Oxime Ethers Research Articles

Photocatalyst-Free Transformation of C(sp3)-H Bonds to Oxime Ethers via Photoinduced Hydrogen Atom Transfer.

Herein, a direct transformation of aliphatic C-H bonds to oxime ethers has been developed via light-promoted hydrogen atom transfer (HAT) in the absence of a photocatalyst. Singlet oxygen and chlorine radical are complementary C(sp3)-H bond cleaving agents in this reaction, enabling the extraction of hydrogen atoms from a diverse range of compounds, like cycloalkanes, ethers, amines, amides, and cyclic sulfides. This method excels in transforming common aliphatic C-H bonds into valuable oxime ethers featuring abundant chemical feedstocks, good functional group tolerance, and catalyst free conditions.

Semisynthetic Ecdysteroid Cinnamate Esters and tert-Butyl Oxime Ether Derivatives with Trypanocidal Activity.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects the lives of millions of indigenous people in Latin America. As medications to treat Chagas disease are limited to the application of benznidazole and nifurtimox, which are not ideal treatments for the chronic stage of the disease, the search for new antichagasic drug candidates is an important need. Ecdysone has previously been shown to interfere with the life cycle of T. cruzi. Here, we report the biological profiling and subsequent semisynthetic structure optimization of 47 ecdysteroids against T. cruzi with the aim of identifying selective trypanocidal ecdysteroids. Two moderately trypanocidal pharmacophores were identified: ecdysteroids containing a 6-tert-butyl oxime ether and a cinnamic ester moiety. These functional groups were combined into the structures of four new semisynthetic ecdysteroids (44-47), among which 44 exerted potent and selective trypanocidal activity (IC50 < 2 μM). Cellular infection assays showed that ecdysteroid 44 potently and efficiently inhibited amastigote replication as determined by trypomastigote release after cellular infection with an IC50 of 2.7 ± 0.1 μM. The compound was similarly potent to benznidazole (IC50 = 3.8 ± 0.7 μM) and more than 5-fold more cytotoxic toward T. cruzi over RAW264.7 host macrophages. Overall, the ecdysteroid cinnamate ester 44 is a novel trypanocidal lead structure that needs to be further characterized in follow-up studies.

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

Design, synthesis, and biological evaluation of imidazolylacetophenone oxime derivatives as novel brain-penetrant agents for Alzheimer's disease treatment

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1−8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9−30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 μM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aβ42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Synthesis and antifeedant activity of 3H-indole derived oxime esters and oxime ethers against cotton bollworm

The O-acylation or O-alkylation of 3H-indole derived oximes is conveniently synthesized from indoles and the corresponding anhydrides or alcohols mediated by tert-butyl nitrite (TBN) under mild conditions. O-Acyloxime esters are obtained with yields up to 82% using anhydrides via a facile one-pot reaction. Fluorinated O-alkyloxime ethers are achieved with yields up to 38% using fluorinated alcohols through an optimized step-by-step strategy or a 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO)-assisted one-pot strategy. Meanwhile, the better reaction yields, up to 64%, are achieved for nonfluorinated O-alkyloxime ethers. These approaches allow access to a diversity of O-acyloxime esters and fluorinated/nonfluorinated O-alkyloxime ethers, underscoring broad substrate scopes, good functional tolerance and easily gram-scale. All the synthesized compounds were evaluated for their potential antifeedant activity and 5f shows good antifeedant activity against cotton bollworm with a negative logarithmic effective concentration for 50% feeding reduction (pEC50) at 4.217.

Phosphine-Catalyzed Ring-Opening Regioselective Addition of Cyclopropenones with Amides.

A series of amides, including α-bromo hydroxamates, N-alkoxyamides, and N-aryloxyamides, were subjected to phosphine-catalyzed ring-opening O-selective addition with cyclopropenones, producing various special α,β-unsaturated esters containing oxime ether motif, in moderate to excellent yields, with high regioselectivity, and exclusive O-selectivity. The methodology is highly atom-economical, with simple operation procedures, and compatible with a wide substrate scope (more than 44 examples).

A new neuroprotective candidate TJ1 targeting amyloidogenesis in 5xFAD Alzheimer’s disease mice

As one of the main pathmechanisms of Alzheimer’s disease (AD), amyloid-β (Aβ) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aβ42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aβ42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aβ42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aβ42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2– and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood–brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aβ42 by acting on Aβ oligomerization and fibrilization. Besides, TJ1 reversed Aβ-, H2O2– and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aβ42 and Aβ plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.

Design, Synthesis and Bioactivities of Novel Pyridyl Containing Pyrazole Oxime Ether Derivatives.

In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through 1H NMR, 13C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against Mythimna separata, Tetranychus cinnabarinus, Plutella xylostella, and Aphis medicaginis at a dosage of 500 μg/mL, and some title compounds were active towards Nilaparvata lugens at 500 μg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against M. separata, T. cinnabarinus, or A. medicaginis at 100 μg/mL, with the mortalities of compounds 8a, 8c, 8d, 8e, 8f, 8g, 8o, 8s, 8v, 8x, and 8z against A. medicaginis, in particular, all reaching 100%. Even when the dosage was lowered to 20 μg/mL, compound 8s also expressed 50% insecticidal activity against M. separata, and compounds 8a, 8e, 8f, 8o, 8v, and 8x displayed more than 60% inhibition rates against A. medicaginis. The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future.

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Discovery of Novel N-Phenyltriazinone Derivatives Containing Oxime Ether or Oxime Ester Moieties as Promising Protoporphyrinogen IX Oxidase Inhibitors.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is one of the most important targets for the discovery of green herbicides. In order to find novel PPO inhibitors with a higher herbicidal activity, a series of novel N-phenyltriazinone derivatives containing oxime ether and oxime ester groups were designed and synthesized based on the strategy of pharmacophore and scaffold hopping. Bioassay results revealed that some compounds showed herbicidal activities; especially, compound B16 exhibited broad-spectrum and excellent 100% herbicidal effects to Echinochloa crusgalli, Digitaria sanguinalis, Setaria faberii, Abutilon juncea, Amaranthus retroflexus, and Portulaca oleracea at a concentration of 37.5 g a.i./ha, which were comparable to trifludimoxazin. Nicotiana tabacum PPO (NtPPO) enzyme inhibitory assay indicated that B16 showed an excellent enzyme inhibitory activity with a value of 32.14 nM, which was similar to that of trifludimoxazin (31.33 nM). Meanwhile, compound B16 revealed more safety for crops (rice, maize, wheat, peanut, soybean, and cotton) than trifludimoxazin at a dose of 150 g a.i./ha. Moreover, molecular docking and molecular dynamics simulation further showed that B16 has a very strong and stable binding to NtPPO. It indicated that B16 can be used as a potential PPO inhibitor and herbicide candidate for application in the field.

Highly Efficient One-pot Electrosynthesis of Oxime Ethers from NOx over Ultrafine MgO Nanoparticles Derived from Mg-based Metal-Organic Frameworks.

Oxime ethers are attractive compounds in medicinal scaffolds due to the biological and pharmaceutical properties, however, the crucial and widespread step of industrial oxime formation using explosive hydroxylamine (NH2OH) is insecure and troublesome. Herein, we present a convenient method of oxime ether synthesis in a one-pot tandem electrochemical system using magnesium based metal-organic framework-derived magnesium oxide anchoring in self-supporting carbon nanofiber membrane catalyst (MgO-SCM), the in situ produced NH2OH from nitrogen oxides electrocatalytic reduction coupled with aldehyde to produce 4-cyanobenzaldoxime with a selectivity of 93 % and Faraday efficiency up to 65.1 %, which further reacted with benzyl bromide to directly give oxime ether precipitate with a purity of 97 % by convenient filtering separation. The high efficiency was attributed to the ultrafine MgO nanoparticles in MgO-SCM, effectively inhibiting hydrogen evolution reaction and accelerating the production of NH2OH, which rapidly attacked carbonyl of aldehydes to form oximes, but hardly crossed the hydrogenation barrier of forming amines, thus leading to a high yield of oxime ether when coupling benzyl bromide nucleophilic reaction. This work highlights the importance of kinetic control in complex electrosynthetic organonitrogen system and demonstrates a green and safe alternative method for synthesis of organic nitrogen drug molecules.

Highly Efficient One‐pot Electrosynthesis of Oxime Ethers from NOx over Ultrafine MgO Nanoparticles Derived from Mg‐based Metal‐Organic Frameworks

AbstractOxime ethers are attractive compounds in medicinal scaffolds due to the biological and pharmaceutical properties, however, the crucial and widespread step of industrial oxime formation using explosive hydroxylamine (NH2OH) is insecure and troublesome. Herein, we present a convenient method of oxime ether synthesis in a one‐pot tandem electrochemical system using magnesium based metal‐organic framework‐derived magnesium oxide anchoring in self‐supporting carbon nanofiber membrane catalyst (MgO‐SCM), the in situ produced NH2OH from nitrogen oxides electrocatalytic reduction coupled with aldehyde to produce 4‐cyanobenzaldoxime with a selectivity of 93 % and Faraday efficiency up to 65.1 %, which further reacted with benzyl bromide to directly give oxime ether precipitate with a purity of 97 % by convenient filtering separation. The high efficiency was attributed to the ultrafine MgO nanoparticles in MgO‐SCM, effectively inhibiting hydrogen evolution reaction and accelerating the production of NH2OH, which rapidly attacked carbonyl of aldehydes to form oximes, but hardly crossed the hydrogenation barrier of forming amines, thus leading to a high yield of oxime ether when coupling benzyl bromide nucleophilic reaction. This work highlights the importance of kinetic control in complex electrosynthetic organonitrogen system and demonstrates a green and safe alternative method for synthesis of organic nitrogen drug molecules.

Stereoisomers of oxime ethers of 1,4-naphthoquinone: Synthesis, characterization, X-ray crystal structures, and DFT studies

In the present work, we use the C-3 substituted 2-hydroxy-1,4-naphthoquinones viz. 2-hydroxynaphthalene-1,4-dione (1), 2-hydroxy-3-methylnaphthalene-1,4-dione (2), and 2-chloro-3-hydroxynaphthalene-1,4-dione (3) as starting materials and obtained naphthoquinoneoxime ethers viz. 3-hydroxy-4-(methoxyimino)naphthalen-1(4H)-one (4), 3-hydroxy-4-(methoxyimino)-2-methylnaphthalen-1(4H)-one (5) and 2-chloro-3-hydroxy-4-(methoxyimino)naphthalen-1(4H)-one (6) via a facile and efficient synthesis involving condensation with methoxyamine hydrochloride. X-ray structure showed that 4 belongs to the orthorhombic (P212121) space group, whereas 5 and 6 (P21/c) crystalize in the monoclinic crystal system. The isomer ratios derived from NMR experiments elucidating stereoisomerism in compounds comprised of carbon-nitrogen double bonds have been analyzed; the naphthoquinone oxime ethers 4, 5, and 6 were also characterized employing the ωB97x-D/6–311++G (d, p) level of density functional theory. Theoretical studies reveal different conformational isomers with the ‘amphi’ and ‘syn’ isomers as low-lying structures along their energy hierarchy in accordance with the X-ray crystallography data. The spectral characterization of vibrational frequencies and 1H /13C NMR chemical shifts in unison with experiments and theory has been presented.

Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors.

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 μg/mL that was superior to that of the agricultural fungicide boscalid (2.2 μg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 μM that was superior to that of boscalid (7.9 μM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.

DFT Insight into a Strain-Release Mechanism in Bicyclo[1.1.0]butanes via Concerted Activation of Central and Lateral C-C Bonds with Rh(III) Catalysis.

Transition-metal-catalyzed, strain-release-driven transformations of "spring-loaded" bicyclo[1.1.0]butanes (BCBs) are considered potent tools in synthetic organic chemistry. Previously proposed strain-release mechanisms involve either the insertion of the central C-C bond of BCBs into a metal-carbon bond, followed by β-C elimination, or the oxidative addition of the central or lateral C-C bond on the transition metal center, followed by reductive elimination. This study, employing DFT calculations on a Rh(III)-catalyzed model system in a three-component protocol involving oxime ether, BCB ester, and ethyl glyoxylate for constructing diastereoselective quaternary carbon centers, introduces an unusual strain-release mechanism for BCBs. In this mechanism, the catalytic reaction is initiated by the simultaneous cleavage of two C-C bonds (the central and lateral C-C bonds), resulting in the formation of a Rh-carbene intermediate. The new mechanism exhibits a barrier of 21.0 kcal/mol, making it energetically more favorable by 11.1 kcal/mol compared to the previously suggested most favorable pathway. This unusual reaction mode rationalizes experimental observation of the construction of quaternary carbon centers, including the excellent E-selectivity and diastereoselectivity. The newly proposed strain-release mechanism holds promise in advancing our understanding of transition-metal-catalyzed C-C bond activation mechanisms and facilitating the synthesis of transition metal carbene complexes.

Palladium-Catalyzed Carbohalogenation of Olefins with Alkynyl Oxime Ethers: Rapid Access to Chlorine-Containing Isoxazoles.

A palladium-catalyzed carbohalogenation of olefins with alkynyl oxime ethers has been described, which provides efficient and practical access to various chlorine-containing isoxazoles. This method exhibits excellent regioselectivity, good functional group compatibility, and mild reaction conditions. The mechanistic studies suggest that the reaction proceeds via a stabilized π-benzyl palladium intermediate, which is essential for the formation of C(sp3)-Cl bonds.

Novel Pyrazole-4-Carboxamide Derivatives Containing Oxime Ether Group as Potential SDHIs to Control Rhizoctonia solani.

In the search for novel succinate dehydrogenase inhibitor (SDHI) fungicides to control Rhizoctonia solani, thirty-five novel pyrazole-4-carboxamides bearing either an oxime ether or an oxime ester group were designed and prepared based on the strategy of molecular hybridization, and their antifungal activities against five plant pathogenic fungi were also investigated. The results indicated that the majority of the compounds containing oxime ether demonstrated outstanding in vitro antifungal activity against R. solani, and some compounds also displayed pronounced antifungal activities against Sclerotinia sclerotiorum and Botrytis cinerea. Particularly, compound 5e exhibited the most promising antifungal activity against R. solani with an EC50 value of 0.039 μg/mL, which was about 20-fold better than that of boscalid (EC50 = 0.799 μg/mL) and 4-fold more potent than fluxapyroxad (EC50 = 0.131 μg/mL). Moreover, the results of the detached leaf assay showed that compound 5e could suppress the growth of R. solani in rice leaves with significant protective efficacies (86.8%) at 100 μg/mL, superior to boscalid (68.1%) and fluxapyroxad (80.6%), indicating promising application prospects. In addition, the succinate dehydrogenase (SDH) enzymatic inhibition assay revealed that compound 5e generated remarkable SDH inhibition (IC50 = 2.04 μM), which was obviously more potent than those of boscalid (IC50 = 7.92 μM) and fluxapyroxad (IC50 = 6.15 μM). Furthermore, SEM analysis showed that compound 5e caused a remarkable disruption to the characteristic structure and morphology of R. solani hyphae, resulting in significant damage. The molecular docking analysis demonstrated that compound 5e could fit into the identical binding pocket of SDH through hydrogen bond interactions as well as fluxapyroxad, indicating that they had a similar antifungal mechanism. The density functional theory and electrostatic potential calculations provided useful information regarding electron distribution and electron transfer, which contributed to understanding the structural features and antifungal mechanism of the lead compound. These findings suggested that compound 5e could be a promising candidate for SDHI fungicides to control R. solani, warranting further investigation.

Synthesis of Helical-Shaped Axially Chiral Bisoxime Ethers via Chiral Phosphoric-Acid-Catalyzed Sequential Enantioselective Condensations.

A successful synthesis of helical-shaped axially chiral bisoxime ethers is reported. This approach utilized symmetric L-shaped diketone scaffolds as carbonyl components for the enantioselective condensation with hydroxylamines, delivering dual axially chiral oxime ethers with up to 99% ee. Additionally, the axially chiral mono-oxime ethers of azabicyclic ketones with high ee's were also successfully produced. Various chiral bicyclic lactams can be readily synthesized via Beckmann rearrangement, demonstrating a potential application in organic synthetic chemistry.

Catalytic Atroposelective Synthesis of Axially Chiral Heterobiaryl Oxime Ethers via the One-Step Dynamic Kinetic Condensation Reaction.

The catalytic atroposelective synthesis of axially chiral heterobiaryls was first developed through the direct one-step dynamic kinetic condensation reaction with the simple transformation of the C═O bond to the C═N bond, delivering a series of novel axially chiral heterobiaryl oxime ethers.

Construction of Si-Stereogenic Silanols by Palladium-Catalyzed Enantioselective C-H Alkenylation.

The construction of silicon-stereogenic silanols via Pd-catalyzed intermolecular C-H alkenylation with the assistance of a commercially available L-pyroglutamic acid has been realized for the first time. Employing oxime ether as the directing group, silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities, featuring a broad substrate scope and good functional group tolerance. Moreover, parallel kinetic resolution with unsymmetric substrates further highlighted the generality of this protocol. Mechanistic studies indicate that L-pyroglutamic acid could stabilize the Pd catalyst and provide excellent chiral induction. Preliminary computational studies unveil the origin of the enantioselectivity in the C-H bond activation step.