Short Reaction Times Research Articles

Environmentally Friendly Green O-Alkylation Reaction for Ethenzamide Synthesis

Ethenzamide (2-ethoxybenzamide), besides acetylsalicylic acid, is one of the mostly used salicylic acid derivatives in pharmaceuticals. It has analgesic and anti-inflammatory effects that originate from the inhibition of cyclooxygenase (COX-1) activity, thus blocking prostaglandin synthesis. In this work, efficient and eco-friendly methods were developed for the synthesis of ethenzamide via the O-alkylation reaction of salicylamide. The reactions were carried out under conventional conditions in a solvent-free system using variant solvents and different phase transfer catalysts (PTC) in the presence of microwave radiation or ultrasonic conditions. It was shown that in solvent-free conditions using TBAB as a catalyst, ethenzamide can be obtained within 15 min at 80 °C with 79% yield. Meanwhile, using microwave radiation under the same conditions, the reaction time can be shortened to 90 s with 92% yield. Notably, high yields can be achieved under PTC in water (or organic solvent-free) conditions using microwave radiation (2 min, 94%) or ultrasound (10 min, 95% efficiency). The studies prove that the PTC synthesis process of ethenzamide can be conducted under mild conditions, with a shorter reaction time and remarkably lower energy consumption in comparison to conventional processes, thus actualizing “green chemistry” for practical ethenzamide preparation.

Acid-decorated chitosan-magnetic aluminum ferrite as a bionanocomposite catalyst for green synthesis of biologically active [4,3‑d]pyrido[1,2‑a]pyrimidin-6‑ones

In this study, a novel hybrid nanostructure consisting of acid-decorated chitosan and magnetic AlFeO3 nanoparticles was fabricated. The acid-decorated chitosan provided a stable and biocompatible matrix for the magnetic AlFeO3 nanoparticles. Various techniques including Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction patterns (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), specific surface area (BET), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS) were used to characterize and confirm the successful synthesis of the hybrid nanostructure. The newly prepared magnetic bio-nanocomposite (AlFeO3@CS-SO3H) was effectively employed in the synthesis of biologically active 7-aryl[4,3d]pyrido[1,2a]pyrimidin-6(7H)one derivatives in an aqueous medium, creating an environmentally friendly process. The desired products were manufactured in high yields (88–98%) without the formation of noticeable side products. This procedure offers numerous advantages, including short reaction times, the use of a green solvent, the ability to reuse the catalyst without a significant decrease in catalytic activity, and easy separation of the catalyst using an external magnet. The high yields and minimal side product formation indicate the efficiency and selectivity of this method, making it a promising strategy for the sustainable production of biologically active compounds.

Chemical catalyst manipulating cancer epigenome and transcription

The number and variety of identified histone post-translational modifications (PTMs) are continually increasing. However, the specific consequences of each histone PTM remain largely unclear, primarily due to the lack of methods for selectively and rapidly introducing a desired histone PTM in living cells without genetic engineering. Here, we report the development of a cell-permeable histone acetylation catalyst, BAHA-LANA-PEG-CPP44, which selectively enters leukemia cells, binds to chromatin, and acetylates H2BK120 of endogenous histones in a short reaction time. Time-course analyses of this in-cell catalytic reaction revealed that H2BK120 acetylation attenuates the chromatin binding of negative elongation factor E (NELFE), an onco-transcription factor. This H2BK120 acetylation-mediated removal of NELFE from chromatin reshapes transcription, slows leukemia cell viability, and reduces their tumorigenic potential in mice. Therefore, this histone acetylation catalyst provides a unique tool for elucidating the time-resolved consequences of histone PTMs and may offer a modality for cancer chemotherapy.

Amine functionalized magnetic resorcinol formaldehyde as a green and reusable nanocatalyst for the Knoevenagel condensation

Herein, a novel amine-functionalized magnetic resorcinol-formaldehyde with a core-shell structure (Fe3O4@RF/Pr-NH2) is prepared through the chemical immobilization of (3-aminopropyl)trimethoxysilane over Fe3O4@RF composite. Characterization through FT-IR, EDX, PXRD, and TGA confirmed successful surface modification while preserving the crystalline structure of Fe3O4. The VSM analysis demonstrated excellent superparamagnetic properties, and SEM and TEM images revealed spherical particles for the designed nanocatalyst. The Fe3O4@RF/Pr-NH2 nanocomposite was employed as a robust nanocatalyst to promote the Knoevenagel condensation of benzaldehydes with ethyl cyanoacetate and malononitrile, resulting in the formation of substituted olefins. Various aromatic aldehydes were used as substrates in the presence of 0.01 g of Fe3O4@RF/Pr-NH2, achieving high to excellent yields (87–97%) within short reaction times (10–50 min) in EtOH at 60 °C. The high performance of Fe3O4@RF/Pr-NH2 is attributed to the hydrophobic nature of RF shell, which facilitates the accumulation of organic precursors around the catalytic active sites and enhances product yields. The designed magnetic catalyst could retain its high efficiency for at least ten runs. The metal-free, low-cost, and environmentally friendly attributes of the Fe3O4@RF/Pr-NH2 catalyst make it a promising alternative to traditional metal-based catalysts.

An Efficient Synthesis of 3,5-Bis-Aminated Pyrazolo[1,5-a]Pyrimidines: Microwave-Assisted Copper Catalyzed C-3 Amination of 5-Amino-3-Bromo-Substituted Precursors

An efficient method has been developed for the rapid production of diverse arrays of 3,5-bis-aminated pyrazolo[1,5-a]pyrimidines. The method utilizes CuI (5 mol%) and carbazole-based ligand L-1 (N-(9H-carbazol-9-yl)-1H-pyrrole-2-carboxamide) (10 mol%) for efficient Ullmann-type coupling of various amines to 5-amino-3-bromopyrazolo[1,5-a]pyrimidine precursors after heating in diethylene glycol (DEG) for only 1 h at 80 °C (microwave heating). 3,5-Bis-aminated products were obtained in good to excellent yields (60–93%, 83% average for 29 examples). 1° and 2° alkylamines, as well as a variety of aryl- or heteroarylamines coupled efficiently, and 1° and 2° alkyl (or aryl) amines at C-5 were well tolerated. The optimized conditions worked well on both the 50 mg and 1.0 g scales and gave products in only two steps from commercially available 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine. Advantages provided by this method include short reaction time, excellent yields, broad substrate scope, and avoidance of toxic reagents commonly utilized for reductive aminations of C-3 NH2 substituted precursors.

Alkyl 4-Alkoxyvalerates: Characterization and Application in Pd-Catalyzed Aminocarbonylation of Iodo(hetero)arene Compounds.

The palladium-catalyzed aminocarbonylation is one of the most effective methods for the synthesis of carboxamides having great importance. Replacing fossil-based organic solvents in this routinely used catalytic protocol with biomass-derived media is crucial for developing environmentally safe alternatives and towards sustainability considerations. In this study, the open-chain derivatives of bio-originated substance γ-valerolactone i. e. alkyl 4-alkoxyvalerates (alkyl: methyl, ethyl, and propyl) were characterized and tested as potential polar aprotic alternatives of fossil-based common N,N-dimethylformamide (DMF) in aminocarbonylation protocols. First, the temperature-dependent physicochemical properties of alkyl 4-alkoxyvalerates were determined. Based on their characteristics, methyl 4-methoxyvalerate (Me-4MeOV) was selected and introduced in the Pd-catalyzed aminocarbonylation of iodobenzene and morpholine as a model reaction, and an optimization study was carried out. Using the optimized conditions, several substituted iodobenzenes, as well as heteroaryl iodides, were successfully applied resulting in the target carboxamides selectively in short reaction time. Furthermore, the aminocarbonylation of iodobenzene in the presence of various amines was also accomplished extending the scope of the carboxamides produced in this alternative medium. Considering our observations, such as high conversions (up to 95 %) in short reaction time and selective amide formation, it has been justified that Me-4MeOV could be an appropriate alternative medium in aminocarbonylation protocols.

A Radiation Heating-Based Oscillatory Polymerase Chain Reaction System for Detecting Donkey-Hide Gelatin

Abstract Polymerase chain reaction (PCR) is a biochemical technique for copying DNA by repeatedly changing the temperature of nucleic acid samples. In this study, we aim to create an oscillatory PCR system with a short reaction time, which could have significant practical implications. The device uses an electromechanical module with a servo motor and a homemade heating–cooling system that combines a halogen lamp, a Peltier element, a cooling fin, and a blower fan. We code the motor program to control the reaction chamber moving back and forth in the infrared thermal cycling system. The system uses one infrared lamp for heating and one Peltier element/thermal dissipation fins/blower fan for cooling to shorten the overall reaction time of the thermal process. Results show that using the radiant heating and convection cooling method and a micro-sample of 10 μL to perform a PCR, the total time spent is 35 min, which saves about 1 h compared to commercially available PCR instruments. The proposed PCR approach could specifically detect donkey-hide gelatin (DHG) made from donkey skin, offering a rapid and cost-effective solution. Therefore, our device has the advantages of easy manufacturing, low cost, and rapid temperature ramping rate for PCR.

Scalable Mechanochemical Synthesis of Biotin[6]uril.

Biotin[6]uril, a chiral, water-soluble and anion binding macrocycle, is formed via dynamic covalent chemistry. In this study, we present a scalable and high-yielding synthesis of biotin[6]uril via a mechanochemical solid-state approach. The optimized protocol involves mechanical grinding of solid d-biotin with paraformaldehyde in the presence of 0.3 equivalents of 48 % aqueous HBr, which functions as a catalyst, template, and liquid grinding additive. This mechanochemical process is carried out in a shaker or planetary mill, followed by aging at an elevated temperature to produce biotin[6]uril with an HPLC yield of up to 96 %. The condensation and macrocyclization reaction was successfully scaled up 82-fold, producing nearly 20 g of biotin[6]uril with a high 92 % isolated yield and 91 % purity. Compared to conventional solution-based method, this mechanochemical approach offers several advantages, including significantly higher yields, shorter reaction times, enhanced scalability, simpler operational requirements, and substantially lower process mass intensity.

Selective Synthesis of Isoquinoline-1-Carboxamides via Palladium-Catalyzed Aminocarbonylation in DMF and Biomass-Derived Solvents

In this study, the palladium-catalyzed aminocarbonylation of 1-iodoisoquinoline was accomplished in the presence of various amines. While the reactions with simple primary and secondary amines were carried out by using the well-known Pd(OAc)2/PPh3 catalyst, the application of amines with lower basicity (e.g., aromatic amines) or more difficult structures (e.g., amino acid methyl esters, nortropine, diethyl (α-aminobenzyl)phosphonate) required the use of bidentate XantPhos ligand to achieve complete conversion in short reaction time (2–8 h). In this way, several valuable isoquinoline-1-carboxamides were synthesized in chemoselective carbonylation and isolated in good to high yields (55–89%). Furthermore, the aminocarbonylation of the model compound in the presence of several amines was also investigated in three biomass-derived solvents (GVL, ethyl levulinate, and 2-MeTHF). After comparing the outcome of the reactions in DMF and the above green solvents, similar reactivity was observed, justifying that they could be considered a feasible alternative reaction medium.

Chemical and Enzymatic Mechanosynthesis of Organocatalytic Peptide Materials Based on Proline and Phenylalanine.

In recent years, mechanosynthesis of peptides through either chemical or enzymatic routes has been accomplished. In part, this advancement has been driven due to the organocatalytic properties of peptide-based biomaterials. In this work, we report the merging of chemical and enzymatic protocols under mechanochemical conditions to synthesize peptide materials based on L-proline and L-phenylalanine. Compared to traditional step-by-step peptide synthesis in solution, our mechanochemical approach combining peptide coupling reagents with the proteolytic enzyme papain offers a more sustainable route by reducing the number of synthetic steps, shortening reaction times, increasing chemical yields, and minimizing waste production. Notably, the mechanosynthesized peptides exhibited organocatalytic activity in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde.

A straightforward process manipulates the dramatic morphological changes of DNA rolling circle amplification products.

Rolling circle amplification (RCA) is a widely used method for the synthesis of DNA nanoparticles and macro-hydrogels. Several strategies, including oscillation-promoted entanglement of DNA chains, multi-round chain amplification, hybridization between DNA chains, and hybridization with functional moieties, were applied to synthesize DNA macro-hydrogels; alternatively, flower-like nanoparticles were also produced. Here we report a straightforward yet effective method to manipulate the morphology of RCA products from nanoparticles to 3D hydrogels using an additional cold treatment step of the circular DNA template prior to elongation using phi29 DNA polymerase. This process induces a minor aggregation of the circular DNA template, significantly enhancing the entanglement of DNA chains in subsequent steps. Compared to contemporary synthesis methods for RCA-based macro-hydrogels, our technique provides milder reaction conditions, shorter reaction time, and a more straightforward system. Notably, our method eliminates the need for oscillation during amplification and requires only a single round of RCA with a single type of circular DNA, thereby simplifying the synthesis process.

DABCO-Based Ionic Liquids: A Non-Conventional Catalyst for the Synthesis of N-Substituted 2-Nitrophenylamines

Isoalloxazines are the essential cofactors of flavoproteins, which are responsible for the different redox reactions in various biological processes. They can be efficiently synthesized using Nsubstituted 2-nitrophenylamines as a precursor. In the present communication, we report a simple and efficient method for the synthesis of N-substituted 2-nitrophenylamines in DABCO-based ionic liquids. The method offers the use of DABCO-based ionic liquids as non conventional catalysts, which eliminates the use of any additional base with excellent yields in short reaction time, easy product isolation, high purity, and recyclability.

Loop-mediated isothermal amplification assay coupled with lateral flow dipstick for the rapid detection of methicillin-resistant Staphylococcus pseudintermedius from dogs.

Staphylococcus pseudintermedius is a global animal pathogen. Traditional identification methods are time-consuming necessitating a more efficient approach. This study validated and enhanced the loop-mediated isothermal amplification (LAMP) technique by integration it with a lateral flow dipstick (LFD) assay for the detection of S. pseudintermedius and methicillin-resistant S. pseudintermedius (MRSP) strains. Conventional identification methods were compared with LAMP and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The isolates were tested for MRSP detection using oxacillin and cefoxitin disk diffusion tests alongside the LAMP assay targeting the mecA gene, a marker for methicillin resistance. Results showed that LAMP combined with LFD effectively detected S. pseudintermedius and MRSP. This study identified 53 isolates as S. pseudintermedius by conventional and LAMP methods, with MALDI-TOF MS correctly identifying 39.62% (21/53). The mecA gene, crucial for methicillin resistance, was detected in all PCR-positive isolates (n = 33) by LAMP, while the disk diffusion method identified 69.70% (23/33) of mecA-positive strains. LAMP and conventional methods exhibited superior accuracy, sensitivity, and specificity (all 100%) compared to MALDI-TOF MS, which showed lower sensitivity (39.62%) for S. pseudintermedius identification. Similarly, the LAMP assay demonstrated higher accuracy, sensitivity, and specificity (all 100%) for MRSP detection compared to the disk diffusion method (83.33%, 69.70%, and 94.87%, respectively). The LAMP assay coupled with the LFD method proved suitable for routine bacterial identification in laboratories, offering adequate sensitivity and specificity with simple steps and short reaction time.

Continuous-Flow Ritter Reaction for Sustainable Amide Synthesis Using a Recyclable m-Phenolsulfonic Acid-Formaldehyde Resin Catalyst.

Herein, a rapid and efficient continuous-flow synthesis of amides is described. The Ritter reaction, catalyzed by a reusable solid acid catalyst composed of m-phenolsulfonic acid-formaldehyde resin (PAFR II), was used to convert nitriles and alcohols to amides in up to 90% yield. The continuous-flow system facilitates short reaction times and maintains activity for several weeks. This method is scalable, environmentally sustainable, and enables catalyst recycling.

New Pyranopyrazole-Based Indolin-2,3-Dione Hybrid as Effective Inhibitors of Xanthine Oxidase: Synthesis, In Vitro, and Molecular Modeling Approaches.

In the current study, new pyranopyrazole analogs (9a-d and 10a-d) were synthesized through a one-pot condensation reaction of 2-arylacetohydrazide. The inhibitory abilities were investigated against the xanthine oxidase (XO) enzyme through experimental and molecular docking analyses. The synthesis studies were based on ultrasound-mediated condensation reactions of four-component containing 2-arylacetohydrazide, ethyl acetoacetate, indoline-2,3-dione, and ethyl 2-cyanoacetate/malononitrile in various solvents and catalysts to yield pyranopyrazole analogs (9a-d and 10a-d) in a short reaction time and remarkably favorable yields ranging from 79% to 92%. On the basis of the XO inhibition study of compounds 9a-d and 10a-d, compound 10d was the most potent (IC50=0.09±0.22µM), followed by 9c (0.12±0.11µM). With IC50 values of 0.20±0.27 and 0.17±0.11µM respectively, compounds 10a and 10c exhibited moderate activity. The other compounds have shown less activity compared to the allopurinol control (IC50=0.14±0.10µM). Furthermore, in the molecular docking analysis, compound 10d was predicted to have the highest binding affinity against the target XO enzyme.

In situ synthesis of ultrafine Cu(ii) metal immobilized on pectin hydrogel, modified by a CoFe2O4/Pr-SO3H nanocomposite as a green catalyst for reduction of nitro compounds and synthesis of 1H-tetrazoles.

Synthesis of 5-substituted 1H-tetrazoles and reduction of a variety of nitro compounds presents a promising solution for the pharmaceutical and agricultural industries. However, the development of green catalysts with superior catalytic performance for this reaction remains a significant challenge. This research introduces a green protocol for the in situ creation of ultrafine Cu(ii) metal immobilized on the surface of pectin hydrogel (HPEC), modified by a CoFe2O4/Pr-SO3H magnetic nanocomposite, enabling the synthesis of tetrazoles and reduction of nitro compounds. This catalyst exhibits superior catalytic performance under green reaction conditions, short reaction time, catalyst separation, and thermal stability. The heterogeneous catalyst's structure and composition were thoroughly analyzed using various techniques such as FT-IR, FE-SEM, VSM, ICP-OES, TGA, XRD, BET, EDX, and X-ray mapping.

Metastable layered lithium-rich niobium and tantalum oxides via nearly instantaneous cation exchange.

Lithium-rich early transition metal oxides are the source of excess removeable lithium that affords high energy density to lithium-rich battery cathodes. They are also candidates for solid electrolytes in all-solid-state batteries. These highly ionic compounds are sparse on phase diagrams of thermodynamically stable oxides, but soft chemical routes offer an alternative to explore new alkali-rich crystal chemistries. In this work, a new layered polymorph of Li3NbO4 with coplanar [Nb4O16]12- clusters is discovered through ion exchange chemistry. A more detailed study of the ion exchange reaction reveals that it takes place almost instantaneously, changing the crystal volume by more than 22% within seconds. The transformation of coplanar [Nb4O16]12- in L-Li3NbO4 into the supertetrahedral [Nb4O16]12- clusters found in the stable cubic c-Li3NbO4 is also explored. Furthermore, this synthetic pathway is extended to access a new layered polymorph of Li3TaO4. NMR crystallography with 6,7Li, 23Na, and 93Nb NMR, X-ray diffraction, neutron diffraction, and first-principles calculations is applied to A3MO4 (A = Li, Na; M = Nb, Ta) to identify local and long-range atomic structure, to monitor the unusually rapid reaction progression, and to track the phase transitions from the metastable layered phases to the known compounds found using high-temperature synthesis. A mechanism is proposed whereby some sodium is retained at short reaction times, which then undergoes proton exchange during water washing, forming a phase with hydrogen bonds bridging the coplanar [Nb4O16]12- clusters. This study has implications for lithium-rich transition metal oxides and associated battery materials and for ion exchange chemistry in non-framework structures. The role of techniques that can detect light elements, local structure, and subtle structural changes in soft-chemical synthesis is emphasized.

Expeditious and environmentally benign synthesis of imidazo[4,5,1-ij]quinolines via sequential Povarov reaction/reductive cyclization.

In this contribution, a novel, simple, diastereoselective and environmentally benign two-step diversity-oriented synthesis of imidazo[4,5,1-ij]quinolines is described for the first time. The synthesis of the target compounds involves a deep eutectic solvent-mediated one-pot Povarov reaction leading to the obtention of 8-nitrotetrahydroquinolines, followed by a microwave-assisted reductive cyclocondensation employing different aromatic and aliphatic aldehydes. The target compounds were obtained in up to 70% overall yield starting from commercially available o-nitroanilines, natural phenylpropanoids (trans-anethole and trans-isoeugenol) and aromatic or aliphatic aldehydes. The eutectic solvent employed in the first step was reused in four runs without observing a drastic decrease in catalytic activity, and sodium dithionite showed to be an efficient and green reducing agent for the second step. This methodology provides significant advantages in terms of synthetic and green chemistry such as mild reaction conditions, short reaction time, energy-efficiency, simple work-up procedure, low cost, scalability and utilization of renewable substrates and a reusable solvent.

Magnetic resorcinol-formaldehyde supported isatin-Schiff-base/Fe as a green and reusable nanocatalyst for the synthesis of pyrano[2,3-d]pyrimidines.

Herein, a novel magnetic resorcinol-formaldehyde-supported isatin-Schiff-base/Fe complex (Fe3O4@RF-ISB/Fe) is prepared and characterized and its catalytic performance is investigated in the synthesis of pyrano[2,3-d]pyrimidines. The Fe3O4@RF-ISB nanomaterial was prepared through the chemical immobilization of (3-aminopropyl)trimethoxysilane over the Fe3O4@RF composite, followed by treatment with isatin. The Fe3O4@RF-ISB was then reacted with FeCl3·6H2O to afford the Fe3O4@RF-ISB/Fe nanocatalyst. Characterization through FT-IR, EDX, PXRD, VSM, SEM and ICP techniques confirmed that the magnetite surface was successfully modified with RF/ISB-Fe while preserving its crystalline structure. The SEM image revealed spherical particles with an average size of 44 nm for the designed nanocomposite. Various aromatic aldehydes were used as substrates in the presence of 0.01 g of Fe3O4@RF-ISB/Fe to give the corresponding pyranopyrimidines in high yields (88-95%) within short reaction times (30-55 minutes) at RT. The designed magnetic catalyst maintained its activity for nine runs.

The synthesis of pyrazole derivatives from hydrazone using Amberlyst A26 resin under ultrasonic radiation

Pyrazoles are highly versatile and find applications in various industries including chemicals, pharmaceuticals, polymers, medications, and agriculture. Pyrazoles and their analogues exhibit a range of biological activities, including anti-inflammatory, anti-tuberculosis, antibacterial, antifungal, anti-cancer, and anti-diabetic effects. In this context, this investigation focuses on the synthesis of pyrazoles containing heterocyclic components using Amberlite resin in reactions with ultrasonic irradiation. Synthesized pyrazoles containing heterocyclic components are intermediates of the apixaban API. Some pyrazole derivatives are key impurities of the apixaban API, which is synthesized by a multistep chemical conversion and has been reported previously. The use of the heterogeneous Amberlyst resin, which acts as a reusable catalyst and is gentle on reactions, allows for a more sustainable solution that reduces costs, accelerates reactions, and shortens reaction times. The procedures for using Amberlyst resin under ultrasonic irradiation to synthesize pyrazole derivatives are cost-effective, energy-efficient, and environmentally friendly for chemical synthesis and material preparation. They also simplify workups and produce quality and yields comparable to or better than existing methods.