Cycloaddition Reactions Of Nitrile Oxides Research Articles

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.

PIDA Mediated Synthesis of Benzopyranoisoxazoles via an Intramolecular Nitrile Oxide Cycloaddition (INOC): Application to the Synthesis 4H‐chromeno[4,3‐c]isoxazol‐4‐ones.

AbstractPresented herein is an approach for the synthesis of highly substituted tricyclic benzopyranoisoxazoles from the corresponding aldoximes via an intramolecular nitrile oxide cycloaddition (INOC) reaction using a hypervalent iodine reagent (Diacetoxyiodo)benzene (PIDA/DIB/(PhI(OAc)2) as the single inexpensive oxidizing agent. The key step involved in this reaction is a sequential intramolecular C−C and C−O bond formation. A variety of benzopyranoisoxazoles were constructed in moderate to high yields. In addition, some of the benzopyranoisoxazoles were converted to 4H‐chromeno[4,3‐c]isoxazol‐4‐ones via allylic oxidation using CrO3 as an oxidant.

Synthesis of 5-ethynylisoxazoles based on 1,3-dipolar cycloaddition reactions of nitrile oxides with conjugated diynes

Synthesis of 5-ethynylisoxazoles based on 1,3-dipolar cycloaddition reactions of nitrile oxides with conjugated diynes

A computational study of 1,3-dipolar cycloadditions of nitrile oxides with dienes

Density functional theory calculations at the M06-2X level of theory were employed to study the reactivity and regioselectivity of 1,3-dipolar cycloaddition reactions of nitrile oxides with cyclodienes. Calculated relative activation free energies reproduce the experimentally observed product ratios. The electronic energies of activation are found to be mainly controlled by distortion energies required to achieve the transition states. Both electronic and steric effects influence regioselectivities. Theoretical predictions were performed on previous experimental data and analyzed with the use of the distortion/interaction model. The obtained results will help in obtaining a better understanding of the factors that affect the relative cycloaddition rate.

Quantum Mechanical Elucidation on [3+2] cycloaddition reaction of aryl nitrile oxide with cyclopentenones

The [3 + 2] cycloaddition (32CA) reaction of benzonitrile oxide (BNO) with 4-substituted 4-hydroxy-2-cyclopentenone has been investigated using molecular electron density theory (MEDT) at the Density Functional Theory (DFT) B3LYP/6-31G (d), M06/6-311G (d,p) and M06-2X/6–311++G (d,p) levels. The present theoretical computations indicate that the reaction of BNO with 4-substituted 4-hydroxy-2-cyclopentenones is via [3 + 2] cycloaddition, where the three atom component (TAC) chemo-selectively adds across the alkene functionality in the 2-cyclopentenones (Path A). Analysis of the electrophilic PA+ and nucleophilic PA− Parr functions at the different reaction sites in the alkene counterpart indicates that the aryl nitrile oxides add across the atomic centers with the highest Mulliken atomic spin densities. The results reported in this study are in good agreement with previous experimental work. The GEDT calculations unravel the low polar character of the [3 + 2] cycloaddition reactions. This reaction occurs with poor enantioselectivity, but a high degree of stereo-, peri-, diastereo, and regioselectivity is seen for the reaction of the BNO with 4-hydroxy-4-methyl-2-cyclopentenones. The regioselectivity of the reactions is the same in all the solvents investigated.

Quantum chemical study on the mechanism and selectivity of [3 + 2] cycloaddition reactions of aryl nitrile oxides with furanone

Quantum chemical study on the mechanism and selectivity of [3 + 2] cycloaddition reactions of aryl nitrile oxides with furanone

[3 + 2] Cycloaddition reactions of nitrile oxides generated in situ from aldoximes with alkenes and alkynes under ball-milling conditions

ABSTRACT A convenient and efficient [3 + 2] cycloaddition reaction of alkenes and alkynes with the in situ generated nitrile oxides from aldoximes in the presence of NaCl, Oxone and Na2CO3 has been developed to afford a series of isoxazoles and isoxazolines at room temperature in yields up to 85% and 86%, respectively. The current methodology exhibits a wide substrate scope, (hetero)aromatic and aliphatic aldoximes, alkenes including acrylate esters, acrylonitrile, chalcone, styrene, N-methylmaleimide and [60]fullerene, phenylacetylene, and alkynes containing CH2OH, SiMe3, COCH3 or CO2CH3 group can be employed. The present protocol features good functional group tolerance, short reaction time, mild reaction conditions and high atom economy, providing an efficient and environmentally friendly access to isoxazoles and isoxazolines.

α,β-Unsaturated β-Methyl-δ-lactones in Nitrile Oxide Cycloaddition Reactions. Synthesis of Saturated Lactones and Lactams

α,β-Unsaturated β-Methyl-δ-lactones in Nitrile Oxide Cycloaddition Reactions. Synthesis of Saturated Lactones and Lactams

Development of regioselective [2 + 3] cycloaddition reactions of nitrile oxides with alkenes using intramolecular reactions through oxime groups [1

Nitrile oxides afford 2-isoxazoline heterocycles through [2 + 3] cycloaddition reactions with alkenes. These heterocycles can be converted to useful intermediates, such as β-hydroxy ketones and γ-amino alcohols, leading to pharmaceutical and agrochemical compounds. However, nitrile oxides directly connected to a carbonyl group show low reactivity owing to the decrease in energy of the dipole HOMO. Furthermore, when dissymmetric internal alkenes are used, regioselective control is difficult. Herein, we have designed nitrile oxides bound to alkenes through the oxime group and demonstrated their intramolecular [2 + 3] cycloaddition reactions. The desired cycloadducts were obtained in high yields and as single regioisomers. Furthermore, face-selective cycloaddition reactions were achieved by introducing a stereocenter into the linker moiety, affording the desired cycloadducts with good diastereoselectivity.

A metal-free approach for in situ regioselective synthesis of isoxazoles via 1,3 dipolar cycloaddition reaction of nitrile oxide with propargyl bromide

A metal-free approach for in situ regioselective synthesis of isoxazoles via 1,3 dipolar cycloaddition reaction of nitrile oxide with propargyl bromide

Synthesis of novel chiral spiro-β-lactams from nitrile oxides and 6-(Z)-(benzoylmethylene)penicillanate: batch, microwave-induced and continuous flow methodologies.

The first examples of the diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides and 6-alkylidene penicillanates leading to chiral spiroisoxazoline-penicillanates are reported. The synthesis of this new type of penicillanate involved the selective generation of two consecutive stereogenic centers, including a quaternary chiral center. Furthermore, the present work also describes the outcomes of these 1,3-dipolar cycloaddition reactions under three distinct reaction conditions (conventional heating, microwave irradiation and continuous flow). The successful use of the continuous flow technique as well as the proper selection of the reaction media allowed the development of a sustainable route to chiral spiroisoxazoline-penicillanates.

Pd-Catalysed [3 + 2]-cycloaddition towards the generation of bioactive bis-heterocycles/identification of COX-2 inhibitors via in silico analysis.

In the current research, we envisaged the synthesis of bis-heterocycles containing the dihydroisoxazole ring by [3 + 2] cycloaddition of VECs (vinyl ethylene carbonates) and nitrile oxides, assisted by a Pd catalyst. Herein we explored hydroximoyl chlorides as versatile precursors for the in situ generation of nitrile oxides that were exploited to achieve the cycloaddition reaction on a vinyl group of VECs to generate bis-heterocycles. In silico-based studies of bis-heterocycles on the cyclooxygenase (COX) enzyme displayed selective COX-2 inhibition.

The 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides in Water Media

The 1,3-dipolar Cycloadditions (DCs) of Nitrile Oxides (NOs) have been used as a powerful tool in synthetic organic chemistry. The cycloadducts arising from Cycloadditions (CAs) of NOs to alkenes and alkynes (2-isoxazolines and isoxazoles respectively) are valuable synthetic intermediates because, among others, their capacity to mask other functionalities including α, β -unsaturated ketones, β -hydroxy carbonyl compounds and 1,3- aminoalcohols. In particular, the β-hydroxy ketone functionality is an illustrative example, making the NOs alkenes CAs reactions a synthetically equivalent methodology of aldol reactions. The vast majority of these reactions are carried out in organic solvents. Nevertheless, the use of water as an alternative solvent has evident advantages on the “Green Chemistry” concept. The critical discussion on the use of water instead of “conventional” solvents in the 1,3-DCs reactions of NOs is the objective of the present review.

Convenient Synthesis of Pyrazolo[4',3':5,6]pyrano[4,3-c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition.

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of 1JCH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed 1H, 13C and 15N NMR spectroscopic experiments and HRMS measurements.

D-Ring modification of steroids: synthesis of isoxazole annulated steroids from des D-formyl alkyne via 1,3-dipolar cycloaddition reaction

The reaction of 17,17-dichloro-androst-16(E)-chloromethylene with secondary amine base afforded substitution products of exocyclic D-ring ketones, in contrast to the reaction of alkaline base which cleaved steroidal D-ring to des-D formyl alkyne. The des-D formyl alkyne was employed to prepare D-ring annulated isoxazolo steroid via 1,3-dipolar nitrile oxide cycloaddition reaction.

1,3-Dipolar cycloaddition reactions of acyl phosphonates with nitrile oxides: synthesis of phosphonate-containing dioxazole derivatives

New phosphonate-containing five-membered heterocyclic dioxazole derivatives are synthesized via 1,3-dipolar cycloaddition reactions of nitrile oxides used as dipole with acyl phosphonates under basic conditions. Herein, acyl phosphonates take part in the cyclization process as a dipolarophile to afford the related dioxazole compounds in moderate-to-good yields (49–84%). Substituted aryl nitrile oxides and aroyl phosphonates were employed in the 1,3-dipolar cycloaddition reactions where triethylamine was the effective tertiary base. Alkyl version of acyl phosphonate also afforded the expected cycloadduct, that is, dimethyl 5-isopropyl-3-phenyl-1,4,2-dioxazol-5-yl-5-phosphonate. Diethyl/dimethyl 3,5-aryl-1,4,2-dioxazol-5-yl-5-phosphonate derivatives are fully characterized by using 1H NMR, 13C NMR, 31P-NMR, and FT along with high-resolution mass spectroscopy.

1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides under "Non-Conventional" Conditions: Green Solvents, Irradiation, and Continuous Flow.

The 1,3-dipolar cycloaddition reactions (DCs) of nitrile oxides (NOs) to alkenes and alkynes are useful methods for the synthesis of 2-isoxazolines and isoxazoles respectively, which are important classes of heterocyclic compounds in organic and medicinal chemistry. Most of these reactions are carried out in organic solvents and under thermal activation. Nevertheless the use of supercritical carbon dioxide (scCO2 ) and ionic liquids (Ils) as alternative solvents and the application of microwave (MW) and ultrasound (US) as alternative activation procedures have evident advantages from the "Green Chemistry" point of view. The critical discussion on the applications of these "unconventional" activation methods and reaction conditions in the 1,3-DCs of NOs is the objective of the present Review.

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.

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.

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.