Active Methylene Research Articles

Divergent and Synergistic Photocatalysis: Hydro- and Oxoalkylation of Vinyl Arenes for the Stereoselective Synthesis of Cyclopentanols via a Formal [4+1]-Annulation of 1,3-Dicarbonyls.

The controllable divergent reactivity of 1,3-dicarbonyls is described, which enables the efficient hydro- and oxoalkylation of vinyl arenes. Both reaction pathways are initiated through the formation of polarity-reversed C-centered-radical intermediates at the active methylene center of 1,3-dicarbonyls via direct photocatalytic C-H bond transformations. The oxoalkylation of alkenes is achieved under aerobic conditions via a Cu(II)-photomediated rebound mechanism, while the corresponding hydroalkylation becomes possible under a nitrogen atmosphere by the combination of 4CzIPN and a Brønsted base. The breadth of these divergent protocols is demonstrated in the late-stage modification of drugs and natural products and by the transformation of the products to a variety of heterocycles such as pyridines, pyrroles, or furans. Moreover, the two catalytic modes can be combined synergistically for the stereoselective construction of cyclopentanol derivatives in a formal [4+1]-annulation process.

Convergent paired electrosynthesis of different types of bis-β-diketone derivatives based on the knoevenagel condensation reaction under green conditions

A green convergent paired electrochemical protocol has been developed for the synthesis of some bis-β-diketones via Knoevenagel condensation reaction. In this method, the electrochemical oxidation of primary alcohols to the corresponding aldehydes have taken at anode and the reduction of β-diketones to active methylene compounds has happened in cathode. In next step, the cathodically activated methylene reacts with anodically generated aldehyde. Different types of bis-β-diketones have been synthesized using C1–C5 primary alcohols and different β-diketones. In this work, we proposed a unique convergent paired mechanism for the synthesis of bis-β-diketones based on possible anodic and cathodic reactions. The effective parameters such as, solution pH, current density, electrode material, alcohol concentration and type of cell have also been optimized. This method provides a new strategy for the synthesis of a wide range of products in the mild conditions and in an undivided cell without using the any catalyst and toxic solvent.

Enhanced antioxidant and cytotoxic activity of ferrocenyl-substituted curcumin via stabilization of promoter c-MYC silencer element

We are reporting a successful attachment of ferrocenyl moiety at the active methylene carbon atom of β-diketone of curcumin via Knoevenagel condensation reaction, to utilize the optimum selectivity toward biological targets. The formation of ferrocenyl curcumin (i.e., Fc-cur) has been confirmed by 1H NMR, 13C NMR, and FT-IR spectra analysis. Further, circular dichroism (CD) spectroscopy, thermal denaturation, absorption, and fluorescence spectroscopy have been used to understand the association of ligand (i.e., Fc-cur) with G-quadruplex. Based on these analysis, the binding mechanism of the ligand i.e., Fc-cur to the parallel and hybrid topology present in different G-quadruplex has been proposed. Further, the binding and modes of the interaction of Fc-cur with Pu27 c-MYC silencer element and H-telo G-quadruplex have unravelled selective and stronger binding via intercalation with the parallel topology of c-MYC G-quadruplex rather than the hybrid topology of H-telo quadruplex. The manifestation of better antioxidant activity of Fc-cur has been demonstrated by showing a stronger radical scavenging capability than pristine curcumin. The cytotoxicity analysis of the proposed ligand i.e., Fc-cur against Vero and HeLa cells have clearly reflected the nontoxicity toward Vero cells and quite effective against the HeLa cells which reduces the cancer cells more effectively than the already reported for curcumin. Communicated by Ramaswamy H. Sarma

Novel Hydrazone Chromophore Sensor for Metallochromic Determination of Cadmium Ions

For the detection of Cd(II) in aquatic media, a novel dicyanomethylene dihydrofuran hydrazone(DCDHFH)-based colorimetric chemosensor was developed. DCDHFH was prepared by an azo-coupling process involving the diazonium chloride of 2, 4-dichloroaniline and a dicyanomethylene dihydrofuran heterocyclic moiety bearing an active methyl group. The DCDHFH chromophore showed strong solvatochromism depending on solvent polarity due to electronic delocalization. The pH sensory effects of the DCDHFH chromophore were also explored. DCDHFH could be used to identify Cd(II) in the presence of other competitive metals, as indicated by variations in color and absorbance spectra. In the presence of cadmium ions, the synthesized DCDHFH probe with hydrazone recognition moiety exhibited a significant sensitivity and selectivity to cadmium ions at the ppm concentration level (10–250 ppm). A DCDHFH-immobilized paper test strip was also prepared and effectively used for the detection of cadmium in aqueous media at various concentrations. According to CIE Lab’s criteria, colorimetric strength (K/S), and the UV–Vis absorbance spectra, the cadmium detection abilities of the DCDHFH-immobilized paper strips were evaluated. The optimal pH range for the determination of Cd(II) was monitored in the area of 5.5–6.3, with a fast chromogenic change from yellow to red relying on the Cd(II) concentration. The deposition of dicyanomethylene dihydrofuran hydrazone onto the paper strip’s surface was studied by scanning electron microscopy (SEM).

Visible light triggered synthesis of spiro[indoline-3,4′-quinoline] via oxidative coupling of indole with enaminone and malononitrile

In the most recent research, a straightforward, effective, and environmentally friendly method for producing spiro[indoline-3,4′-quinoline] was developed in ethanol using a photocatalyst eosin y and a 22 W LED lamp. This method involves the oxidative coupling of indole with enaminone and malononitrile. This method's key features include the absence of metals, low cost, environmental friendliness, greenness, non-toxicity, ease of handling, and use of renewable energy like visible light. This method exhibits a wide substrate scope for indole and active methylene compounds, including different enaminones. For the first time, spiro compounds were produced using visible light-mediated metal-free multicomponent synthesis under benign reaction conditions.

Synthesis and in Silico Antiviral Activity of Novel Bioactive Thiobarbituric Acid Based Hydrazones and Pyrazoles against SARS-CoV-2 Main Protease (Mpro)

Owing to its broad spectrum biological activity, pyrimidines have been extensively employed as building blocks for synthesizing various drug mimic molecules. In the present work, a novel 2-hydrazineyl-5-(2-phenylhydrazineylidene)pyrimidine-4,6(1H,5H)-dione 3 was prepared and was subsequently reacted with a variety of substituted benzaldehyde derivatives 4a–c, 6, and heteroaryl ketones namely, 2-acetylthiophene 8, acetophenone 10a, 2-acetylpyridine 10b, or 3-acetylindole 12 to give the respective hydrazones 5a–c, 7, 9, 11a,b, or 13. Moreover, the reaction of hydrazine 3 with commercially available active methylene compounds, namely, ethyl benzoylacetate 14, acetylacetone 16, and diethyl malonate 18, afford the respective pyrazole derivatives 15, 17, and 19. All reactions were preceded in good yields and the structures of the synthesized compounds were confirmed by elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral data. The anti-viral activity of the synthesized derivatives was investigated against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MD). The docking scores against (PDB: 6LU7), were calculated via Standard Precision (SP) method of the Glide docking module of Meastro. The docking score of the novel compounds ranged between −7.29 and −6.02 with good affinity toward Mpro. Pyrazolinone 19 demonstrated the lowest docking score (-7.293 kcal/mol) and glide emodel −72.978, showed three hydrogen bond interactions with GLU166, GLY143 and the catalytic dyad CYS145. Thus, compound 19 was chosen for further molecular dynamics simulation study for 20 ns. The results indicated that the protein was almost stabilized with average four to five hydrogen bonds with compound 19 during the simulation period. This means the potential inhibitory activity of the promising pyrazolinone 19 against SARS-CoV-2 Mpro.

Template‐assisted Preparation of Self‐standing 2D‐MOF Membranes for Application in Cascade Reactions

AbstractSelf‐standing metal‐organic framework (MOF) membranes open up several application areas where their use in the powder form is either not possible or non‐sustainable. Most MOF membranes are prepared as a thin layer either on a supporting substrate or used as a composite membrane with additional supporting material. In this work, we present the preparation procedure for making highly stable, easy‐to‐handle, reusable, efficient pure MOF membranes (UiO‐66‐SO3H and UiO‐66‐NH2 membranes; thickness 240±12 μm and 265±10 μm, respectively) with hollow fiber morphology and their use in cascade reactions in one‐pot catalyzed by incompatible acid‐base in tea‐bag‐type concept. The catalytic performance of the catalyst membranes was tested by reacting benzaldehyde dimethyl acetal with three active methylene compounds. The membranes exhibited excellent catalytic activity in cascade reactions in one pot (the yield of the product was as high as 99.9 %) and can be reutilized up to 15 times without any significant loss in activity. Stable pure MOF membranes, as shown in this work, would be of interest for several other applications beyond catalysis.

Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones.

Dehydroacetic acid and triacetic acid lactone are known to be versatile substrates for the synthesis of a variety of azaheterocycles. However, their fluorinated analogs were poorly described in the literature. In the present work, we have investigated reactions of trifluorotriacetic acid lactone and hexafluorodehydroacetic acid with primary amines, phenylenediamine, and phenylhydrazine. While hexafluorodehydroacetic acid reacted the same way as non-fluorinated analog giving 2,6-bis(trifluoromethyl)-4-pyridones, trifluorotriacetic acid lactone had different regioselectivity of nucleophilic attack compared to the parent structure, and corresponding 3-amino-6,6,6-trifluoro-5-oxohex-3-eneamides were formed as the products. In the case of binucleophiles, further cyclization took place, forming corresponding benzodiazepine and pyrazoles. The obtained 2,6-bis(trifluoromethyl)-4-pyridones were able to react with active methylene compounds giving fluorinated merocyanine dyes.

Non-covalent immobilized sultone based protic ionic liquids on nano silica sulfuric acid as novel heterogeneous catalysts for the efficient synthesis of tetrazolopyrimidines

In this research work, a novel strategy for the heterogenization of sultone based acidic ionic liquids via their non-covalent immobilization on nano silica sulfuric acid is reported and the catalytic ability of the prepared heterogeneous catalysts for the synthesis of tetrazolopyrimidines derivatives is investigated. The physicochemical properties of the prepared catalysts were studied using thermal and spectroscopic techniques such as 1H and 13C NMR, FTIR, SEM, TEM, TGA, EDX and BET. In the following, three-component reaction of aromatic aldehydes, active methylene compounds and 5-aminotetrazole to achieve tetrazolopyrimidine products in the presence of the introduced nano silica sulfuric acid supported acidic ionic liquids as new organic–inorganic nanohybrid catalysts was performed. The obtained results showed that the supported protic ionic liquids have better catalytic activity than their non-supported forms. Moreover, the recoverability, reusability and thermal stability of the acidic ionic liquids were also significantly improved by immobilization on nano silica sulfuric acid.

Chain Transfer Approach for Terminal Functionalization of Alternating Copolymerization of CO2 and Epoxide by Using Active Methylene Compounds as Chain Transfer Agents

Chain Transfer Approach for Terminal Functionalization of Alternating Copolymerization of CO₂ and Epoxide by Using Active Methylene Compounds as Chain Transfer Agents

Heteropolyacid coupled with cyanoguanidine decorated magnetic chitosan as an efficient catalyst for the synthesis of pyranochromene derivatives

In this study, a novel nanocatalyst was successfully prepared by heteropolyacid immobilization of magnetic chitosan-cyanoguanidine composite and fully characterized by different analysis methods, including FTIR, XRD, TGA, SEM, and EDS. The catalytic activity of fabricated composite was examined in a one-pot three-component reaction, involving the diverse active methylene compounds, various aryl aldehydes, and malononitrile in water. The results revealed the efficient catalytic performance of composite, while all reactions proceeded smoothly and led to the formation of the corresponding pyranochromene derivatives in high to excellent yields.

The Rise of Carbon‐based Leaving Groups

AbstractInconspicuous yet carbon‐based leaving groups has presented us with novel C−C bond cleaving avenues for organic transformations over the past few years. This initial review of the emerging field aims to highlight the chemistry that allows C−C bond cleavage in unstrained molecules in mild and sometimes metal‐free reaction conditions. A wide variety of carbon‐based leaving groups has been reported that demonstrate its vast utility for the formation of new C−H, C−N, C−C, C−O, and C−S bonds. The review has been divided in three main sections discussing the leaving group aptitude of active methylene compounds, active methyl compounds and electron‐rich arenes. With uncomplicated pre‐requisites for a carbon‐based fragment to act as leaving groups, we expect more such efficient leaving groups will be identified in the near future.

Immobilized sulfonic acid functionalized ionic liquid on magnetic cellulose as a novel catalyst for the synthesis of triazolo[4,3-a]pyrimidines

The Brønsted acidic ionic liquid 1-(propyl-3-sulfonate) vinyl imidazolium hydrogen sulfate [IL] was supported on modified magnetic cellulose. The physical structure, composition, and functional groups of the novel supported ionic liquid catalyst were characterized via XRD, FT-IR, EDS, SEM, VSM, TGA, TEM, and BET techniques. Owing to the combination of nano-support features and flexible imidazolium linkers, it acted as a “quasi-homogeneous” catalyst to catalyze the preparation of triazolo[4,3-a]pyrimidine derivatives by a one-pot three-component reaction of active methylene compounds (ethyl cyanoacetate or malononitrile), aminotriazole and aryl aldehydes. The catalyst shows good catalytic activity for the synthesis of triazolo pyrimidines after six times of recycling.

Self‐Sustaining Fluorination of Active Methylene Compounds and High‐Yielding Fluorination of Highly Basic Aryl and Alkenyl Lithium Species with a Sterically Hindered N‐Fluorosulfonamide Reagent

AbstractFluorination of carbanions is pivotal for the synthesis of fluorinated compounds, but the current N‐F fluorinating agents have significant drawbacks due to many reactive locations that surround the reactive N−F site. By developing a sterically hindered N‐fluorosulfonamide reagent, namely N‐fluoro‐N‐(tert‐butyl)‐tert‐butanesulfonamide (NFBB), we discovered a conceptually novel base‐catalyzed, self‐sustaining fluorination of active methylene compounds and achieved the high‐yielding fluorination of the hitherto difficult highly basic (hetero)aryl and alkenyl lithium species. In the former, the mild and high yield fluorination of active methylene compounds exhibited wide functional group tolerance and its novel catalytic fluorination‐deprotonation cycle mechanism was demonstrated by deuterium‐tracing experiments. In the latter, NFBB reacted with a variety of highly basic (hetero)aryl and alkenyl lithium species to provide the desired fluoro (hetero)arenes and alkenes in unprecedented high or quantitative yields.

Self-Sustaining Fluorination of Active Methylene Compounds and High-Yielding Fluorination of Highly Basic Aryl and Alkenyl Lithium Species with a Sterically Hindered N-Fluorosulfonamide Reagent.

Fluorination of carbanions is pivotal for the synthesis of fluorinated compounds, but the current N-F fluorinating agents have significant drawbacks due to many reactive locations that surround the reactive N-F site. By developing a sterically hindered N-fluorosulfonamide reagent, namely N-fluoro-N-(tert-butyl)-tert-butanesulfonamide (NFBB), we discovered a conceptually novel base-catalyzed, self-sustaining fluorination of active methylene compounds and achieved the high-yielding fluorination of the hitherto difficult highly basic (hetero)aryl and alkenyl lithium species. In the former, the mild and high yield fluorination of active methylene compounds exhibited wide functional group tolerance and its novel catalytic fluorination-deprotonation cycle mechanism was demonstrated by deuterium-tracing experiments. In the latter, NFBB reacted with a variety of highly basic (hetero)aryl and alkenyl lithium species to provide the desired fluoro (hetero)arenes and alkenes in unprecedented high or quantitative yields.

Hantzsch-like three-component synthesis of bis(1,4-dihydropyridines) and bis(fused-1,4-dihydropyridines) linked to piperazine core via 2-phenoxyethanone linkage: Novel hybrid molecules

The molecular hybridization of various compounds with known pharmacological activity is a particularly popular approach for the development of potential drugs with improved pharmacokinetic profiles. In this respect, a novel series of bis(1,4-dihydropyridine-3,5-dicarbonitrile), bis(decahydroacridine), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin), and bis(tetrahydropyrimido[4,5-b]quinoline-2,4,6-trione) derivatives linked to piperazine core via phenoxyethanone linkages were prepared via Hantzsch like reaction of the ((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))dibenzaldehydes, with the appropriate active methylene containing reagents. Attempted synthesis of the target products via bis-alkylation of the appropriate phenol with 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) in different basic conditions were unsuccessful.

Highly Active and Efficient Cu@SiO2 Catalyst: Enabled Nucleophilic and Electrophilic Activation of Active Methylene Compounds

AbstractThe utility of copper is strikingly afforded due to the variable oxidation state being widely used in various organic reactions. The copper‐catalyzed C−C bond formation with active methylene compounds are a straightforward approach with widespread uses in synthetic organic chemistry. A significantly lower amount of Cu‐supported SiO2 catalyst was synthesized through sol‐gel method. The microscopy analysis reveals the formation of spherical morphology and the uniform distribution of Cu nanoparticles of 2.5 nm size. Furthermore, copper was found in Cu+2 state by XPS analysis. The NH3‐TPD analysis estimated the 0.092 mmol/g acidic sites. The synthesized multifunctional catalyst was used for gabapentin intermediates through a series of active methylene compounds through tandem organic reactions. The catalyst gave excellent conversion (99%) and selectivity (99%) of the desired product. The catalyst was found to be highly stable and recycled for six cycles without losing any activity and selectivity to the reaction product.

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH4I.

The electrochemical preparation of 2-aminothiazoles has been achieved by the reaction of active methylene ketones with thioureas assisted by ᴅʟ-alanine using NH4I as a redox mediator. The electrochemical protocol proceeds in an undivided cell equipped with graphite plate electrodes under constant current conditions. Various active methylene ketones, including β-keto ester, β-keto amide, β-keto nitrile, β-keto sulfone and 1,3-diketones, can be converted to the corresponding 2-aminothiazoles. Mechanistically, the in situ generated α-iodoketone was proposed to be the key active species.

Regioselective Synthesis, Structural Characterization, and Antiproliferative Activity of Novel Tetra-Substituted Phenylaminopyrazole Derivatives.

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two N-methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.

The regioselective one-pot four-component synthesis of novel functionalized 4H-pyrano[2, 3-b]quinoline derivatives using DABCO as a homogeneous organocatalyst.

This study deals with the synthesis of the regioselective and facile domino one-pot four-component reaction of 2-chloroquinoline-3-carbaldehydes, 1, 3-cyclodione compounds (as cyclic active methylene), ethyl acetoacetate (as β-keto ester), and hydrazine hydrate in the presence of DABCO as a homogeneous organocatalyst yielding a novel series of 4H-pyrano[2, 3-b]quinolones. This multicomponent reaction has some advantages; the significant one is C-O bond formation under metal-free conditions. Other benefits include simple procedure, mild and green condition, high yield, easy purification, and excellent regioselectivity. All polycyclic products (7a-k, 11 new compounds) were characterized by IR, 1H NMR, 13C NMR, and mass spectra.