Nitrile Oxides Research Articles

General Alkene 1,2-syn-Cyano-Hydroxylation Procedure Via Electrochemical Activation of Isoxazoline Cycloadducts.

Stereoselective alkene 1,2-difunctionalization is a privileged strategy to access three-dimensional C(sp3)-rich chiral molecules from readily available "flat" carbon feedstocks. State-of-the-art approaches exploit chiral transition metal-catalysts to enable high levels of regio- and stereocontrol. However, this is often achieved at the expense of a limited alkene scope and reduced generality. 1,3-Dipolar cycloadditions are routinely used to form heterocycles from alkenes with high levels of regioselectivity and stereospecificity. Nevertheless, methods for the ring-opening of cycloadducts to reveal synthetically useful functionalities require the use of hazardous reagents or forcing reaction conditions; thus limiting their synthetic applications. Herein, we describe the implementation of a practical, general and selective electrosynthetic strategy for olefin 1,2-syn-difunctionalization, which hinges on the design of novel reagents-consisting of a nitrile oxide 1,3-dipole precursor, equipped with a sulfonyl-handle. These can selectively difunctionalize alkenes via "click" 1,3-dipolar cycloadditions, and then facilitate the telescoped electrochemical single electron transfer activation of the ensuing isoxazoline intermediate. Cathodic reduction of the cycloadduct triggers a radical fragmentation pathway delivering sought-after stereodefined 1,2-syn-hydroxy nitrile derivatives. Our telescoped electrochemical procedure tolerates a wide range of functionalities, and─crucially─enables the difunctionalization of both electron-rich, electron-poor and unactivated olefins, with diverse degree of substitution; thus providing a robust, general and selective metal-free alternative to current alkene difunctionalization strategies. Capitalizing on these features, we employed our electrosynthetic method to enable the late-stage syn-hydroxy-cyanation of natural products and bioactive compounds, and streamline the de novo synthesis of pharmaceutical agents.

1,3-Dipolar Cycloaddition of Nitrile Oxides and Nitrilimines to (-)-β-Caryophyllene: Stereoselective Synthesis of Polycyclic Derivatives and Their Biological Testing.

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.

One‐Pot Synthesis of Fused Isoxazolo[4′,5′:3,4]pyrrolo[2,1‐b] Quinazolines as Potent EGFR Targeting Anticancer Agents

AbstractIn response to the need for scaffolds for medical applications, synthetic chemists have developed simple and efficient methods for optimal synthesis. To investigate the synthesis of fused isoxazoles in the presence of [3+2] cycloaddition followed by C−N bond formation reaction between 3‐((4‐iodo‐3‐phenylisoxazol‐5‐yl)methyl)quinazolin‐4(3H)‐one and various nitrile oxides was carried out by previously reported conditions. The cancer activities of the synthesized compounds were then tested in vitro against two cancer cell lines, MCF‐7 and A‐549. Three of the compounds, 3‐(3,5‐dichlorophenyl) isoxazolo[4′,5′:3,4]pyrrolo[2,1‐b]quinazolin‐9(11H)‐one, 3‐(4‐fluorophenyl)isoxazolo[4′,5′:3,4]pyrrolo[2,1‐b]quinazolin‐9(11H)‐one, and 3‐(4‐(trifluoromethyl)phenyl)isoxazolo[4′,5′:3,4] pyrrolo[2,1‐b] quinazolin‐9(11H)‐one has shown superior activity against the non‐small‐cell lung cancer cell line (A‐549) than the standards 5‐fluorouracil and erlotinib. Later, in vitro EGFR results revealed that a more potent compound was more effective than the conventional medicine, erlotinib. In silico investigations of more potent compounds and erlotinib on the EGFR protein indicated that more potent compounds had comparable binding energies and inhibition constants to erlotinib.

One-pot synthesis of fused isoxazolo[4′,5′:4,5]thiopyrano[2,3-d]pyrimidines as potent EGFR targeting anti-lung cancer agents

The requirement for scaffolds has prompted synthetic chemists to devise simple and effective methods for optimal synthesis, which are critical in the medical industry. Under comparatively optimized conditions, a click followed by a CC bond coupling reaction between iodoalkyne (4) and substituted nitrile oxide was utilized to explore the synthesis of fused isoxazoles containing thiopyrano[2,3-d]pyrimidine under microwave irradiation. The synthesized compounds were tested for their anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H460 and A549). The compounds 6i and 6l have shown more potent activity against both cancer cell lines as compared to standard drugs doxorubicin and erlotinib. And also compounds 6e, 6j, and 6k have shown more potent activity as compared to Doxorubicin and moderate activity compared to erlotinib. Later, in vitro EGFR results of more potent compounds revealed that compounds 6l and 6k have shown potent EGFR activity compared to standard erlotinib. To evaluate the molecular interactions of more potent compounds with the human epidermal growth factor receptor. It was observed that all the potent compounds exhibited greater binding energies in comparison to the standard drug erlotinib.

Facile synthetic route to isoxazoles from β-sulfinyl- and β-sulfonyl-cyclohexenones via regioselective nitrile oxide cycloaddition and in-situ elimination

A facile synthetic route to isoxazole is reported. Through examination of the reaction of stable nitrile oxides, β-substituted cyclohexenones, particularly sulfinyl and sulfonyl derivatives, show excellent regioselectivity in the 1,3-dipolar cycloaddition, forming isoxazoline cycloadducts, which undergo in-situ 1,2-elimination either with the assistance of a base (for the β-sulfonyl derivative) or without the need for a base (for the β-sulfinyl derivative), enabling a direct, high-yield access to isoxazoles.

Synthesis and photooxygenation of 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles: facial selectivity.

Two 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles were synthesized by 1,3-dipolar cycloaddition of the corresponding nitrile oxides with cycloheptatriene. Two endoperoxides were synthesized as facially selective and single products in high yields (93%-95%) from the reactions of isoxazole derivatives with singlet oxygen. The exact configurations of the endoperoxide with a methyl group in the phenyl ring and the diol synthesized from it were confirmed by X-ray analysis. To elucidate the mechanism, the formation energy of the endoperoxide was investigated by simulations using the software package Gaussian 09 and density functional theory calculations via the M06-2X/6-311+G(d,p) level method in dichloromethane. The results were consistent with experimental findings showing the formation of isoxazole products.

Deciphering the cytotoxic and antioxidant potential of 3,5-disubstituted isoxazole-linked benzimidazolone derivatives

A series of new isoxazole derivatives containing a benzimidazolone has been synthesized by cycloaddition reaction using various nitrile oxides. In all cases, these cycloadditions are completely chemo and regioselective. The structures of the new cycloadducts were characterized by 1H, 13C NMR spectroscopy, HRMS and confirmed in one case by a single crystal structure determination. The isoxazole compounds were evaluated for in vitro antioxidant activity using the DPPH and ABTS methods. As a result, compound 5a showed good antioxidant activity. The results of the acute toxicity study of the heterocycles studied by the oral route showed no deaths and no clinical signs of toxicity. Additionally, the Hirshfeld surface analysis and the molecular electrostatic potential using density functional theory (DFT) modeling at the B3LYP/6–31G(d,p) level. Hirshfeld surface analysis (dnorm surface and 2D-fingerprint plots) revealed the nature of intermolecular contacts. H⋯H interactions make the most significant contribution to crystal packing. The optimized structural parameters obtained through DFT calculations closely matched those determined via X-ray analysis, demonstrating strong agreement between theoretical predictions and experimental observations.

1,3-Dipolar Cycloaddition Reaction of Nitrile Oxide to Thiocyanates: An Efficient and Eco-Friendly Synthesis of N-Aryl-2-((3-aryl-1,2,4-oxadiazol-5-yl)thio)acetamides

AbstractAn 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.

The Active Chlorine Mediated Electrochemical Synthesis of Aromatic Nitriles through Cascade Reaction

An efficient and transition-metal-free synthesis strategy of aromatic nitriles from corresponding aldehydes with H2SO4(NH2OH)2 as the nitrogen source and Cl−/ClO− as the redox mediator was developed. The redox Cl−/ClO− showed electrochemical reversibility in acidic condition. The possible mechanism involving the transformation of Cl−, the generation and electrochemical reduction of nitrile oxides based on the results of cyclic voltammetry and constant current electrolysis was proposed.

A quantum mechanistic investigation into the unusual reactions of nitrilimine and nitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone.

The theoretical study investigates the [3 + 2] cycloaddition (32CA) reactions between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone and benzonitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone. Nitrilimines and nitrile oxides are dipoles used in the synthesis of several heterocyclic compounds, including spiropyrazoline oxindoles and isoxazolines. The derivatives of these compounds are found with different biological activities, such as ion channel blockers, anti-inflammatory and anticancer agents as well as antimalarial. Conceptual density functional theory (CDFT) analysis, along with the activation energies of the 32CA reaction between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone, demonstrates concordance with the empirical findings. The 32CA reaction is found to proceed through a very polar single-step asynchronous mechanism. While deductions from the activation energies of the 32CA reaction between benzonitrile oxide and 2,3,4,5-tetraphenylcyclopentadienone are found to lead to the experimental product, the parr function analysis could not explain the observed chemo- and regioselectivity. This 32CA reaction is also found to proceed through a one-step asynchronous mechanism, though with a non-polar character. The modulation of substituents positioned at the reactive sites of the reactants is found to influence the kinetics, thermodynamics, and CDFT parameters of the two 32CA reactions, consequently impacting the observed selectivities. The 32CA reactions between C, N-diphenyl nitrilimine with 2,3,4,5-tetraphenylcyclopentadienone and benzonitrile oxide with 2,3,4,5-tetraphenylcyclopentadienone have been explored theoretically using the density functional theory method at the hybrid ωB97X-D coupled with the split valence triple-ξ (TZ) basis set as implemented in the Gaussian 09. Solvent effects were taken into account by full optimization of the gas phase geometries through the polarizable continuum model developed within the self-consistent reaction field.

Harnessing Gold(I)-Catalyzed Hydroamination/1,3-Sulfonyl Migration Cascade for Divergent Synthesis of Isoxazolidine and Isoxazoline from O-Alkynyl Hydroxylamine.

Gold-catalyzed 5-exo-dig hydroamination on O-homopropargylic hydroxylamine gave expeditious access to methylene isoxazolidine. Excess catalyst loading led to facile 1,3-sulfonyl migration in a cascade fashion to furnish the isoxazoline. Mechanistic studies using react-IR and NMR as well as crossover experiments indicated that 1,3-sulfonyl group migration is an intramolecular concerted process. The ene-hydroxylamine moiety also underwent dipolar cycloaddition reactions with nitrile oxide and nitrones leading to the first examples of spirocyclic bis-isoxazolidine derivatives.

Exploring the specific chemistries of the cycloaddition reactions of 5‐benzoyl‐3(2H)‐isothiazolone and stable nitrile oxides: Insights from Density Functional Theory analysis

AbstractIsothiazolones are important heterocyclics with pharmacological potency such as anti‐inflammatory, anticancer, antimicrobial, and robust biocidal (used in agrochemicals). This study seeks to provide mechanistic insight into the chemo‐ and regio‐selectivities of the [3 + 2] cycloaddition reaction of 5‐benzoyl‐3(2H)‐isothiazolone (A1) with two stable nitrile oxides, that is, mesitonitrile oxide (A2) and dichlorobenzonitrile oxide (A3) using M06‐2X hybrid density functional calculations coupled with the 6‐311G (d, p) basis sets. Mesitonitrile oxide A2 chemo‐selectively adds across the carbonyl of the benzyl group of A1 while dichloro benzonitrile oxide A3 preferentially adds across the ethylene center of A1. Derivatization of A1 with electron‐donating groups lowers the activation barriers by a very minute margin ranging from 0.1 to 0.5 kcal/mol whereas electron‐withdrawing groups significantly decrease the energetics of the reaction by a margin of 1.1 to 2.5 kcal/mol. Solvation with chloroform does not affect the selectivity of the reaction but tends to increase both activation and reaction energies of the various routes. Analysis of the Parr function on different reactive sites of A1 shows the addition of A2 via the atomic center with the largest Mullikan atomic spin densities. Substitution of the S‐heteroatom with C, O, or N does not affect the regioselectivity of the reaction but lowers the activation energies in the reaction of A1 with A3. The global electron density transfer (GEDT) values predict a polar reaction between A1 and A2 whereas the reaction of A1 and A3 is non‐polar.

Design and synthesis of mono/bis isoxazoline and pyrroline pendant chromone derivatives-anti-cancer activity

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.

Synthesis, molecular docking, molecular dynamics and ADMET prediction studies of novel (S)-Verbenone-Arylidene -Isoxazoline hybrids

The main objective of this work was to develop novel hybrid compounds from naturally occurring (S)-Verbenone. This last was used as a starting material to prepare new isoxazoline-verbenone-arylidene hybrids in two steps. All targeted compounds as well as their intermediates were fully characterized by 1H-, 13CNMR and HRMS spectroscopic techniques. Then, a DFT study was carried out to understand the reactivity between the verbenone-arylidene as a source of two dipolarophiles with nitrile oxides. Finally, in silico molecular docking method was carried out to analyze the interactions of the prepared compounds with EGFR and Bcl-2 proteins. Moreover, the best-docked protein-ligand complexes was assessed using molecular dynamic simulation.

Toward the Briarane Core via 1,3-Dipolar Cycloaddition.

The complete C20 framework of brianthein W was established, featuring hydroboration/allylation, to provide the C1-C2 quaternary/tertiary stereoarray with excellent stereocontrol. Intramolecular nitrile oxide cycloaddition (INOC) was adopted as the key transformation to establish the trans-fused 6/10-bicyclic ring system. Evolution of the second INOC event revealed the intricacies governing regioselectivity, which ultimately led to construction of the highly strained 10-membered carbocycle.

Rational construction of perylenequinone annulated porphyrins via cycloaddition reactions

Acenequinone-fused porphyrins show remarkable long wavelength absorption, low-lying LUMO orbital and uniform π,π-stacking, enabling the potential applications as opto-electronic materials and catalysts. At present, the synthesis of large quinone fused porphyrins remains challenging. To address this, the cycloaddition reactions of naphthoquinone-fused porphyrin (Ni4NQ), followed by oxidative aromatization, have been employed. Through Diels-Alder reaction with perylenes in the presence of chloranil, a series of perylenequinone-fused porphyrins (1Ni–4Ni) have been synthesized with an overall yield above 70 %. Later, the tri-adduct 3Ni underwent 1,3-dipolar cycloaddition with nitrile oxide and the following DDQ oxidation to outcome the unsymmetrical tetra-adduct 5Ni. Although the peripheral perylenequinones fusion in 1Ni–4Ni has limited impact on the absorption with respect to the naphthoquinone-fused counterpart Ni4NQ, introduction of an isoxazole via 1,3-cycloaddition (5Ni) leads to a bathochromic Q band. This result has been rationalized by theoretical calculations. Additionally, the incorporation of perylenequinone units gives rise to intense intermolecular π,π-stacking and CH-π interactions within the crystal packing. The self-assembly behavior using a good/bad solvent strategy are structural dependence. The tri-perylenequinone-fused porphyrins 3Ni formed spherical architecture, while tetraperylenequinone-fused porphyrin 4Ni afforded cubic or petal-type assemblies.

Spontaneous resolution of diastereomeric glycosyl isoxazolines: A combined theoretical and experimental study in solution and in the crystalline form

In this study, a glycosyl isoxazoline has been prepared by cycloaddition of phenyl nitrile oxide to 6-O-allyl galactopyranose. Crystallization of the galactosyl isoxazoline resulted in the spontaneous resolution of its two diastereomers. Their conformational behavior has been studied in solution and in crystalline form by NMR and X-ray diffraction analysis showing that both diastereomers have essentially the same OS2 conformation. To complete the study of the diastereomeric isoxazolines, Density Functional Theory was applied. The theoretical and experimental 1H NMR, as well as 13C NMR chemical shifts, showed very good correlation. Furthermore, structures resulting from X-ray analysis provided excellent starting points for DFT calculations.

Acridine-Isoxazole and Acridine-Azirine Hybrids: Synthesis, Photochemical Transformations in the UV/Visible Radiation Boundary Region, and Anticancer Activity.

Easy-to-handle N-hydroxyacridinecarbimidoyl chloride hydrochlorides were synthesized as convenient nitrile oxide precursors in the preparation of 3-(acridin-9/2-yl)isoxazole derivatives via 1,3-dipolar cycloaddition with terminal alkynes, 1,1-dichloroethene, and acrylonitrile. Azirines with an acridin-9/2-yl substituent attached directly or via the 1,2,3-triazole linker to the azirine C2 were also synthesized. The three-membered rings of the acridine-azirine hybrids were found to be resistant to irradiation in the UV/visible boundary region, despite their long-wave absorption at 320-420 nm, indicating that the acridine moiety cannot be used as an antenna to transfer light energy to generate nitrile ylides from azirines for photoclick cycloaddition. The acridine-isoxazole hybrids linked at the C9-C3 or C2-C3 atoms under blue light irradiation underwent the addition of such hydrogen donor solvents, such as, toluene, o-xylene, mesitylene, 4-chlorotoluene, THF, 1,4-dioxane, or methyl tert-butyl ether (MTBE), to the acridine system to give the corresponding 9-substituted acridanes in good yields. The synthesized acridine-azirine, acridine-isoxazole, and acridane-isoxazole hybrids exhibited cytotoxicity toward both all tested cancer cell lines (HCT 116, MCF7, and A704) and normal cells (WI-26 VA4).

Cascade Rearrangement: Nitro Group-Participating Syntheses of 1,2,5-Thiadiazoles and 1,2,4-Thiadiazolones.

A trifluoroacetic anhydride-mediated cascade process for the synthesis of thiadiazole derivatives is described. 1,2,5-Thiadiazoles and 1,2,4-thiadiazolones could be obtained by variation of the reaction conditions. A group of functionalized thiadiazole derivatives were synthesized in moderate to good yields from nitro-group-containing N-tert-butanesulfinamides. The reactions involved in this tandem process are a Pummerer-like rearrangement of the tert-butanesulfinamide unit, a nitrile oxide formation via nitro group rearrangement, addition of oxygenated nucleophiles, and an N-S bond forming cyclization followed by concomitant elimination.

Functionalization of Alkenes with Difluoromethyl Nitrile Oxide to Access the Difluoromethylated Derivatives.

Electron-rich, electron-deficient, and non-activated alkenes can be rapidly functionalized by in situ-generated difluoromethyl nitrile oxide. The (3+2) cycloaddition proceeds at room temperature, has broad functional group tolerance, and can be used for the late-stage modification of bioactive molecules (finasteride and carbamazepine). The obtained CF2H-isoxazolines can be easily transformed into CF2H-containing building blocks for medicinal chemistry: amines, amino acids, amino alcohols, and spirocyclic scaffolds.