Nitrile Oxides Research Articles

Nitrile oxide cycloaddition reactions of alkenes or alkynes and nitroalkanes substituted with O-alkyloxime groups convertible to various functional groups

Nitrile oxides, which are easily generated in situ from widely available nitroalkanes, can be used to directly access 2-isoxazoline heterocycles through 1,3-dipolar cycloaddition reactions with alkenes. These heterocycles are not only useful core fragments in pharmaceutical and agricultural chemistry, but also valuable building blocks convertible to multifunctional groups, such as β-hydroxy ketones. Herein, we have developed nitrile oxide cycloaddition reactions between nitrile oxides derived from O-alkyloxime-substituted nitroalkanes and various alkenes. This methodology can be applied to construct 2-isoxazolines possessing electron-withdrawing groups, which are difficult to access using the conventional approach.

Synthesis, characterization, and biological evaluation of new heterocyclic systems 1, 2, 3-triazole-isoxazoline from eugenol by the mixed condensation reactions

We report the synthesis of new series of heterocyclic systems eugenol 1 derivatives by the mixed condensation reaction of 1,3-dipolar azide and the oxide of p-chlorophenylnitrile on the 4-allyl-2-methoxy-1-(prop-2-yn-1-yloxy)benzene 2. The mono and bicycloadducts, whose structure is homologous to compounds having a broad spectrum of activity, were obtained in good yields. The monocondensation reaction of azides on 4-allyl-2-methoxy-1-(prop-2-yn-1-yloxy)benzene 2 is completely chemoselective, regioselective and stereospecific. The condensation of nitrile oxide on 1,2,3-triazole monocycloadducts prepared was chemoselective and regioselective. The structure of all cycloadducts were characterized and confirmed by the 1H, 13C, 2D nuclear magnetic resonance and mass spectrometry analysis. All the newly synthesized mono and bis-heterocyclic compounds have been selected for their antiproliferative activity against HT-1080 fibrosarcoma, A549 lung carcinoma, and MCF-7 and MDA-MB-231 breast carcinoma cell lines. Among the derivatives, only the compounds 4a, 4b, 5a, 5b, 5d, 5e and 5g showed significant cytotoxicity with IC50 values ranging from 15.31 to 18.81 µM against HT-1080 cells, and 17.32 to 25.94 µM against the other cell lines.

Facile synthesis of tricyclic isoxazole-fused benzo[b]thiophene 1,1-dioxide derivatives via 1,3-dipolar cycloaddition

A facile and efficient [3 + 2] 1,3-dipolar cycloaddition reaction of nitrile oxides generated in situ from hydroximoyl chlorides with benzo[b]thiophene 1,1-dioxides has been achieved for rapid access to tricyclic isoxazole-fused benzo[b]thiophene 1,1-dioxide derivatives in excellent yields (up to 98%) with high diastereoselectivities (dr > 19:1). The present process is characterized by mild reaction conditions and broad substrate scope. The conversion of the cycloadduct to other useful structure has also been achieved. The chemical structures of the typical compounds were confirmed by X-ray single-crystal structure analysis.

The Theoretical Study on the Mechanism of [3+2] Cycloaddition Reactions between α,β-unsaturated Selenoaldehyde with Nitrone and with Nitrile Oxide

Abstract. The reaction mechanisms of [3+2] cycloaddition (32CA) between the α,β-unsaturated selenoaldehyde with nitrone and nitrile oxide were investigated theoretically using the molecular electron density theory (MEDT). Selenoaldehyde has two unsaturations which allow for the cycloaddition occurring. It was expected to undergo four regioisomeric reaction paths in two separate reactions with nitrone and nitrile oxide. The study was conducted using ab initio approach at MP2/6-31G(d) level of theory. Potential energy surfaces were generated from the energies of the stationary points involved in the mechanisms and the dominant reaction pathways were identified. It was found that Pathway 3 and 4 are the two competing reaction channels, where the cycloaddition reaction occurs at the selenium-analogue carbonyl group of selenoaldehyde. The reactivity indices were analysed at the ground state of the reactants to predict the reactivity of studied organic molecules in 32CA reactions. Analysis of the electronic structure of nitrone and nitrile oxide, the three-atom-components (TACs), and their participation in 32CA reactions towards selenoaldehyde allows establishing a useful classification of 32CA reactions into zwitterionin-type (zw-type) reactions involving TACs with a high zwitterionic character. 
 Resumen. Se estudia teóricamente, utilizando la teoría de la densidad electrónica molecular (MEDT), el mecanismo de reacción de la cicloadición [3+2] (32CA) entre selenoaldehídos α, β insaturados con nitrona y óxido de nitrilo. El selenoaldehído tiene dos insaturaciones que permiten la cicloadición. Se esperaba que la reacción se llevara a cabo a lo largo de cuatro caminos regioisoméricos en dos reacciones separadas con la nitrona y el óxido de nitrilo. Se realizó un estudio ab initio con el nivel de teoría MP2/6-31G(d). Se generaron superficies de energía potencial a partir de las energías de los puntos estacionarios involucrados en el mecanismo y se identificaron los caminos de reacción dominantes. Se encontró que dos rutas, la 3 y la 4, son los canales de reacción que compiten para que ocurra la cicloadición en el grupo carbonilo análogo al selenio del selenoaldheído. Se analizaron los índices de reactividad de los estados basales de los reactivos para predecir la reactividad de las moléculas orgánicas estudiadas en las reacciones 32CA. El análisis de la estructura electrónica de la nitrona y el óxido de nitrilo, de las componentes triatómicas (TACs) y de su participación en las reacciones 32CA hacia el selenoaldheído permite clasificar a las reacciones 32CA en tipo zwitteriónico (zw) que involucran a los TACs con un elevado carácter zwitteriónico.

Synthesis and cytotoxicity of novel 14α-O-(andrographolide-3-subsitutedisoxazole-5-carboxylate) derivatives

Simple and efficient method was established for the synthesis of a new family of 14α-O-(andrographolide-3-subsitutedisoxazole-5-carboxylate) derivatives (10a-j) from naturally occurring andrographolide (1) by selective esterification with propiolic acid at C-14 using protection and deprotection strategy followed by metal free 1,3-dipolar cycloaddition with aryl nitrile oxides. All the synthesised derivatives were tested for their cytotoxicity against HCT-15, HeLa and DU145 cell lines. Most of the compounds exhibited improved cytotoxic activity compared to the parent molecule andrographolide (1), as the compounds 10b, 10c, 10i, 10j, 11d and 11f showed significant cytotoxicity against three cancer cell lines. Except the compound 10b and 11d, all the compounds did not inhibit the normal cell line (VERO). Based on these studies isoxazole ester derivatives at C-14 of andrographolide with various substitutions promoting anticancer activities and better safety profiles. Further studies in this direction with improved water solubility and oral bioavailability are in progress in future.

1,3-Dipolar cycloaddition of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones and nitrile oxides: An experimental and theoretical investigation

Cycloaddition reactions of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones proceeds regio- and stereoselectively on the double bond of the N-allyl substituent giving substituted isoxazolidines with good yields. Regioselectivity of the cycloaddition of this dipolarophiles with nitrile oxides depends on the structure of unsaturated hydrocarbon scaffold and the reaction selectively leads to adducts on endocyclic or the double bond of the N-allyl substituent. DFT calculations were used to investigate the reasons of the selectivity.

A simple approach to prepare isoxazoline-based porous polymer for the highly effective adsorption of 2,4,6-trinitrotoluene (TNT): Catalyst-free click polymerization between an in situ generated nitrile oxide with polybutadiene

• Click polymerization was used for efficient adsorption of TNT. • The synergistic effect of dipole-π interaction and π-π interaction was applied. • The maximum adsorption capacity at 298 K was up to 177.3 mg/g within 4 h. • The isoxazoline-based porous polymer was reversible and could be reused. • No metal ion catalyst was added to the reaction to avoid secondary contamination. This paper presents the application of click polymerization between an in situ generated nitrile oxide and polybutadiene leading to an isoxazoline-based porous polymer for the adsorption of 2,4,6-trinitrotoluene (TNT). Because the synergistic effect of dipole–π interaction and π–π interaction enlarges the binding area between the organic porous polymer and TNT, the resulting adsorbent exhibited efficient adsorption of TNT in water. The adsorption kinetics fit well with the pseudo-second-order model, and adsorption equilibrium could be achieved in 4.0 h. The Langmuir model exhibited better correlation for equilibrium data analysis, and the maximum adsorption capacity at 298 K was as high as 177.3 mg/g. The adsorption capacity remained relatively high after five desorption–adsorption cycles for acetone eluent. Additionally, no metal ion catalyst was added to this reaction, thereby avoiding secondary pollution. This click polymerization provides a simple, yet highly effective, method for the preparation of porous organic polymers to be used in the efficient adsorption of TNT, and the synergistic effect is believed to be a novel rationale for the design of TNT adsorption materials.

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory

The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having a different reactivity. The analysis of the conceptual Density Functional Theory (DFT) indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting MEDT as the theory able to explain chemical reactivity in Organic Chemistry.

Synthesis of amide‐linked benzazolyl isoxazoles adopting green methods and evaluation as antimicrobials

AbstractSome new benzoxazolyl isoxazoles, benzothiazolyl isoxazoles and benzimidazolyl isoxazoles connected by amide bonds (7‐9) were prepared from N‐benzazolylcarbamoylmethylcinnamamides (1‐3) adopting eco‐friendly synthetic methodologies. In fact, cycloaddition of nitrile oxide generated from araldoxime using iodosobenzene and cetyltrimethylammonium bromide to 1‐3 followed by treatment with iodine in dimethyl sulfoxide led to the formation of title compounds with good yields and in shorter reaction times. The structures of all the synthesized compounds were confirmed by spectral parameters, viz, IR, NMR, and mass spectra and were assayed for antimicrobial activity. Among all the tested compounds, 8a and 8c displayed excellent antibacterial activity, whereas 9a and 9c showed promising antifungal activity.

Iron Nitrate-Mediated Selective Synthesis of 3-Acyl-1,2,4-oxadiazoles from Alkynes and Nitriles: The Dual Roles of Iron Nitrate.

A direct strategy for the selective synthesis of 3-acyl-1,2,4-oxadiazoles from alkynes and nitriles has been developed under iron(III) nitrate-mediated conditions. The mechanism includes three sequential procedures: iron(III) nitrate-mediated nitration of alkynes leads to α-nitroketones, dehydration of α-nitroketones provides the nitrile oxides, and 1,3-dipolar cycloaddition of nitrile oxides with nitriles produces 3-acyl-1,2,4-oxadiazoles under iron-mediated conditions. Iron(III) nitrate plays dual roles in the nitration of alkynes and the activation of nitriles, while the formation of pyrimidine/isoxazole byproducts can be efficiently inhibited.

Synthesis of Strophasterols C, E, and F.

The synthesis of strophasterols C, E, and F has been accomplished from a 14,15-secoergostane derivative via a 1,3-dipolar cycloaddition of a nitrile oxide intermediate to simultaneously install an isolated cyclopentane ring and a C23 oxygen functionality in a diastereoselective manner and a regio- and diastereoselective selenohydroxylation of an olefinic intermediate under thermodynamic conditions. This synthesis also enabled the stereochemical confirmation of strophasterol C.

Toxicities of 4,5-Dihydroisoxazoles Against Root-Knot Nematodes and in Silico Studies of Their Modes of Action.

The present work sought to contribute to the development of new nematicides. Benzaldehydes were initially converted to nitrile oxides that underwent 1,3-dipolar cycloaddition reactions with methyl acrylate to generate 4,5-dihydroisoxazoles. In in vitro tests, methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (1) and methyl 3-(4-chlorophenyl)-4,5-dihydroisoxazole-5-carboxylate (4) increased the mortality of Meloidogyne exigua and Meloidogyne incognita second-stage juveniles (J2). Compounds 1 and 4 presented necessary concentrations of 398 and 501 μg mL-1, respectively, to kill 50% of M. incognita J2 (LC50 values), while the value for carbofuran (positive control) was 168 μg mL-1. In in vivo tests, compounds 1 and 4 reduced the number of M. incognita galls in tomato roots by 70 and 40%, respectively, and the number of eggs by 89 and 44%. Using an in silico approach, we showed that compounds 1 and 4 were toxic to the nematodes by binding to the allosteric binding sites of the agonist-binding domains of the nematode nicotinic acetylcholine receptors. These results opened up possibilities for further investigations aimed at developing novel commercial nematicides.

Synthesis and application of α-carbonyl nitrile oxides

A strategy has been developed to synthesize α-carbonylfuran and isoxazole using tert-butyl nitrite (TBN) as a nitrogen source.

Finding furoxan rings

Dinitromethyl groups form an unstable nitrile oxide and its dipole isomer which cyclize to a furoxan ring.

Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently.

GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. Although most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently the protein's catalytic selenocysteine residue, the discovery and mechanistic elucidation of structurally diverse GPX4-inhibiting molecules have uncovered novel electrophilic warheads that bind and inhibit GPX4. Here, we report our discovery that diacylfuroxans can act as masked nitrile oxide prodrugs that inhibit GPX4 covalently with unique cellular and biochemical reactivity compared to existing classes of GPX4 inhibitors. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also expand the collection of reactive groups capable of targeting GPX4.

New Strategy of Synthesis of Peramivir Analogues as Potential Neuraminidase Inhibitors

Highly functionalised potential neuraminidase (NA) inhibitors, analogues of peramivir, were synthesised via a new and versatile method starting from a stereoselective 1,3-dipolar cycloaddition reaction between the nitrile oxide derived from 2-ethylbutanal and the commercially available and inexpensive cyclopentadiene and 1,3-cyclohexadiene, which afforded the isoxazolino-cyclopentene or cyclohexene intermediates, respectively. The subsequent reaction of the C=C bond in different conditions allowed the functionalisation of the five (or six) membered carbon nucleus. Further functionalised derivatives displaying an amino and a hydroxyl group were achieved via the final opening of the isoxazoline ring.

Copper-Catalyzed Cascade Cyclization Reactions of Diazo Compounds with tert-Butyl Nitrite and Alkynes: One-Pot Synthesis of Isoxazoles.

A novel copper-catalyzed [3 + 2] cycloaddition reaction of alkynes with nitrile oxides generated in situ from the coupling reaction of copper carbene and nitroso radical has been developed. The three-component reaction provides a simple and efficient method for the construction of isoxazoles in a highly regioselective manner in a single step. On the basis of the experimental results and density functional theory calculations, a catalytic cycle (CuI-CuII-Cu0-CuI) for this cascade cyclization reaction is proposed.

Cover Feature: Synthesis of 3,5‐Disubstituted Isoxazoles through a 1,3‐Dipolar Cycloaddition Reaction between Alkynes and Nitrile Oxides Generated from O‐Silylated Hydroxamic Acidss (Eur. J. Org. Chem. 44/2019)

Cover Feature: Synthesis of 3,5‐Disubstituted Isoxazoles through a 1,3‐Dipolar Cycloaddition Reaction between Alkynes and Nitrile Oxides Generated from <i>O</i>‐Silylated Hydroxamic Acidss (Eur. J. Org. Chem. 44/2019)

1,3‐Dipolar Cycloadditions of β‐Fluoroalkyl Vinylsulfones and Nitrile Oxides for Fluoroalkylated Isoxazolines and Isoxazoles

AbstractThe 1,3‐dipolar cycloadditions of β‐fluoroalkyl vinylsulfones and nitrile oxides to deliver 5‐fluoroalkyl‐3‐substituted 2‐isoxazolines has been established under mild conditions in up to 85% yield with excellent regio‐ and diastereoselectivities (all d.r. &gt;99 : 1), and thus facilitated rapid access to 5‐fluoroalkyl‐3‐Ph‐2‐isoxazoles by DBU‐mediated elimination of the pyridyl sulfone group.

The substituent effects on the [3+2] cycloaddition of nitrile oxides generated by photooxidation of arylazides to acetonitrile

The DFT approach in M06L/6-311 + G(d,p) approximation was used to study the transformation of unsaturated nitrile oxides (RCNO), which were generated by photooxidation of the corresponding aromatic azide, to oxadiazoles via [3 + 2]cyclization with acetonitrile. It was found that the cycloaddition activation enthalpy was within 60–93 kJ/mol, depending on the structure of the nitrile oxide. A significant mesomeric effect of the substituent and its position in the conjugated molecular system on the activation barrier of the reaction studied was identified. The relationship between the thermodynamic characteristics of [3 + 2] cycloaddition and electron density distribution in RCNO was demonstrated by a representative set of compounds including mono- and disubstituted nitrile oxides.