Oxime Esters Research Articles

Iron-Catalyzed One-Pot Cascade Reactions of Oximes with Inactivated Saturated Ketones: Entry to Highly Substituted Pyridines.

An iron-catalyzed oxidative [3 + 3] annulation of oxime esters with inactivated saturated ketones is described. This cascade strategy allows one-step rapid synthesis of various structurally important pyridines through an oxidative dehydrogenation/annulation/oxidative aromatization sequence via direct α,β-dehydrogenation of simple saturated ketones followed by annulation with oximes. This method shows good functional group tolerance, readily accessible starting materials, a wide substrate scope, high chemoselectivity, and no need for extra stoichiometric oxidant and is also applicable to the late-stage functionalization of natural products.

Synthesis of antibiofilm (1R,4S)-(-)-fenchone derivatives to control Pseudomonas syringae pv. tomato.

Biofilm plays a crucial role in Pseudomonas syringae pv. tomato (Pst) infection. We identified (1R,4S)-(-)-fenchone (FCH) as the most potent antibiofilm agent against Pst among 39 essential oil compounds. Subsequently, we synthesized a series of FCH oxime ester and acylhydrazine derivatives to explore more potent derivatives. II3 was screened out as the most potent derivative, exhibiting a minimal biofilm inhibitory concentration of 60 μg mL-1 and a lowest concentration with maximal biofilm inhibition (LCMBI) of 200 μg mL-1, lower than those of FCH (80 and 500 μg mL-1, respectively). II3 and FCH showed minimum inhibitory concentration values >1000 μg mL-1 and similar maximal biofilm inhibition extents of 48.7% and 49.5% at their respective LCMBIs, respectively. Meanwhile, neither of them influenced cell viability or the activity of metabolic enzymes at their respective LCMBIs. II3 at its LCMBI significantly reduced biofilm thickness, extracellular polysaccharide content, and pectinase and cellulase production indices. In vivo assay results indicated that II3 could preventatively reduce the bacterial contents in tomato leaves at its LCMBI, and when combined with kasugamycin (KSG) (10 μg mL-1), II3 achieved the same level of bacterial reduction as the sole application of KSG (70 μg mL-1), thereby reducing the required dosage of KSG. Mechanistic studies demonstrated that II3 can down-regulate biofilm-related genes and inhibit PsyR/PsyI quorum sensing system, which differs from the bactericidal mechanisms. These results underscore the potential of II3 as an antibiofilm agent for the control of Pst or FCH as a promising natural candidate for future in-depth optimization. © 2024 Society of Chemical Industry.

Selective 1,2‐Carboimination of Isothiocyanates to Access S‐Substituted Isothioureas via Energy Transfer Catalysis

Herein, we introduce a novel method for the synthesis of S‐substituted isothiourea compounds via the selective 1,2‐carboimination between oxime esters as bifunctional reagents and the C=S bond of isothiocyanates under visible‐light catalysis. This approach deviates from conventional methods by precisely modulating the substrate electronics to selectively functionalize the C=S bond of isothiocyanates over the C=N bond, eliminating the need for strong bases and high temperatures and bypassing the formation of thiourea intermediates. Consequently, this protocol enables the efficient one‐step synthesis of S‐alkyl isothioureas, with featuring mild reaction conditions, operational simplicity and broad substrate scope.

Photochemical direct C3 cyanoalkylation of quinoxalin-2(1H)-ones with cyclobutanone oxime esters under catalyst-free conditions

A photochemical direct C3 cyanoalkylation of quinoxalin-2(1H)-ones was achieved for the first time, using cyclobutanone oxime esters as cyanoalkyl precursors, without the need for a photocatalyst. The mild and environmentally friendly conditions make this protocol a valuable alternative for synthesizing C3 cyanoalkylated quinoxalin-2(1H)-ones.

Decarboxylative Xanthylation under Photocatalytic Conditions.

Xanthates are widely used in organic synthesis for the construction of various molecules and have numerous applications as bioactive compounds. Here, we present their preparation via a straightforward photocatalytic decarboxylative xanthylation process involving readily available oxime esters and xanthate dimers. This approach provides access to a wide variety of xanthate compounds in moderate to good yields, including xanthates derived from relevant pharmaceutical and bioactive molecules.

4+1] Heteroannulation to Form 1‐Pyrrolines through Alder‐Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine

AbstractWe report in this paper a novel Cu‐catalyzed synthesis of polysubstituted 1‐pyrrolines. The reaction of β,γ‐unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2′‐biquinoline affords the corresponding 1,6‐enynimines, which undergo a highly stereoselective Alder‐ene reaction to afford 1‐pyrrolines with concomitant generation of a quaternary carbon and a 2‐azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1‐difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron‐rich alkyne during the pericyclic reaction. The resulting 1‐pyrrolines undergo facile acid‐catalyzed regioselective Wagner–Meerwein rearrangement to provide 2H‐pyrroles in excellent yields. The 2H‐pyrroles are also accessible from 4 and 5 in a one‐pot manner without isolation of the 1‐pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5‐tetrasubstituted pyrrolidine, is accomplished.

Inside Back Cover

Simple reaction, useful chemistry. The electron donor‐acceptor complex (EDA) photochemistry provides a simple and efficient platform for organic synthesis. A general EDA complex strategy formed by readily accessible thiophenolate anion and oxime ester successfully realizes the diverse synthesis of thioethers under visible light irradiation. Such a strategy could also enable a thiol‐catalysis for the synthesis of phenanthridines. More details are discussed in the article by Zhong et al. on pages 2751—2756. image

The Construction of Furocoumarins through Iron-Catalyzed Relay Annulation of Oxime Esters with 4-Hydroxycoumarins.

An iron-catalyzed relay annulation protocol was disclosed, which utilizes oxime esters and 4-hydroxycoumarins as the readily available starting materials and showcases broad substrate scope and good functional group tolerance. This method allows the simultaneous generation of two C-C and one C-O bonds and two rings in one step, affording structurally new furocoumarins in moderate to good yields.

Solvent‐Free Synthesis of Carvone Oxime Ester and Carvone Oxime Sulfonic Esters

AbstractA ZnO‐mediated benzoylation between carvone oxime and acyl is reported, enabling access to diverse carvone oxime ester and carvone oxime sulfonic esters under solvent‐free conditions. The operationally simple procedure provides a novel method for the synthesis of oxime‐ester bonds with excellent chemo selectivity. This strategy provides a mild, direct, and green approach for synthesizing carvone oxime ester in moderate to excellent yields with good substrate tolerance. In addition, carvone oxime was synthesized under solvent‐free conditions.

Photoredox/Copper-Cocatalyzed Domino Annulation of Oxime Esters and NH4SCN: Access to Fully Substituted 2-Aminothiazoles.

Domino cyclization of oxime esters and NH4SCN facilitated by photoredox and copper cocatalysis has been established. Various structurally diverse fully substituted 2-aminothiazoles have been obtained in good yields at room temperature. It is featured by mild conditions, favorable functional group tolerance, and wide substrate scope. The present reaction is amenable to gram-scale synthesis, which is expected to find potential applications in organic synthesis and drug discovery. A plausible reaction mechanism is proposed.

Thermal Rearrangement of the S-N Bond of Thiooxime Esters.

The labile O-N bond of oxime esters has enabled versatile access to many heterocyclic scaffolds. Alternatively, the analogous chemistry for thiooxime esters, which contain an S-N bond, has not been explored. Herein, we interrogate the reactivity of thiooxime esters and identify a homolytic fragmentation and rearrangement mechanism. This work provides the first exploration of the reactivity of this S-N functional group.

Synthesis of β-Silyl Amines via Merging Photoinduced Energy and Hydrogen Atom Transfer in Flow.

The development of efficient methods for synthesizing β-silyl amines has long been a significant goal in organic synthesis. Previous methods mainly relied on the use of prefunctionalized substrates or special reagents. Herein, we present a visible-light-promoted synthesis approach for β-silyl amines, utilizing a combination of photoinduced energy and hydrogen atom transfer processes. Using flow chemistry technology, a variety of valuable skeletons, including β-silyl amines and α-amino esters, can be produced from readily available feedstocks such as hydrosilanes and simple alkanes. Moreover, the strategy's full-process fluidized production capability highlights its potential for industrial-scale manufacturing. Mechanistic studies revealed that oxime esters can act as radical precursors as well as hydrogen atom transfer reagents.

Discovery of Novel Cyclobutyl Oxime Ester Derivatives Containing an α,β-Unsaturated Carbonyl Moiety as Potential Mitochondrial Toxins.

As part of continuous work to explore novel and efficient fungicides originating from natural products, a series of cyclobutyl oxime ester derivatives containing an α,β-unsaturated carbonyl moiety were designed and synthesized. In line with the primary evaluation of the inhibitory effect on common pathogenic fungi causing crop failure, a systematic study on the antifungal activity of target compounds against Rhizoctonia solani was carried out. Most target compounds exhibited satisfactory antifungal activity, and 10 of them were superior to the positive control trifloxystrobin. The most notable median effective concentration (EC50) of compound 6b was 1.70 μg/mL, which was considerable for an intensive study. The control efficacy of compound 6b on potted rice against R. solani was superior to trifloxystrobin at identical concentration. The mycelial morphology and cell membrane permeability of the treated fungi were disrupted, and the meaningful enzyme activities of SDH and POD were also restrained. The reactive oxygen species, nuclear morphology, and mitochondrial membrane potential of the treated hypha reflected an apparent difference compared with the normal morphology, which represented mitochondrial function damage. In addition, chemical features essential for the activity and docking mode within the compound and cytochrome bc1 complex were accessed by computer-aided technology. This study provided insights into the development of new green and efficient fungicides targeting the mitochondria.

Oxime esters: Potential alternatives to phosphine oxides, for overcoming oxygen inhibition in material jetting applications

Material jetting technology is emerging as a prominent technique within the additive manufacturing domain for printing multi-material objects. Despite its various advantages, including high printing resolution, oxygen inhibition remains the main issue for UV-curable materials. Oxime esters are interesting photoinitiators for this application due to their ability to undergo a photocleavage reaction followed by decarboxylation, limiting the diffusion of oxygen. A series of four commercially available oxime esters were studied as Type I photoinitiators, with the photoinitiating ability and photochemical properties of two of them never having been investigated before. Initially, their UV–visible absorption properties were studied, revealing significant absorption up to 420nm. Photopolymerization kinetic studies indicate that the oxime esters can outperformed benchmark photoinitiators such as phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO) by reaching around 80% of double bond conversion in 12µm layer under air (for O-16) against 60% for BAPO under the same conditions. Finally, the oxime esters were tested in 3D-inkjet printing applications, displaying highly promising results with tack-free surfaces.

A screen for cell envelope stress uncovers an inhibitor of prolipoprotein diacylglyceryl transferase, Lgt, in Escherichia coli

The increasing prevalence of antibiotic resistance demands the discovery of antibacterial chemical scaffolds with unique mechanisms of action. Phenotypic screening approaches, such as the use of reporters for bacterial cell stress, offer promise to identify compounds while providing strong hypotheses for follow-on mechanism of action studies. From a collection of ∼1,800 Escherichia coli GFP transcriptional reporter strains, we identified a reporter that is highly induced by cell envelope stress-pProm rcsA -GFP. After characterizing pProm rcsA -GFP induction, we assessed a collection of bioactive small molecules for reporter induction, identifying 24 compounds of interest. Spontaneous suppressors to one compound in particular, MAC-0452936, mapped to the gene encoding the essential prolipoprotein diacylglyceryl transferase, lgt. Lgt inhibition by MAC-0452936 inhibition was confirmed through genetic, phenotypic, and biochemical approaches. The oxime ester, MAC-0452936, represents a useful small molecule inhibitor of Lgt and highlights the potential of using pProm rcsA -GFP as a phenotypic screening tool.

Chalcone-derived oxime esters with efficient photoinitiation properties under LED irradiation

Chalcone-derived oxime esters with efficient photoinitiation properties under LED irradiation

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.

4+1] Heteroannulation to Form 1-Pyrrolines through Alder-Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine.

We report in this paper a novel Cu-catalyzed synthesis of polysubstituted 1-pyrrolines. The reaction of β,γ-unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2'-biquinoline affords the corresponding 1,6-enynimines, which undergo a highly stereoselective Alder-ene reaction to afford 1-pyrrolines with concomitant generation of a quaternary carbon and a 2-azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1-difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron-rich alkyne during the pericyclic reaction. The resulting 1-pyrrolines undergo facile acid-catalyzed regioselective Wagner-Meerwein rearrangement to provide 2H-pyrroles in excellent yields. The 2H-pyrroles are also accessible from 4 and 5 in a one-pot manner without isolation of the 1-pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5-tetrasubstituted pyrrolidine, is accomplished.

Synthesis of Acylation Polycyclic Derivatives via Regioselective Acylation/Cyclization of 1,7-Dienes with Acyl Oxime Esters.

A visible-light-induced radical cascade regioselective acylation/cyclization of 1,7-dienes with acyl oxime esters for the preparation of acylation polycyclic compounds via NCR-mediated C-C σ-bond cleavage is established. The transformation involves the cleavage of the C-C σ-bond in acyl oxime esters and selective addition of the electron neutral C═C bonds in 1,7-dienes for the synthesis of acyl polycyclic quinolinone derivatives, not the traditional seven-membered ring products. The strategy offers several advantages, including broad substrate tolerance, no need for bases, hyperstoichiometric radical initiators, and other auxiliaries.

Phenothiazine-carbazole-based bis oxime esters (PCBOEs) for visible light polymerization

In this study, a series of seven PCBOEs was innovatively designed and successfully synthesized for the first time by bridging a phenothiazine and a carbazole unit by mean of an acetylene spacer and bearing oxime ester groups as end groups on both sides. Structures of the different difunctional oxime esters were confirmed through NMR and HRMS. All PCBOEs exhibited excellent light absorption properties in the visible range. Upon excitation with a 405 nm LED for 60 s, a complete photolysis of the oxime esters could be achieved. Parameters such as the singlet state energy and the triplet state energy demonstrated the facile generation of the corresponding radicals upon light absorption by PCBOEs. Photopolymerization kinetics in TMPTA confirmed the homolytic cleavage of oxime esters and the generation of radicals. CO2 absorption peaks were detected when the PCBOEs/TMPTA systems were excited with a 405 nm LED. Based on the positive results, the photochemical mechanisms of polymerization with PCBOEs was proposed. PCBOE3 was identified as the best candidate of the series and this bifunctional oxime ester was successfully used for the 3D-printing of the “IS2M” logo via DLW. Experimental results from DSC also confirmed that PCBOEs not only serve as photoinitiators but also possess high reactivity as thermal initiators.