinating substrates for these reactions because the corresponding exocyclic 1,3‐diene products can be further transformed into sp3‐rich carbocycles and heterocycles via functionalization of the diene moiety. The dual catalytic system can facilitate not only the cycloaddition based on the activation of the π‐bond only, such as alkyne cyclotrimerization, but also the cycloaddition involving σ‐bond activation. This Concept highlights the recent advances in Co/photoredox cooperative‐catalysis‐enabled cycloaddition reactions, focusing on the reactions of 1,6‐diyne substrates, which are difficult to perform when well‐defined cationic CoI catalysis is employed.