Kabachnik-Fields Reaction Research Articles

A novel route for the synthesis of phosphonate-containing siloxanes by the catalyst-free Kabachnik—Fields reaction

A novel route for the synthesis of phosphonate-containing siloxanes by the catalyst-free Kabachnik—Fields reaction

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M − HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33−80 μM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 μM), demonstrated good activity (IC50 = 17 μM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 μM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.

Synthesis, characterization, antibacterial activity, DFT and molecular docking studies of four4-phenyldiazenyl phenyl aminophosphonates

Four 4-phenyldiazenyl phenyl aminophosphonates were successfully synthesized using an eco-friendly one-pot Kabachnik-Fields reaction. The reaction involved aromatic aldehydes, 4-(Phenyldiazenyl) aniline, and diethylphosphite, with Ni(SO4).6H2O (5 mol%) serving as an efficient catalyst. Conducted at room temperature under solvent-free conditions within 20 min, the reaction yielded excellent chemical results, with up to 90 % yields. The compounds underwent characterization through IR, UV-vis, NMR (1H, 13C, 31P), and HRMS. The antibacterial activity of the synthesized molecules was evaluated against two Gram-negative bacteria (Escherichia coli ATTC 25922, Pseudomonas aeruginosa ATTC 27853) and the Gram-positive bacterium (Staphylococcus aureus ATTC 25923) at different compound concentrations (32-128 µg/ml) compared to Cefixime. The results revealed significant antibacterial activity of molecules 4b, 4c and 4d against the two Gram-negative bacteria and 4b against S. aureus, with a minimum inhibitory concentration (MIC) of 0.5 µg/mL, surpassing the reference drug. DFT calculations at B3LYP 6-311G (2d, p) basis set were employed for geometry optimization, stability and reactivity studies, including HOMO/LUMO, ΔEGAP, dipole moment, electronegativity, electrophilicity, and calculated thermodynamic descriptors (Enthalpy and Gibbs Free Energy). The molecular docking studies confirmed strong interactions between the synthesized compounds and proteins, with binding affinities ranging from -9.6 to -6.8 kcal/mol. Notably, diethyl (4-biphenyl (4-phenyldiazenyl) phenylamino) methylphosphonate (4b) demonstrated the highest efficiency, making it a promising antibacterial candidate according to both experimental and computational assessments.

Recent Developments in Functional Polymers via the Kabachnik–Fields Reaction: The State of the Art

Recently, multicomponent reactions (MCRs) have attracted much attention in polymer synthesis. As one of the most well-known MCRs, the Kabachnik–Fields (KF) reaction has been widely used in the development of new functional polymers. The KF reaction can efficiently introduce functional groups into polymer structures; thus, polymers prepared via the KF reaction have unique α-aminophosphonates and show important bioactivity, metal chelating abilities, and flame-retardant properties. In this mini-review, we mainly summarize the latest advances in the KF reaction to synthesize functional polymers for the preparation of heavy metal adsorbents, multifunctional hydrogels, flame retardants, and bioimaging probes. We also discuss some emerging applications of functional polymers prepared by means of the KF reaction. Finally, we put forward our perspectives on the further development of the KF reaction in polymer chemistry.

Механосинтез полимерных α-аминофосфонатов

Kabachnik–Fields reaction is widely used to obtain α-aminophosphonates, including polymeric ones. In addition, methods for the mechanosynthesis of α-aminophosphonates under mechanosyn-thesis conditions are being developed. The article examined methods for the preparation of aryl-substituted polymeric α-aminophosphonates by reacting isomeric diaminobiphenyls, terephthalic aldehyde and diethylphosphonate in the absence of a solvent in a ball mill. As a result, polymeric α-aminophosphonates 4 were obtained. The structure of the products was established on the basis of 1H, 31P and IR NMR spectra. In the 1H NMR spectrum, it should be noted the presence of charac-teristic signals of the protons of aromatic fragments in the form of multiplets at 8.62, 8.07 and 7.54 ppm, signals of the proton at the sp3-hybridized carbon atom in the form of a broadened singlet at 3.75 ppm, as well as a signal of the protons of the group OСH2CH3 as a multiplet at 4.14 ppm. and a multiplet at 1.20 ppm. In the 31P spectrum there was the presence of a phosphorus signal at 22.96 ppm. Absorption bands at 1161 cm–1 (P=O), 1051 cm–1 (P-C-O), 2957 cm–1 (OCH3) and 3445 cm–1 (NH amide fragment) were observed in the IR spectra. Additionally, the possibility of post-modification of polyvinyl chloride (PVC) with fragments of α-aminophosphonates was investigat-ed by reacting the former with 2-aminothiophenol, benzoaldehyde and diethylphosphonate in the absence of a solvent in a ball mill, as well as by reacting with 2-aminothiophenol, terephthalic aldehyde and diethylphosphonate under similar conditions. Thus, a possibility of mechanosynthesis of α-aminophosphonates was demonstrated, as well as the possibility for the post-modification of PVC with fragments of α-aminophosphonates.

N-Functionalization of β-aminophosphonates: cytotoxic effects of the new derivatives.

β-Aminophosphonates obtained by the Michael addition of primary amines to the double bond of diethyl vinylphosphonate proved to be suitable starting materials (amine components) in the Kabachnik-Fields reaction with formaldehyde and dialkyl phosphites or secondary phosphine oxides to afford N-phosphonylmethyl- and N-phosphinoylmethyl-β-aminophosphonates. On the other hand, the starting aminophosphonates were modified by N-acylation using acid chlorides. The N-acyl products were found to exist in a dynamic equilibrium of two conformers as suggested by the broad NMR signals. At 26 °C, there may be rotation around the N-C axis of the acylamide function. At the same time, low-temperature NMR measurements at -5 °C revealed the presence of two distinct rotamers that could be characterized by 31P, 13C and 1H NMR data. The modified β-aminophosphonic derivatives were subjected to a comparative structure-activity analysis on MDA-MB-231, PC-3, A431 and Ebc-1 tumor cell lines, and in a few cases, significant activity was detected.

Box–Behnken design for the optimisation of Kabachnik–Fields reaction catalysed by natural kaolinite clay under eco-friendly conditions

Kaolin catalysed the Kabachnik–Fields reaction. Box–Behnken design optimisation. Green chemistry conditions.

New biocidal hybrids bearing acridine and aminophosphonate Scaffolds against different bacterial pathogens

New hybrids containing acridine and α-amino phosphonate scaffolds 6a-h were synthesized by three one-pot reactions via Kabachnik–Fields reaction of 9-aminoacridine derivatives 3a-d, aldehydes 4a,b and triphenyl phosphite 5 in equimolar ratio under stirring at room temperature. The installation of the afforded hybrids was affirmed by different spectroscopic methods as IR, 1HNMR, 13CNMR, 31P NMR, MS and elemental analysis. The antibacterial activities of hybrids 6a-h were screened against both Gram-positive and Gram-negative bacteria of four pathogenic strains, comparable to ampicillin and chloramphenicol drugs. Most hybrids showed higher activity compared to the reference drugs. Notably, the antibacterial performance of 6c was more substantial than other analogues with best minimum inhibitory concentration (MIC) and highest zone of inhibition (ZOI) of 31, 34, 35, 38 mm, against Serratia marcescens, Streptococcus mutans, MRSA and Klebsiella pneumoniae clinical isolates respectively. In addition, Transmission Electron Microscopes (TEM) was carried out to study the mode of action of 6c with MRSA, the results confirmed that the titled hybrid caused the disruption of bacterial cell wall. Moreover, the time-dependent kill study revealed that the investigated compounds were time and dose-effective bactericidal agents and could be used as potential leads for further development and optimization of novel antibacterial agents.

Flexible interactions of the rare-earth elements Y, La, and Lu with phosphorus in metallacyclohexane rings.

A geometrically flexible bifunctional (bis)aminophosphine ligand was synthesized in a three-component, one-pot Kabachnik-Fields reaction using tert butylphosphine, paraformaldehyde, and 3,5-dimethyl aniline. The product, bis((3,5-dimethylphenyl)aminomethyl) tert butylphosphine (ArBiAMP t Bu), containing two secondary amines and a tertiary phosphine, was isolated in good yields. Deprotonation of both N-H groups with (trimethylsilyl)methylpotassium (K-CH2SiMe3), followed by salt metathesis with LaI3, YI3, and LuI3 generated the corresponding MI(ArBiAMP t Bu)(thf)3 complexes (M = Y (1), La (2), and Lu (3)) in good yields. A sterically encumbered indene, 1,3-diisopropyl-4,7-dimethyl-1H-indene, iPrMeInd, was deprotonated in situ and installed via salt-metathesis to generate the organometallic series of η5-indenide complexes, M(ArBiAMP t Bu)(η5-iPrMeInd)(thf) (M = Y (4), La (5), and Lu (6)). 1H, 31P, 13C, and 89Y NMR experiments, IR spectroscopy, and single crystal X-ray diffraction (SC-XRD), were used to characterize these complexes. The Y-P coupling constant was found to be variable depending on the modifiable coordination environment of the metal center, indicating potential as both a spectroscopic handle as well as providing insight into the influence of additional ligands on the metal center.

Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

Preparation of Ar–P–N-structured flame retardant via Kabachnik–Fields reaction for fire safety and mechanical reinforcement of polyurethane

Fire safety of polyurethanes (PUs) has limited their further practical applications. To address this problem, we designed novel phosphorus-based flame retardants (P-FR) by incorporating aryl (Ar) groups via Kabachnik–Fields reaction, realizing π–π interaction-reinforced Ar2 and Ar5. Total heat release and peak heat release rate of PU/Ar5, whose flame-retardancy-index of 5.02 due to reduced combustion time, decreased 23.24 and 9.23 %, respectively, compared with neat PU. Moreover, UL94 rating for PU/Ar5 was improved from V-2 to V-0. These results demonstrate that Ar5 effectively generate a barrier effect that blocks oxygen, fuel, and heat. Sluggish mobility and phase transition are responsible for such enhancement due to a delay effect with the existence of π–π interactions and steric hindrance. Encouragingly, tensile strength and toughness of PU/Ar5 were greatly improved by 1345.8 and 670.3 %, respectively, compared with neat PU. We believe that this study could provide a promising method for introducing specific function to flame retardants to enhance fire safety and mechanical properties of composites.

TBAPMNP as an Effective and Recyclable Heterogeneous Catalyst for Single-Pot Three Component Synthesis of α-Aminophosphonates through Kabachnik–Fields Reaction

TBAPMNP as an Effective and Recyclable Heterogeneous Catalyst for Single-Pot Three Component Synthesis of α-Aminophosphonates through Kabachnik–Fields Reaction

Ultrasound mediated nano ZnO catalyzed synthesis of new α-aminophosphonates as potential anti-diabetic agents; an in silico ADMET, molecular docking study, α-amylase and α-glucosidase inhibitory activity

A more efficient and ecologically friendly method has been devised for the preparation of α-amino phosphonates by Kabachnik-Fields (K-F) reaction in a solvent-free environment using an ultrasonication technique catalyzed by nano ZnO. Primarily, an in silico ADMET and molecular docking analysis was carried out on each molecule prior to synthesis to get insight into drug-likeliness behavior and their capacity to inhibit α-amylase and α-glucosidase. The structure of the newly synthesized compounds was confirmed using spectroscopic analysis, and each one’s in vitro inhibitory action against α-amylase and α-glucosidase was evaluated. The compounds diethyl (4-(4-oxo-4H-chromen-2-yl)phenylamino)(4-hydroxy-3-nitrophenyl)methylphosphonate (7e) and diethyl (4-(4-oxo-4H-chromen-2-yl)phenylamino)(benzo[d][1,3]dioxol-6-yl)methylphosphonate (7h) exhibited the highest inhibitory activity against α-amylase in comparison to the reference substance acarbose. The compounds diethyl (4-(4-oxo-4H-chromen-2-yl)phenylamino)(4-fluorophenyl)methylphosphonate (7d), diethyl (4-(4-oxo-4H-chromen-2-yl)phenylamino)(3-(trifluoromethyl)phenyl)methylphosphonate (7 g) and diethyl (4-(4-oxo-4H-chromen-2-yl)phenylamino)(benzo[d][1,3]dioxol-6-yl)methylphosphonate (7h) have shown the highest inhibitory activity against α-glucosidase than the reference drug, Acarbose. The remaining compounds have shown equipotent to good inhibitory activity against both the tested enzymes.

Synthesis and surface activity of two novel phosphate silicone surfactants

Two phosphate amphoteric surfactants based on silicone were synthesized. Phosphate Gemini surfactant ((C12P2)2Si2) with disiloxane as bridging group and double-chain surfactant (C12P2Si3) with hydrophobic hydrocarbon chain and trisiloxane were prepared by hydrolysis reaction, Kabachnik-Fields reaction, and quaternization reaction. FT-IR, 1H NMR and TGA confirmed the chemical structure and thermal stability of the synthesised (C12P2)2Si2 and C12P2Si3. The physicochemical behavior at the air–liquid interface was investigated. The results showed that the critical micelle concentration (CMC) values of (C12P2)2Si2 and C12P2Si3 are 0.53 and 0.78 mmol/L, respectively. The two new surfactants had surface tension at CMC equal to approximately 28 mN/m and their surface tension varied with temperature and electrolyte (NaCl, CaCl2, and MgCl2) concentration. At high temperatures and with high concentration electrolytes, they exhibited good air–liquid interfacial activity. In addition, the size of the aggregates of the surfactants in aqueous solutions above CMC was determined by the dynamic light scattering (DLS) measurements.

A new class of anticancer activity with computational studies for a novel bioactive aminophosphonates based on pyrazole moiety

The present study involves synthesis a new series of α-aminophosphonates 2a-f and 4a-d derivatives in good yield with a simple workup via Kabachnik-Fields reaction in the presence of lithium perchlorate as Lewis acid catalyst. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data. The in vitro anticancer activities of each compound were evaluated against colorectal carcinoma Colon cancer (HCT-116) and Epdermoid carcinoma (HEP2) and also Human lung fibroblast normal cell line (WI38) compared with Doxorubicin. The results showed that Compounds 2a, 4b and 4d exhibited more potent inhibitory activity for Epdermoid Carcinoma (HEP2) compared with doxorubicin. For colon carcinoma cells (HCT-116) Compounds 2a, 2d and 4b gave the strongest activity among all compounds compared with doxorubicin. Moreover, all designed structures were docked into the active site of VEGFR2 and FGFR1 proteins. The result reveals that compound 2b and have the strongest inhibitory activity of the VEGFR2 and FGFR1 proteins indicating that these substances might conceivably operate as VEGFR2 and FGFR1 inhibitors and hence might take role in anticancer activities with various binding interactions. The 3D-QSAR models produced strong statistical results since they were defined by PLS factors 4 and confirmed by parameters as R2, R2 CV, Stability, F-value, P-value, RMSE, Q2, and Pearson-r.

Crystal Structure, quantum chemical analysis and apoptotic propensity of diaryl substituted α-aminophosphonates as selected C[sbnd]P bonded systems

Three component Kabachnik-Fields reaction under sonochemical conditions was utilized for synthesizing library of electronically diverse aryl substituted α-aminophosphonates as representative carbon phosphorus bonded systems. Single crystal X-ray structures of four novel α-aminophosphonate derivatives with comprehensive Hirshfeld surface analysis for highlighting influence of different functionalities over α-aminophosphonate motif on the crystal packing pattern and formation of molecular assemblies via supramolecular aggregation have been presented. Solid state absorption and photoluminescence studies corroborated electronic and crystal packing influences. The computational methodologies for evaluating quantum chemical descriptors of electronic properties of α-aminophosphonates were bench marked. The bioactivity potential of synthesized library of α- aminophosphonates was evaluated from their cytotoxic propensity towards human cancer lines in NCI-60 panel via SRB assay. The screened derivatives showed a range of cytotoxicity against cancer cell lines in NCI-60 panel. Compound 3 exhibited highest cell growth inhibition in prostate cancer cells with IC50 value of 10.94 μM. For mechanistic insights apoptotic propensity was evaluated using caspase-3 enzyme assay in PC-3 cells. The onset of apoptosis via caspase-3 activation was evidenced as a major pathway from morphological changes under fluorescence microscope with and without DAPI staining. The triggering of apoptosis via caspase 3 activation by the lead compound 3 was also confirmed from western blot analysis of PARP-1 in PC-3 cancer cells. Furthermore, the anti-metastatic potential of compound 3 can be predicted from its efficacy in restricting the migration of PC-3 cancer cells under in vitro conditions observed from wound healing assay.

The Last Decade of Optically Active α-Aminophosphonates.

α-Aminophosphonates and related compounds are important due to their real and potential biological activity. α-Aminophosphonates may be prepared by the Kabachnik-Fields condensation of oxo compounds, amines and dialkyl phosphites, or by the aza-Pudovik addition of the same P-reagents to imines. In this review, the methods that allow for the synthesis of α-aminophosphonates with optical activity are surveyed. On the one hand, optically active catalysts or ligands may induce enantioselectivity during the Kabachnik-Fields reaction. On the other hand, asymmetric catalysis during the aza-Pudovik reaction, or hydrogenations of iminophosphonates, may prove to be a useful tool. Lastly yet importantly, it is possible to start from optically active reagents that may be associated with diastereoselectivity. The "green" aspects of the different syntheses are also considered.

Catalyst‐ and Solvent‐Free Room Temperature Synthesis of α‐Aminophosphonates: Green Accomplishment of the Kabachnik–Fields Reaction

AbstractA catalyst‐ and solvent‐free room temperature method has been elaborated for the three‐component (carbonyl compounds, primary or secondary amines and phosphites) Kabachnik–Fields synthesis of α‐aminophosphonates. First, we have studied some parameters that potentially influence the course of the reaction using benzaldehyde, aniline and diethyl phosphite. In order to extend the reaction under the new reaction conditions, we then carried out 3 series of experiments always varying one of the three reagents. In general, with a few exceptions, good yields were obtained, although in some cases long reaction times were required.

Synthesis and Characterization of a New Series of Bis(allylic-α-aminophosphonates) under Mild Reaction Conditions.

Several bis(α-aminophosphonates) have been conveniently prepared in good yields using a straightforward multicomponent Kabachnik-Fields reaction between ethane 1,2-diamine or propane 1,3-diamine, diethylphosphite and aldehydes under catalyst-free conditions. The nucleophilic substitution reaction of bis(α-aminophosphonates) prepared and ethyl (2-bromomethyl)acrylate under mild reaction conditions afforded an original synthetic approach to a new series of bis(allylic-α-aminophosphonates).