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Enantioselective synthesis of chiral heterocyclic derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, a silver‐catalyzed asymmetric 1,3‐dipolar cycloaddition of glycine iminoesters with 3‐isopropylidene‐2‐oxindoles was developed. The DTBM‐Segphos‐induced spirooxindole cycloaddition reaction was used to synthesize a range of stereodivergent alkyl‐substituted 3‐methylene‐2‐oxindoles, achieving excellent enantioselectivities (up to 99 % ee), good diastereoselectivities (up to 20 : 1 dr), and high yields under mild reaction conditions. Computational insights from DFT calculations indicate that the Michael addition step is crucial in determining the reaction rate and enantioselectivity. [ABSTRACT FROM AUTHOR]

Herein, we describe the development of a continuous flow approach to chiral spiropenicillanates with remarkable bioactive properties from 6‐alkylidenepenicillanates through phosphine‐catalyzed [3+2] annulation of allenoates or 1,3‐dipolar cycloaddition with diphenyldiazomethane. Model reactions were carried out using simple alkenes, such as methyl vinyl ketone and N‐substituted maleimides, leading to the corresponding products in excellent yields (up to 96 %). The [3+2] annulation reaction was subsequently extended to the reactivity of 6‐alkylidenepenicillanates, a more complex 2π‐component with an exocyclic carbon‐carbon double bond, allowing the synthesis of spirocyclic compounds. The 1,3‐dipolar cycloaddition reactions between 6‐alkylidenepenicillanates and diphenyldiazomethane under continuous flow conditions gave the corresponding spiro‐1‐pyrazolinepenicillanates in high yields (up to 81 %). Thermal ring contraction, via N2 extrusion, of spiro‐1‐pyrazolinepenicillanates under continuous flow conditions led to spirocyclopropanepenicillanates in quantitative yields. The continuous flow proved to be an efficient methodology for the synthesis of spiropenicillanates and represents a more sustainable approach for the larger‐scale synthesis of spiropenicillanates with relevant biological activity. [ABSTRACT FROM AUTHOR]

A new regioselective approach to the synthesis of 3,4,5-pyrazoles containing a diterpene moiety via 1,3-dipolar cycloaddition of diazoketones obtained from N-maleopimarimide-substituted amino acids to an allenoate was proposed. [ABSTRACT FROM AUTHOR]

The cycloaddition of nitrile oxides and nitrilimines to one or both of the C=C double bonds of caryophyllene is described. The possibility of introducing five-membered fused and spiro-linked heterocycles into the structure of sesquiterpenes by the 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrilimines to caryophyllene was demonstrated. As a result of these reactions, pharmacophore fragments of isoxazoline and pyrazoline are introduced into the structure of caryophyllene, which leads to an increase in the conformational rigidity of the molecule. A complete stereochemical assignment of 1,3-dipolar cycloaddition adducts to caryophyllene was carried out. The study of antiviral and cytotoxic activity for some heterocyclic derivatives synthesized in this work revealed relatively high biological activity of previously little-studied cycloaddition adducts at the exocyclic C=CH2 bond of caryophyllene. The effect of substituents in the synthesized heterocycles on biological activity was demonstrated. Compounds with a good inhibitory effect on the H1N1 influenza virus were revealed. The activity of the compound was demonstrated up to 6 h post infection, and this could be due to slight inhibiting activity against viral neuraminidase, necessary at the stage of progeny virion budding. [ABSTRACT FROM AUTHOR]

An efficient and eco-friendly procedure was developed for the synthesis of N -aryl-2-((3-aryl-1,2,4-oxadiazol-5-yl)thio)acetamides from N -aryl-2-thiocyanatoacetamides and substituted N -hydroxybenzimidoyl chlorides that were prepared easily from the commercially available anilines and aryl aldehydes, respectively. The N -aryl-2-thiocyanatoacetamide acts as a dipolarophile while the nitrile oxide formed in situ from substituted N -hydroxybenzimidoyl chloride acts as the nucleophilic partner in a 1,3-dipolar cycloaddition reaction mediated by triethylamine base in ethanol medium. The procedure affords excellent yields of desired products containing electron-withdrawing and electron-donating groups on the aromatic rings, in short reaction time with ease of operation. The procedure for the synthesis of scaffolds that are potentially valuable for their biological properties also offers the possibility of scale-up to higher quantities. [ABSTRACT FROM AUTHOR]

Context: This study investigates the energetic and polarizability characteristics of three 1,3-dipolar cycloaddition reactions between diazene oxide and substituted ethylenes, focusing on the transition from synchronous to asynchronous mechanisms. Synchronicity analysis, using the reaction force constant, indicates that the bond evolution process becomes increasingly decoupled as the number of cyano groups increases. Polarizability analysis reveals that isotropic polarizability reaches its maximum near the transition state in all cases, while anisotropy of polarizability shifts from the transition state toward the product direction as asynchronicity increases. The larger the shift, the more asynchronous the mechanism, as reflected by the weight of the transition region. A detailed examination of the parallel and perpendicular polarizability components to the newly formed sigma bonds shows that the evolution of the parallel component is closely aligned with the energetic changes along the reaction coordinate, particularly in the synchronous reaction. We have also identified a relationship between the displacement in the maximum state of the parallel component from the transition state and the synchronicity of the mechanism. The larger the displacement, the more asynchronous the mechanism. These findings suggest that asynchronous 1,3-dipolar cycloaddition mechanisms are characterized by a decoupling of isotropic and anisotropic polarizabilities and a shift in the maximum polarizability state of the parallel component toward the product direction. Methods: Density functional theory calculations were performed at the B3LYP/6–311 + + G(d,p)//B3LYP/6-31G(d,p) level of theory. The polarizability was calculated at each point of the reaction path, obtained using the intrinsic reaction coordinate method, as implemented in Gaussian 16. [ABSTRACT FROM AUTHOR]

A new and efficient method has been developed to synthesize dispiro[oxindole/acenaphthylenone-benzofuranone]pyrrolidine compounds. This is done by triggering the 1,3-dipolar cycloaddition reaction of azomethine ylides by reacting isatin/acenaphthoquinone with L-picolinic acid/L-proline/sarcosine/L-thioproline/tetrahydroisoquinolines, in a highly regioselective manner in an ionic liquid [DBU][Ac] with 4′-chloro-auron[2-(4-chlorobenzylidene)benzofuran-3(2H)-one]. Single-crystal X-ray diffraction data support the proposed structures of the new compounds. The heterocycles derived from amino acids such as L-picolinic acid, L-proline, and L-thioproline showed significant inhibitory effects against six human solid tumors, including lung, breast, cervix, colon, and others. These new structures were also tested in the active sites of the MDM2 receptor to further study their antiproliferative effects. [ABSTRACT FROM AUTHOR]

A series of novel hybrid derivatives of spirochromanone and isoxazole/isoxazoline was synthesized by 1,3-dipolar cycloaddition of the corresponding spirochromanone alkyne/alkene with nitrile oxides, in situ generated from substituted oximes in the presence of eco-friendly oxidant (sodium hypochlorite) under mild reaction conditions. All new compounds were structurally characterized by 1H, 13C NMR and HRMS techniques. All synthesized compounds were evaluated for their antimicrobial and antifungal activities. [ABSTRACT FROM AUTHOR]

5-(4,5-Dihydro-1H-pyrazol-3-yl)isoxazoles (pyrazoline-isoxazoles) are readily oxidized by active manganese dioxide in benzene or dichloromethane at room temperature. As a result, a simple and efficient method for the synthesis of the corresponding pyrazoleisoxazoles in 94–99% yields was developed. It was shown that 3-ethynyl-1H-pyrazoles are inactive in the 1,3-dipolar cycloaddition reaction with nitrile oxides and nitrile imines. The synthesized di- and trisubstituted pyrazole-isoxazoles showed weaker luminescent properties compared to pyrazoline-isoxazoles. [ABSTRACT FROM AUTHOR]

Reactions between the model compound N-1,4,5-trimethyl-1H-imidazole-3-oxide and electron-deficient olefins including 2-(4-methoxybenzylidene)malononitrile, (E)-ethyl-2-cyano-3-(4-methoxyphenyl)acrylate, 2-benzoyl-3-(4-methoxyphenyl)acrylonitrile, and 5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione were theoretically studied in terms of the density functional theory. It was demonstrated that the reactions can proceed either by the 1,3-dipolar cycloaddition mechanism or by the Michael addition mechanism depending on the type of electron-withdrawing substituents in the olefin molecule. The reaction pathways were calculated and the intermediate structures were determined. [ABSTRACT FROM AUTHOR]

The development of efficient synthetic strategies for the preparation of tetrasubstituted N−H pyrrole derivatives, especially in an environmentally benign fashion is important yet challenging. Herein, we report a copper(II)‐catalyzed tandem reaction involving 1,3‐dipolar cycloaddition of α,β‐ynones and glycine iminoesters, followed by copper(II)‐promoted oxidative (air) dehydrogenative aromatization, allowing de novo access to tetrasubstituted N−H pyrroles in up to 81 % yield under green reaction conditions. A possible reaction pathway is tentatively proposed. Finally, fully substituted pyrroles are available by N‐alkylation, and a preliminary phase‐transfer catalytic asymmetric N‐alkylation was also studied to give an axially chiral pyrrole. [ABSTRACT FROM AUTHOR]

Using Ni(II) as the catalyst, electron-deficient 3,5-dimethylacryloylpyrazole olefin was reacted with C,N-diarylnitrones alone for 10 min to prepare novel five-member heterocyclic products, 4-3,5-dimethylacryloylpyrazole isoxazolidines with 100% regioselectivity and up to 99% yield. And then, taking these cycloadducts as substrates, six kinds of derivatization reactions, like ring-opening, nucleophilic substitution, addition-elimination and reduction, were studied. Experimental results showed that all kinds of transformations could obtain the target products at a high conversion rate under mild conditions, a finding which provided the basic methods for organic synthesis methodology research based on an isoxazolidine skeleton. [ABSTRACT FROM AUTHOR]

A catalyst‐free, one‐pot 1,3‐dipolar cycloaddition reaction between azomethine ylides (generated in situ) and (E)‐3‐styrylquinoxalin‐2(1H)‐ones led to the formation of a series of quinoxalinone containing spiropyrrolidine‐oxindoles. Subsequently, the in vitro cytotoxicity of the synthesized derivatives against the panel of Human NCI‐60 cancer cell lines alongside normal cell lines was evaluated using SRB assay. Among all the derivatives, 4 h was found to be the most potent, selective, restrict cell migration and induce apoptosis with elevated ROS levels in HCT‐116. This study emphasizes the potency of the derivatives as promising leads for the further development of potent anti‐cancer agents. [ABSTRACT FROM AUTHOR]

A simple and efficient route for the synthesis of a series of new mono/bis isoxazolines, and pyrroline linked chromone heterocyclic hybrids has been developed from 2-aminochromone via key intermediate mono and 2-(diallylamino)chromen-4-one. The intermediate subjected to the [1,3] dipolar cycloaddition with insitu generated nitrile oxides and ring-closing metathesis to generate the regio selective Isoxazolines and 3-pyrrolines. All the derivatives were screened for their anti-cancer activity (Cell viability), compared to the standard drug Imatinib. Compounds 13b and 13e, 14b and 14g showed good inhibition at 10 µM concentration. [ABSTRACT FROM AUTHOR]

Starting from two different cyano‐functionalized organoboranes, we demonstrate that 1,3‐dipolar [3+2] azide‐nitrile cycloaddition can serve to generate libraries of alkyl‐tetrazole‐functionalized compounds capable of intramolecular N→B‐Lewis adduct formation. Due to the relatively low basicity of tetrazoles, structures can be generated that exhibit weak and labile N→B‐coordination. The reaction furnishes 1‐ and 2‐alkylated regio‐isomers that exhibit different effective Lewis‐acidities at the boron centers, and vary in their optical absorption and fluorescence properties. Indeed, we identified derivatives capable of selectively binding cyanide over fluoride, as confirmed by 11B NMR. This finding demonstrates the potentialities of this synthetic strategy to systematically fine‐tune the properties of lead structures that are of interest as chemical sensors. [ABSTRACT FROM AUTHOR]

The 1,3-dipolar cycloaddition reaction of substituted dinitroacetonitriles with isoquinoline in the presence of acetylene dicarboxylic acid dimethyl ester results in the formation of a mixture of diastereomeric dimethyl 2-dinitromethyl-1,1bH-pyrimido[2,1-a]isoquinoline-3,4-dicarboxylates. The obtained compounds can be considered as promising synthons with potential antituberculosis and fungicidal activity. [ABSTRACT FROM AUTHOR]

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development. [ABSTRACT FROM AUTHOR]

New 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–d, obtained by a 1,3-dipolar cycloaddition reaction between the corresponding N-ylides of 1,10-phenanthrolinium bromides 2a–d, generated in situ and acrylonitrile as a dipolarophile, were investigated by single-crystal X-ray diffraction and computational studies to assess their druglikeness and evaluate their structure-activity properties. The non-covalent interactions present within the supramolecular landscape of the new 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines were correlated with the SAR investigations with the aim of estimating the propensity for bioactivity in these compounds. [ABSTRACT FROM AUTHOR]

Since the beginning of click chemistry, 1,2,3-triazoles has been at the center of modern organic chemistry. This versatile framework has found broad applications in organic synthesis, drug discovery, chemical biology, polymer chemistry, supramolecular chemistry, bioconjugation, fluorescent imaging, and materials sciences. Due to tremendous use of 1,2,3-triazoles in chemistry, synthesis of this moiety from the easily available chemicals is desirable. This review covers different conventional and non-conventional approaches adopted for the synthesis of 1,2,3-triazole derivatives. [ABSTRACT FROM AUTHOR]

Sixteen new 1-aryl-1,2,3-triazole linked nucleosides (7a-7i, 8a-8 g) were designed and synthesized by using Copper (I)-catalysed Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition reaction of propargylated nucleoside with substituted fluoro aryl azides in good yields. All compounds (7a-7i, 8a-8 g) were characterized by analysis their 1H NMR, 13C NMR, 2D-NMR and mass spectral data. Compounds were screened in vitro for their antibacterial activity against Xanthomonas citri pv. malvacearum, Ralstonia solanacearum, Bacillus siamensis and Pseudomonas aeruginosa. All the synthesized compounds exhibited antibacterial potential against four bacterial strains in the range of 0.318 mm to 3.596 mm. On the basis of zone of inhibition, potential of compounds against bacteria was assessed by determining the MIC value of three compounds. The results indicated that three compounds 7f, 7 g and 8f were found effective even at minimal concentration of 2 µg/ml. Therefore development of such type of new antibacterial agents is the need of time in order to overcome the problem of resistance and modification may lead to the development of new antibacterial agents.

The reaction of hydrazonoyl halides with different carbodithioate derivatives in the presence of triethylamine was studied, resulting in the synthesis of a series of unsymmetrical azine derivatives with yields ranging from 64 % to 80 %. The structures of these compounds were confirmed through spectroscopic analysis (1H NMR, 13C NMR, IR, and mass spectrometry) and elemental analysis. Quantum mechanical calculations were employed to gain deeper insights into the structural and electronic properties of these molecules. Notably, parameters such as heat of formation, net charges, and dipole moments were computed, revealing good agreement between the experimental and theoretical results. This correlation validates the theoretical calculations and further elucidates the stability and reactivity of the unsymmetrical azines. Molecular docking studies further revealed that compounds 5h and 5e achieved the highest docking scores, suggesting potential therapeutic applications. These results, supported by ADMET studies, indicate that substituted 2,3-dihydro-1,3,4-thiadiazole scaffolds hold promise for further development as therapeutic agents. This research advances the understanding of heterocyclic chemistry and underscores the potential for developing new compounds, providing promising opportunities for drug development.

A series of substituted spiro 4‐thia‐1,2,6,9‐tetraazaspiro[4.4]non‐2‐ene‐7,8‐diones were synthesized with good yields through 1,3‐dipolar substituted hydrazonoylchloride's substituted 2‐thioxoimidazolidin‐4,5‐diones under mild conditions as described. This switchable C−S and C−N bond connection with simple execution and broad substrate scope. In this study, the synthesized compounds 3 a–q were screened against four distinct cancer cell lines (PANC‐1, MIA PaCa‐2, MDA MB231 and DU145) along with a standard cell line HEK‐293, to determine their in vitro anticancer activities, and assessed using the Sulphorhodamine B assay to determine their viability [ABSTRACT FROM AUTHOR]

An efficient one‐pot synthesis of 1H‐pyrazoles has been realized via cascade cyclocondensation of β‐nitroalkenes as C2 synthon with α‐diazoesters as C1N2 unit. The reaction proceeds via concomitant formation of two new (C−N & C−C) bonds in one stretch leading to ethyl‐5‐nitro‐4‐phenyl‐4,5‐dihydro‐3H‐pyrazole‐3‐carboxylate intermediate, which undergoes base mediated denitration enabling the formation of NH−pyrazoles. This protocol not only features easy operation, catalyst−free conditions, good to high yields, wide scope and late‐stage functionalization, but also opens up a new avenue for synthetically demanding and structurally non‐traditional pyrazoles. A combination of experimental and DFT studies provide evidence for the proposed mechanism. [ABSTRACT FROM AUTHOR]

The given text is a scientific research article that explores the synthesis and characterization of various compounds using different reactions and starting materials. The compounds synthesized include isoxazolines, pyrazolines, isoxazolidines, cinnamyl- and indenyl-linked moieties, and 2-phosphorylated 2,5-dihydrofurans. The document provides detailed information on the reaction conditions, yields, physical properties, and spectroscopic data of the synthesized compounds. The information presented can be useful for researchers studying the synthesis and characterization of these compounds. [Extracted from the article]

A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized β-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60–94% of yields with excellent diastereoselectivities (10: 1−>99: 1 dr). This reaction not only realizes a concise THPI- or THIQs-based 1,3-dipolar cycloaddition, but also provides a practical strategy for the construction of two distinctive spirooxindole skeletons. [ABSTRACT FROM AUTHOR]

A three-component organocatalytic reaction of 1,3-dipolar cycloaddition between the in situ generated azomethine ylides and 3-substituted 1,2-diphenylcyclopropenes is described. The azomethine ylides have been generated via condensation of aromatic compounds (such as isatins and acenaphthenequinone) with benzylamines. The reaction has afforded derivatives of 3-azabicyclo[3.1.0]hexane, spiro-fused with the fragments of 2-oxindole and acenaphthylene-1(2H)-one. The cycloadducts have been obtained with yield up to 91%, mainly as individual diastereomers. The influence of bifunctional squaramide-based organocatalysts on the course of these three-component reactions has been investigated. Antiproliferative activity of selected synthesized compounds with respect to the human erythromyelosis (K562) and melanoma (Sk-mel-2) cell lines has been assessed in vitro by means of MTS analysis. [ABSTRACT FROM AUTHOR]

Design of spirocyclic scaffolds, which are able for direct interaction with biological targets, is a developing trend in medicinal chemistry. In continuation of the previous work on HIV‐1 inhibitors, a synthetic approach towards spiro[imidazole‐4,3′‐pyrrolo[1,2‐a]quinolin]‐5‐ones via 1,3‐dipolar cycloaddition of quinolinium ylides with arylydeneimidazol‐4‐ones was outlined. Derivatives with various substitution pattern were prepared in 42–86 % yields. Use of 2,2,2‐trifluoroethanol as a solvent is crucial for successful preparation of the derivatives, its role is sought as prolonging lifetime of the cycloadducts. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) has become a growing health problem, across all globe. Many factors have contributed into this issue, among them inappropriate lifestyle, unhealthy eating habits and growing spiritual/mental concerns are to be rated higher. Likewise much research needed to be diverted in progress for treatment of DM. Herein, we report synthesis and antidiabetic activity evaluation of ten novel phenolic derivatives of triaryl‐1,2,4‐oxadiazole 7 a–j. The compounds have synthesized using multistep reactions in acceptable purity and yields. Final step was done using 1,3‐dipolar cycloaddition reaction between various Schiff bases and arylnitrile oxides. 7 a–j were characterized by spectroscopic methods (1H NMR, 13C NMR, MS and IR) and their purities were confirmed using elemental analysis. All 7 a–j were evaluated for their α‐Glucosidase inhibitory activity. All compounds showed higher activity in inhibiting the enzyme, in comparison to standard, acarbose. Compounds 7 e and 7 g exerted the best activity with the IC50 value of 193.6 and 222.0 μM respectively. Furthermore, enzyme kinetic study approach was adopted to judge the effect of 7 e on enzyme inhibition. Finally, docking simulations revealed the possible mode of interactions between 7 e and 7 g and enzyme active sites. Final conclusion of results showed that oxadiazole scaffold/s are a potential antidiabetic target. [ABSTRACT FROM AUTHOR]

Cycloheptatrienyl (tropyl) molecules are representative non‐alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3‐dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium‐catalyzed cyclization. X‐ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character. [ABSTRACT FROM AUTHOR]

cis-5-Arylpyrrolidine-2-carboxylates, obtained by 1,3-dipolar cycloaddition reactions from glycine aryl aldimines and vinyl sulfones, undergo oxidative aromatization under the action of Mn(IV) oxide to form the corresponding 5-arylpyrrole-2-carboxylates in high yields. Factors responsible for the retention of the sulfonyl substituent in the pyrrole backbone were determined. [ABSTRACT FROM AUTHOR]

The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N–O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and enzymatic systems. This makes them valuable molecular tools for studying the structure and functions of biomolecules directly in a living cell and for functional EPR and NMR tomography in vivo. The first example of highly strained pyrrolidine nitroxides with both ethyl and tert-butyl groups at each of the α-carbon atoms of the nitroxide moiety with cis-configuration of the tert-butyl groups was prepared using a three-component domino reaction of tert-leucine and 2,2-dimethylpentan-3-one with dimethyl fumarate with subsequent conversion of the resulting strained pyrrolidine into 1-pyrroline-1-oxide and addition of EtLi. The nitroxide has demonstrated unexpectedly fast reduction with ascorbate, the rate constant k2 = (2.0 ± 0.1) × 10−3 M−1s−1. This effect was explained by destabilization of the planar nitroxide moiety due to repulsion with the two neighboring tert-butyl groups cis to each other. [ABSTRACT FROM AUTHOR]

One of the promising directions in 1,3-dipolar cycloaddition is the implementation of these reactions under organocatalysis conditions, which makes it possible to achieve not only high products yields, but also complete stereocontrol of the process. The presented review analyzes data published over the past 5 years according to the types of 1,3-dipoles involved into reactions. In a number of cases, the mechanisms of 1,3-dipolar cycloaddition reactions occurring in the presence of organocatalysts are discussed in detail. [ABSTRACT FROM AUTHOR]

Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies. [ABSTRACT FROM AUTHOR]

Naphtho[1,8-de][1,2]oxazin-4-ol and its acyl or benzyl derivatives ring open to various 2,8-dihydroxy-1-naphthonitriles, which, through (de)protection protocols and reduction, afford the target (E)-2-hydroxy-8-methoxy-1-naphthaldehyde. This was converted to its corresponding oxime, which was oxidatively o-cyclized with phenyliodine(III) diacetate (PIDA) to 9-methoxynaphtho[1,2-d]isoxazole 2-oxide. The latter, in deuterated DMSO at room temperature, was rearranged to its isomer 2-hydroxy-8-methoxy(naphthalen-1-yl)nitrile oxide. The isomerization was detected by time-course plot 1H NMR spectroscopy and further identified from its 13C NMR and HRMS spectra. The nitrile oxide was stable in (non)deuterated DMSO for at least 18 h. A 3,4-bis(2-hydroxy-8-methoxynaphthalen-1-yl)-1,2,5-oxadiazole 2-oxide, as a dimerization product or an isocyanate as a rearrangement isomer, was ruled out, the former by its HRMS spectrum and the latter by its 1,3-dipolar cycloaddition reactions to substituted isoxazoles. [ABSTRACT FROM AUTHOR]

Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using the recently proposed diffusion mixing technique, which led to ~5–15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. [ABSTRACT FROM AUTHOR]

Novel 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 6a–d were obtained by an efficient one-pot regioselective reaction between 1,10-phenanthrolinium bromides 2a–d and acrylonitrile as a dipolarophile, in the presence of triethylamine and tetrakis-pyridino-cobalt(II) dichromate (TPCD) as oxidizing agents. The optical properties of the compounds were investigated through UV–Vis spectrophotometry and steady-state photoluminescence measurements, while their structures were elucidated by single-crystal X-ray diffraction. The structural characterization revealed that the molecular structures of the four compounds were stabilized by hydrogen bonds and π–π interactions. [ABSTRACT FROM AUTHOR]

Arboviruses, including Zika (ZIKV) and Chikungunya virus (CHIKV), replicate in both arthropods and vertebrates and are transmitted through mosquito, tick, and sandfly bites. The development of specific antiviral drugs and vaccines for these viruses is limited, highlighting the importance of investigating potential drug candidates. In this study, we examined the effects of hydroxy-triazole-based compounds on the in vitro replication of ZIKV and CHIKV. Hydroxy-1,2,3-triazoles were synthesized from 4-acyl-1,2,3-triazoles, previously prepared by the cycloaddition of enaminones and aryl azides, yielding good results. Cytotoxicity assessments using Vero cells showed low toxicity for the tested compounds, with a CC50 greater than 200 µM. Among these compounds, LSO150 and LSO163 demonstrated potent inhibitory effects against ZIKV, while LSO149, LSO151, LSO155, and LSO166 showed remarkable inhibitory effects on CHIKV. These molecules exhibited 99 % inhibition of viral replication at a concentration of 20 µM, with LSO163 and LSO149 particularly effective against ZIKV and CHIKV, respectively. The compounds maintained an inhibitory potential above 80 % when added to infected cells within 8 h after infection. Further investigation into the mechanism of action revealed that LSO163 had strong activity in viral adsorption, with a dose-dependent effect of over 90 % inhibition at a concentration of 20 µM. Additionally, when combined with suboptimal doses of Ribavirin (0.5 µM), the compound LSO149 showed a strong effect on CHIKV replication, inhibiting it by over 90 %. Our results suggest that LSO163 and LSO149 have high potential as drugs against ZIKV and CHIKV.

A series of 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines containing both aryl and thienyl substituents were synthesized by exploiting the 1,3-cycloaddition reaction of N(1)-ethyl-1,2,4-triazinium tetrafluoroborates with dimethyl acetylenedicarboxylate. The antiviral activity of the synthesized compounds against influenza virus strain A/Puerto Rico/8/34 (H1N1) was studied in experiments on Madin-Darby canine kidney (MDCK) cell culture. Among the pyrrolo[2,1-f][1,2,4]triazine derivatives, compounds with low toxicity and high antiviral activity were identified. Dimethyl 4-(4-methoxyphenyl)-7-methyl-2-p-tolylpyrrolo[2,1-f][1,2,4]triazine-5,6-dicarboxylate was found to demonstrate the best antiviral activity (IC50 4 µg/mL and selectivity index 188). Based on the results of in vitro tests and molecular docking studies performed, a plausible mechanism of action for these compounds was suggested to involve inhibition of neuraminidase.

Using Ni(II) as the catalyst, electron-deficient 3,5-dimethylacryloylpyrazole olefin was reacted with C,N-diarylnitrones alone for 10 min to prepare novel five-member heterocyclic products, 4-3,5-dimethylacryloylpyrazole isoxazolidines with 100% regioselectivity and up to 99% yield. And then, taking these cycloadducts as substrates, six kinds of derivatization reactions, like ring-opening, nucleophilic substitution, addition-elimination and reduction, were studied. Experimental results showed that all kinds of transformations could obtain the target products at a high conversion rate under mild conditions, a finding which provided the basic methods for organic synthesis methodology research based on an isoxazolidine skeleton.

New 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines 5a–d, obtained by a 1,3-dipolar cycloaddition reaction between the corresponding N-ylides of 1,10-phenanthrolinium bromides 2a–d, generated in situ and acrylonitrile as a dipolarophile, were investigated by single-crystal X-ray diffraction and computational studies to assess their druglikeness and evaluate their structure-activity properties. The non-covalent interactions present within the supramolecular landscape of the new 9-cyano-pyrrolo[1,2-a][1,10]phenanthrolines were correlated with the SAR investigations with the aim of estimating the propensity for bioactivity in these compounds.

An efficient and environmentally benign synthesis of a new class of acridinedione embedded spirooxindolo/acenaphthenothiopyrrolizidines and spirooxindolo/acenathenoindolizidines has been synthesized in good to excellent yields employing ionic liquid accelerated one-pot [3 + 2]-cycloaddition strategy. The pre-requisite starting substrates, O-acryloyl acridinediones were prepared from dimedone in three good yielding steps, while the 1,3-dipole was derived in situ from isatin/acenaphthenequinone and thiazolidine-4-carboxylc acid/l-pipecolinic acid via decarboxylative condensation. The cycloadduct possesses three stereogenic carbons, one of which is a spiro carbon through the formation of two C–C and one C–N bonds in one-pot synthetic transformation. Geometrical parameters of the synthesized compounds were calculated using the B3LYP/6-311g(d,p) level of theory. The activity of these molecules was evaluated against main protease of COVID-19 to screen them for their inhibitor efficiency. In order to get a broad understanding of the interactions of these synthesized ligands, a detailed molecular docking analysis was performed. Molecular docking analysis shows that compound 8b has the highest binding affinity toward the protein. The compound can be a potential candidate for the treatment of COVID-19.

This document provides a detailed account of the synthesis and characterization of various compounds, specifically aminobenzothiazole-fused spirooxindole derivatives. The compounds were synthesized using a three-component 1,3-dipolar cycloaddition reaction and were found to have high yields and specificity. The document also includes information on the chemical properties of the compounds, as well as in vitro enzyme inhibition assays and molecular docking simulations. The findings suggest that these compounds have potential applications in the field of medicinal chemistry. [Extracted from the article]

A series of 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines containing both aryl and thienyl substituents were synthesized by exploiting the 1,3-cycloaddition reaction of N(1)-ethyl-1,2,4-triazinium tetrafluoroborates with dimethyl acetylenedicarboxylate. The antiviral activity of the synthesized compounds against influenza virus strain A/Puerto Rico/8/34 (H1N1) was studied in experiments on Madin-Darby canine kidney (MDCK) cell culture. Among the pyrrolo[2,1-f][1,2,4]triazine derivatives, compounds with low toxicity and high antiviral activity were identified. Dimethyl 4-(4-methoxyphenyl)-7-methyl-2-p-tolylpyrrolo[2,1-f][1,2,4]triazine-5,6-dicarboxylate was found to demonstrate the best antiviral activity (IC50 4 µg/mL and selectivity index 188). Based on the results of in vitro tests and molecular docking studies performed, a plausible mechanism of action for these compounds was suggested to involve inhibition of neuraminidase. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sphodroxia maroccana Ley is a pest of cork oak crops that damages the roots of seedlings and can severely impair cork oak regeneration. Since the banning of carbosulfan and chlorpyriphos, which were widely used against the larvae of Sphodroxia maroccana because of their harmful impact on the environment, until now there has been no pesticide against these pests. Therefore, it is particularly urgent to develop highly effective insecticidal molecules with novel scaffolds. Isoxazolines are a class of insecticides that act on γ‐aminobutyric acid (GABA)‐gated chloride channel allosteric modulators. In this work, a green synthesis of novel 3,5‐disubstituted isoxazoline‐sulfonamide derivatives was achieved in water via ultrasound‐assisted four‐component reactions, and their insecticidal activities against fourth‐instar larvae of S. maroccana were evaluated. RESULTS: Most of the tested compounds showed insecticidal activity compared to fluralaner as positive control and commercially available insecticide. Especially, the isoxazoline‐secondary sulfonamides containing halogens (Br and Cl) on the phenyl group attached to the isoxazoline, 6g (LC50 = 0.31 mg/mL), 6j (LC50 = 0.38 mg/mL), 6k (LC50 = 0.18 mg/mL), 6L (LC50 = 0.49 mg/mL), 6m (LC50 = 0.24 mg/mL), 6q (LC50 = 0.46 mg/mL), exhibited much higher larvicidal activity than fluralaner (LC50 = 0.99 mg/mL). CONCLUSION: Novel isoxazolines containing sulfonamide moieties were designed, synthesized and confirmed by two single‐crystal structures of 4e and 6q. Their bioassay results showed significant larvicidal activity with significant morphological changes in vivo. These results will lay the foundation for the further discovery and development of isoxazoline‐sulfonamide derivatives as novel crop protection larvicides of cork oak. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The stereodivergent asymmetric synthesis of 2,5‐trans/cis pyrrolidines by 1,3‐dipolar cycloaddition using two different types of activated alkenes is described. When ylidene‐isoxazolones were employed as dipolarophiles, the Ag/(S,Sp)‐iPr‐FcPHOX‐catalyzed asymmetric [3+2] cycloaddition of imino lactones proceeded with 2,5‐trans selectivity. Subsequent decarboxylation of the isoxazolone rings produced pyrrolidines with 2,5‐trans stereoretention. In the reaction using acyclic enones as activated alkenes, the Ag/(R,Sp)‐ThioClickFerrophos complex‐catalyzed asymmetric [3+2] cycloaddition afforded 2,5‐cis substituted pyrrolidines in high yields and enantioselectivities. Therefore, these methods can be considered as a formal stereodivergent synthesis of 2,5‐cis/trans pyrrolidines. [ABSTRACT FROM AUTHOR]

Nitrile imine derivative 3 added regioselectively to α-(benzothiazol-2-yl)cinnamonitrile derivatives 1a–c to afford 5-(benzothiazol-2-yl)-5-cyano-4,5-dihydro-1H-pyrazole derivatives 4a–c. Compound 4a underwent thermal elimination of hydrogen cyanide in sodium ethoxide solution to give the pyrazole derivative 6. The isoxazole derivative 10 was synthesized by reacting nitrile oxide 8 with cinnamonitrile derivative 1d. The structures of the synthesized compounds were characterized by FT-IR, NMR, and MS spectroscopic techniques. The reaction mechanism was studied via density functional theory (DFT) quantum chemical calculations at the B3LYP/6-31G (d) level of theory. [ABSTRACT FROM AUTHOR]

Green chemistry, which is an application of a set of principles to decrease or eliminate the use or creation of hazardous chemicals in the design, manufacture, and use of chemical commodities, is one of the most appealing concepts in chemistry for sustainability. Green chemistry has grown in popularity as a consequence of the understanding that environmentally friendly products and methods save mother nature over time. A fundamental key of synthetic chemistry is the creation of ecologically acceptable methods for the synthesis of organic molecules. In many biological applications, new molecules have been synthesized using environmentally friendly processes throughout the past few decades. It is also observed that, in the cycloaddition processes, nature-friendly approaches were focused significantly to avoid environmental pollution caused by toxic solvents and other additives. Hence, we as responsible chemists highly motivated to showcase the green synthetic methods adopted for cycloaddition reactions. In this study, we have reviewed nature-friendly methods utilized for the synthesis of new compounds via Diels–Alder and 1,3-dipolar cycloaddition reactions. [ABSTRACT FROM AUTHOR]