Cycloaddition Of Nitrile Oxides Research Articles

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.

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.

Synthesis of a Novel Tetracyclic Isoxazole by Intramolecular Nitrile Oxide Cycloaddition

Intramolecular cycloadditions have the great advantage of forming two rings simultaneously. We report the use of intramolecular [3 + 2] cycloaddition of the nitrile oxide derived from an N-propargylbenzimidazole oxime in the synthesis of a hitherto unreported tetracyclic isoxazole-containing ring system bearing “6-5-5-5”-membered ring fusions. The initial condensation was achieved through reaction of o-phenylenediamine with ethyl diethoxyacetate, followed by alkylation with propargyl bromide, deprotection of the acetal to the aldehyde, formation of an aldoxime, and intramolecular nitrile oxide cycloaddition (INOC). Characterization of the aldoxime and tetracyclic isoxazole is included herein.

3 + 2] Cycloaddition of nitrile oxides to dichloropropenes and 1,3‐dichlorobut‐2‐ene: A regioselectivity issue

AbstractThe reaction of nitrile oxides with 2,3‐dichloroprop‐1‐ene, 1,3‐dichloroprop‐1‐ene, and 1,3‐dichlorobut‐2‐ene leads to 5‐(chloromethyl)isoxazoles, 4‐(chloromethyl)isoxazoles, or to mixtures of both regioisomers. The direction of cycloaddition and reactivity of substrate is determined by the steric hindrance at the terminal carbon atom of the alkene double bond. It has been found that the isomeric products of cycloaddition of nitrile oxides to 1,3‐dichloropropene have significantly different dehydrochlorination capabilities. The experimental data on the regioselectivity of cycloaddition and the relative reactivity of substrates are in agreement with the results of quantum chemical calculations.

Design, synthesis, anti-mycobacterial activity, molecular docking and ADME analysis of spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition reaction under ultrasound irradiation.

The development of anti-tuberculosis (anti-TB) drugs has become a challenging task in medicinal chemistry. This is because Mycobacterium tuberculosis (TB), the pathogen that causes tuberculosis, has an increasing number of drug-resistant strains, and existing medication therapies are not very effective. This resistance significantly demands new anti-TB drug profiles. Here, we present the design and synthesis of a number of hybrid compounds with previously known anti-mycobacterial moieties attached to quinoxaline, quinoline, tetrazole, and 1,2,4-oxadiazole scaffolds. A convenient ultrasound methodology was employed to attain spiroquinoxaline-1,2,4-oxadiazoles via [3 + 2] cycloaddition of quinoxaline Schiff bases and aryl nitrile oxides at room temperature. This approach avoids standard heating and column chromatography while producing high yields and shorter reaction times. The target compounds 3a-p were well-characterized, and their in vitro anti-mycobacterial activity (anti-TB) was evaluated. Among the screened compounds, 3i displayed promising activity against the Mycobacterium tuberculosis cell line H37Rv, with an MIC99 value of 0.78µg/mL. However, three compounds (3f, 3h, and 3o) exhibited potent activity with MIC99 values of 6.25µg/mL. To further understand the binding interactions, the synthesized compounds were docked against the tuberculosis protein 5OEQ using in silico molecular docking. Moreover, the most active compounds were additionally tested for their cytotoxicity against the RAW 264.7 cell line, and the cytotoxicity of compounds 3f, 3h, 3i, and 3o was 27.3, 28.9, 26.4, and 30.2µg/mL, respectively. These results revealed that the compounds 3f, 3h, 3i, and 3o were less harmful to humans. Furthermore, the synthesized compounds were tested for ADME qualities, and the results suggest that this series is useful for producing innovative and potent anti-tubercular medicines in the future.

A Convenient Synthesis of Novel Isoxazolidine and Isoxazole Isoquinolinones Fused Hybrids.

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.

Ethynyl-B(dan) in [3+2] Cycloaddition and Larock Indole Synthesis: Synthesis of Stable Boron-Containing Heteroaromatic Compounds.

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling.

1,6-Dioxo-2-azaspiro[3.4]oct-2-enes and Related Spirocycles: Heterocycles from [3 + 2] Nitrile Oxide Cycloadditions with 2-Methyleneoxetanes, -Thietanes, and -Azetidines.

Isoxazolines and 4-membered heterocycles are significant structural motifs in numerous synthetic intermediates and natural products. [3 + 2] Cycloadditions between enol ethers and nitrile oxides have been well studied; however, nitrile oxide cycloadditions with 4-membered heterocycles to give spiroisoxazolines are unreported. Here, we showcase the regio- and diastereoselective [3 + 2] nitrile oxide cycloadditions of 2-methyleneoxetanes, -azetidines, and -thietanes to give an array of 1,6-dioxo-2-azaspiro[3.4]oct-2-enes and related spirocycles. 2D NMR experiments suggested that most of the observed diastereoselectivities were dictated by steric interactions; however, dipolarophiles with H bonding donors reversed the stereochemical outcome. X-ray crystallography confirmed the structural assignments.

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.

Enantioselective 1,3-Dipolar Cycloadditions of α-Methylene Lactams to Construct Spirocycles.

Spirocyclic scaffolds are important motifs due to their potential to bestow favorable effects on pharmaceutical compounds. However, there is a need for efficient methods for their enantioselective construction. We report a method for the asymmetric 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with α-methylene lactams to prepare chiral spirocyclic heterocycles. The methodology is high yielding (up to 91% yield) and enantioselective (up to 89% ee) for a wide range of N-substituents and 6- and 7-membered ring lactam substrates.

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.

Glycosyl Isoxazoles for Targeting of Tumor Microenvironment and Cancer Cells: Highly Selective Inhibitors of Carbonic Anhydrases IX and XII Showing Cytotoxic Activity

AbstractWe report the synthesis of twelve novel O‐glycosylmethyl isoxazoles incorporating the phenoxyaryl moiety, that were designed to selectively target the cancer‐related human carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The O‐glycosides have been prepared by cycloaddition of nitrile oxides to O‐propargyl glycosides. Compounds were assessed as inhibitors of the physiologically dominant isozymes hCA I and II and the tumor‐associated isozyme hCA IX and hCA XII. In this study, several glycosides have been identified as highly selective inhibitors of hCA IX and XII. Glycoconjugation enhances the anticancer activity against human osteosarcoma cell line. Thus, these glycosides may prove interesting lead candidates for a targeted cancer therapy.

Divergent synthesis of 5- and 4-(2,1-azaborine) substituted isoxazoles via regioselective [3 + 2] cycloadditions of nitrile oxides and B-ethynyl-1,2-azaborines

A new class of terminal alkyne reagents was developed and applied to the divergent synthesis of 5- and 4-(2,1-azaborine) substituted isoxazoles with excellent regioselectivities.

Diastereomerically pure (S)‐verbenone‐isoxazoline hybrids: Synthesis, molecular structure, Hirshfeld surface analysis, density functional theory, cytotoxic effect, and apoptosis induction

AbstractIn this paper, a new diastereomerically pure isoxazolines were efficiently prepared from (S)‐verbenone, the procedure involves a regioselective and a diastereoselective 1,3‐dipolar cycloaddition of nitrile oxides on the monoterpene's enone. The structures of the newly obtained cycloadducts were confirmed by analytical and spectral studies (HRMS, 1H NMR, and 13C NMR). The relative stereochemistry of isoxazoline compounds 3a, 3c, and 3d were confirmed by x‐ray single crystal analysis. Hirshfeld surface analysis and two‐dimensional fingerprint plots were performed to analyze the different intermolecular contacts in crystal packing. Further, density functional theory calculations have been used to analyze the electronic and geometric frontier molecular orbital and molecular electrostatic map analyses of the compounds to predict the reactive site. All compounds were evaluated in vitro for their cytotoxic activity against four human cancer cell lines including fibrosarcoma HT‐1080, lung carcinoma A‐549 and breast adenocarcinoma (MCF‐7 and MDA‐MB‐231). Compound 3d was the most potent compound especially against HT‐1080 and A‐549 cancer cells with IC50 values of 21.35 ± 1.51 and 14.92 ± 1.74 μM, respectively. Mechanistically, the compound 3d induced apoptosis by significant caspase activation in HT‐1080 and A‐549 cancer cell lines utilizing flow cytometric analysis and caspase 3/7 activation assay. The examined compound 3d caused S cell cycle arrest in both HT‐1080 and A‐549 cells.

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

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides.

Herein we report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1–2 hours, which provides an environmentally friendly access to 3,4,5-trisubstituted isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Additionally, we optimized the reaction conditions to produce trifluoromethyl-substituted isoxazoles, a prevalent scaffold in biomedical research and drug discovery programs. We also proposed a plausible mechanism for the selectivity of the [3 + 2]-cycloaddition reaction to produce 3,4,5-trisubstituted isoxazoles. Not to be overlooked are our optimized reaction conditions for the dimerization of hydroximoyl chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability.

Negligible Substituent Effect as Key to Synthetic Versatility: a Computational‐Experimental Study of Vinyl Ethers Addition to Nitrile Oxides

AbstractA tangible substituent effect may be perceived as a good feature in developing an organic reaction. This work demonstrates that, on the contrary, a zero‐slope Hammet plot should be sought. The synthesis of isoxazoles by consecutive cycloaddition of nitrile oxides to vinyl ethers and alcohols elimination was studied computationally and experimentally. We performed a Hammett studyin silicoto demonstrate a negligible substituent effect (i. e., broad substrate scope) in the addition of benzyl vinyl ether to nitrile oxides. The modeling was performed at the ωB97X‐V/def2‐TZVP//PBE0‐D4/def2‐TZVP+SMD(benzene) level of theory within the RIJCOSX approximation. The experimental evaluation validated the computational model. A versatile methodology for synthesizing substituted isoxazolines and isoxazoles was proposed as the main result. We present this work as a successful example of how quantum chemical modeling can re‐boost the classic Hammett approach to the optimization and design of organic synthetic methodologies. We anticipate further Hammett studiesin silico, considering the current trend for data‐driven chemical research.

Design, synthesis, and biological evaluation of novel (E)-1-arylethan-1-one O-((3-arylisoxazol-5-yl) methyl) oxime derivatives as potent non-nucleoside HBV inhibitors

• Synthesized (E)-1-arylethan-1-one O-((3-arylisoxazol-5-yl)methyl) oximes derivatives • These oxime derivatives as potent HBV inhibitor • Chlorinating at phenyl when excessive NCS reacting with some benzaldehyde oximes • The synthesized compounds interacting to HBV core protein in molecular docking • Crystal structure confirmed the reaction path A series of novel O-((3-arylisoxazol-5-yl) methyl) oxime derivatives were synthesized by highly regioselective dipolar cycloadditions of nitrile oxides with ( E )-1-arylethan-1-one O-prop-2-yn-1-yl oxime substrates. Results showed that in the formation of (E)-N-hydroxy-3,4-dimethoxybenzimidoyl chloride, chlorinating substitution in phenyl occurred when excess N-chlorosuccinimide. The crystal structure of 10 among the series of compounds revealed it was cis-cyclization product and moiety of -C(CH 3 )=N-O- was E configuration. As a triclinic crystal, the twist angle between the isoxazol-5-yl ring ( B ) and phenyl ring ( A ) was 57.43°, at dihedral angles of 25.22°. Screening for anti-HBV activities of these compounds was carried out. The results showed compounds 11, 19 and 12 effectively inhibited HBeAg (IC 50 = 158.28 ± 0.02, 127.51 ± 0.01, and 213.26 ± 0.04 respectively). Compounds 11, 19 and 23 manifested stronger inhibition on HBsAg (IC 50 =12.68 ± 0.06, 61.24 ± 0.02, and 89.59 ± 0.02 µM respectively). Compound 15 was the effctivest inhibition of DNA replication (IC 50 =43.52±0.02 µM) among the compounds. Docking study of bioactive compounds with HBV core protein (3KXS) was carried out to explore their interaction.This study determined a new non-nucleoside analogs with inhibition of HBV.

Green Biphasic Synthesis, X‐Ray Diffraction Structure and Conformational Analysis of O‐Glycosylmethyl Isoxazoles: Potential Substrates of GLUT‐1 Glucose Transporter.

AbstractAn efficient synthesis of new 1‐O‐β‐glycosylmethyl isoxazoles is described. The title compounds are obtained by cycloaddition of nitrile oxides generated in situ in 2‐MeTHF/sodium hypochlorite solution. The developed approach provides the first use of this green methodology to prepare isoxazole derivatives. X‐ray diffraction structure and conformational analysis in solution show that glycosyl isoxazoles possess the structural features required to be substrates of GLUT‐1.

Stereoconvergent and stepwise 1,3-dipolar cycloadditions of nitrile oxides and nitrile imines

The first example of stereoconvergent 1,3-dipolar cycloaddition of nitrile oxides and nitrile imines with E/Z isomeric mixture of electron-deficient olefins is reported, delivering isoxazolines and pyrazolines bearing two vicinal stereogenic tertiary and trifluoromethylated quaternary carbon centers with perfect regio- and diastereoselectivities. The possibility of concerted cycloaddition/epimerization sequence under basic condition to form the thermodynamically stable diastereomers is excluded through some control experiments and DFT calculations, and a stepwise mechanism is proposed.