Aromatic Hydrazine Research Articles

Ultrasound-assisted synthesis of 1,5-disubstituted pyrazoles via HFIP-mediated cascade cyclization of enaminones with aryl hydrazine

A simple and efficient metal-free strategy has been developed for the synthesis of 1,5-disubstituted pyrazole derivatives by using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) medium and ultrasound irradiation. The condensation reactions of β-enaminone and aromatic hydrazine have taken place at room temperature with the assistance of sonication. The protocol provides rapid access to various N-aryl substituted pyrazole compounds with excellent functional group tolerance and yields. Notably, the eco-friendly and cost-effective method allows the conversion within a short time and under mild conditions.

Preparation and Catalytic Properties of Carbonic Anhydrase Conjugated to Liposomes through a Bis-Aryl Hydrazone Bond.

Liposomes (lipid vesicles) with sizes of about 100-200 nm carrying surface-bound (immobilized) water-soluble enzymes are functionalized molecular compartment systems for possible applications, for example, as therapeutic materials or as catalytic reaction units for running reactions in aqueous media in vitro. One way of covalently attaching enzyme molecules under mild conditions in a controlled way to the surface of preformed liposomes is to apply the spectrophotometrically traceable bis-aryl hydrazone (BAH) bond between the liposome and the enzyme molecules of interest. Using bovine carbonic anhydrase (BCA), an aqueous dispersion of liposome-BAH-BCA - conjugates of defined composition was prepared. The liposomes used consisted of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), N-(methylpolyoxyethylene oxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG), and N-(aminopropylpolyoxyethylene oxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG-NH2). The amino group of some of the DSPE-PEG-NH2 molecules present in the liposomes were converted into an aromatic aldehyde, which (after purification) reacted with (purified) BCA molecules that had on their surface on average one acetone protected aromatic hydrazine. After purification of the liposome-BAH-BCA conjugate dispersion obtained, it was characterized in terms of (i) BCA activity, (ii) overall BCA structure, and (iii) storage stability. For an average liposome of 138 nm diameter, about 1200 BCA molecules were attached to the outer liposome surface. Liposomally bound BCA was found to exhibit (i) similar catalytic activity at 25 °C and (ii) similar storage stability when stored in a dispersed state in aqueous solution at 4 °C as free BCA. Measurements at 5 °C clearly showed that liposome-BAH-BCA is able to catalyze the hydration of carbon dioxide to hydrogen carbonate.

Metal-free visible-induced C(sp2)-C(sp2) coupling of quinoxalin-2(H)-ones via oxidative cleavage of the C-N bond.

A C(sp2)-C(sp2) reaction between aromatic hydrazines and quinoxalines has been developed through a photocatalytic system. The protocol is established for C(sp2)-N bond cleavage and direct C(sp2)-H functionalization for the coupling of C(sp2)-C(sp2) via photocatalysis under mild and ideal air conditions without the presence of a strong base and metal. The mechanistic studies reveal that the generation of a benzene radical via the oxidative cleavage of aromatic hydrazines for the cross-coupling of C(sp2)-C(sp2) with the assistance of a photocatalyst is essential. The process exhibits excellent compatibility with functional groups and provides convenient access to various 3-arylquinoxalin-2(1H)-ones in good to excellent yields.

Synthesis of ring-A serjanic acid derivatives and their cytotoxic evaluation through the brine shrimp lethality assay (BSLA)

Abstract Sixteen serjanic acid derivatives were synthesized by modification of the A-ring of the triterpenoid skeleta. Fischer indolization of intermediate 2 with the requisite aromatic hydrazines afforded the indolo-triterpenes 8–13. Also, reaction of 2 with hydroxylamine hydrochloride in pyridine provided the desired C-3 oxime 14, while pyrazine 15 was obtained by condensation of 2 in the presence of ethylenediamine and sulphur in morpholine. Finally, the Claisen-Schmidt condensation of intermediate 2 with corresponding substituted benzaldehydes 16–23, afforded benzylidine ketones 24–31. All compounds were elucidated on the basis of NMR and HR-MS spectroscopic data and evaluated for their in-vitro cytotoxicity to the Brine Shrimp Lethality Assay (BSLA). As a result, the compounds exhibited medium to good cytotoxic potential and this activity was as high as eight times that of serjanic acid (1) on the tested zoophytes.

Synthesis, insecticidal activities, and structure–activity relationships of 1,3,4‐oxadiazole‐ring‐containing pyridylpyrazole‐4‐carboxamides as novel insecticides of the anthranilic diamide family

AbstractThe preparation of novel anthranilic diamide derivatives is extremely important for agricultural pest control. In this study, pyridylpyrazole‐4‐carboxamides containing a 1,3,4‐oxadiazole ring were designed and synthesized via the dehydration of aromatic hydrazine derivatives and formanilides in the presence of an alkali. The insecticidal activities of these new compounds against the diamondback moth (Plutella xylostella) were evaluated. N‐(4‐chloro‐2‐methyl‐6‐(5‐(4‐nitrophenyl)‐1,3,4‐oxadiazol‐2‐yl)phenyl)‐5‐methyl‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carboxamide (8h6) showed 67%, 50%, 34%, 20%, and 17% activity at concentrations of 100, 50, 10, 5, and 1 μg ml−1, respectively. Density functional theory calculations showed that the introduction of the 1,3,4‐oxadiazole ring significantly changed the electron distributions in both the highest occupied and lowest unoccupied molecular orbitals, resulting in these compounds having much larger energy gaps than the well‐known insecticide chlorantraniliprole, which may account for their lower activity. The results of this study demonstrate that anthranilic diamides substituted with a 1,3,4‐oxadiazole ring are effective insecticides that can be used for pest management.

Ultrasound assisted regioselective synthesis, photophysical and structural studies of 1-substituted indazol-4(5H)-ones and enaminodiketones of dimedone

Enaminodiketone, obtained from reaction of dimedone with DMF-DMA, on reaction with nucleophiles such as amines, guanidine hydrochloride and substituted aromatic hydrazines furnished enaminodiketones, quinazolines and indazole derivatives respectively. The structure of synthesised compounds was assigned on the basis of spectral data (IR, NMR and Mass). X-ray crystallographic studies of representative compound 6b have been reported. DFT studies were carried out on indazole derivative and its regioisomer for validation of the assigned structure. Also experimental NMR is correlated with that obtained from theoretical studies. Photo physical (UV and fluorescence) studies of compounds 4 and 6 have also been reported.

Synthesis and Antibacterial Screening of Some Pyrazole Derivatives Catalyzed by Cetyltrimethylammoniumbromide (CTAB).

In this article, we have developed an eco-friendly one-pot multi-component reaction methodology employed for the green synthesis of functionalized pyrazole derivatives viz cyclo-condensation of aromatic aldehydes, ethyl acetoacetate and phenyl hydrazine and/or hydrazine hydrate in the presence of cetyltrimethylammoniumbromide (CTAB) at 90°C temperature in an aqueous medium. In the present protocol, we developed a green method for the synthesis of functionalized pyrazole derivatives through one-pot, multi-component cyclo-condensation of aromatic aldehydes, phenyl hydrazine or hydrazine hydrate and ethyl acetoacetate using cetyltrimethylammoniumbromide (CTAB) as a catalyst in water as a solvent. Our methodology confers advantages such as short reaction time, atom economy, purification of the product without using column chromatographic and hazardous solvent. The reaction is being catalyzed by cetyltrimethylammoniumbromide (CTAB) and thus, products are formed under the green reaction conditions. Initially, the reaction of benzaldehyde and phenylhydrazine with ethyl acetoacetate was carried out in water at room temperature in the absence of the catalyst; no product was obtained after 24 h (Table 1 entry 1). When the reaction was carried out using L-proline as a catalyst in ethanol at 70°C, the yield of the product was 20%. This research not only provides a green and efficient method for the synthesis of sulfinic esters but also shows new applications of electrochemistry in organic synthesis. We consider that this green and efficient synthetic protocol used to prepare sulfinic esters will have good applications in the future. In conclusion, we have developed successfully a green and efficient one-pot multi-component methodology for the synthesis of substituted pyrazoles using CTAB as a catalyst in water as a solvent with excellent yields. Purifications of compounds were achieved without the use of traditional chromatographic procedures. This methodology has advantages of operational simplicity, clean reaction profiles and relatively broad scope, which make it more attractive for the diversity oriented synthesis of these heterocyclic libraries. In this methodology, we suggest a further alternative possibility for the formation of substituted pyrazoles. The compound 7h can be used as an anticancer drug in the pharma industry.

A Versatile Protocol for Synthesis of 2H-Indazolo[2,1-b]Phthalazine Triones Using γ-Al2O3/BFn/Fe3O4 as an Efficient Magnetic Nano-Catalyst

A four-component reaction of aromatic aldehydes, phthalic anhydride, hydrazine monohydrate and dimedone has been achieved in the presence of nano-γ-Al2O3/BFn/Fe3O4 as a highly effective heterogeneous catalyst to produce 2H-indazolo[2,1-b]phthalazine triones. Atom economy, low catalyst loading, reusable catalyst, applicability to a wide range of substrates and high yields of products are some important features of this protocol.

Rapid access to 3-aminoindazoles from nitriles with hydrazines: a strategy to overcome the basicity barrier imparted by hydrazines.

A practical and efficient base mediated synthesis of free 3-aminoindazoles has been developed from the reaction of nitriles with hydrazines, which successfully overcomes the difficulty of using aromatic hydrazines as substrates and allows for the synthesis of a wide range of N-aryl substituted free 3-aminoindazoles in moderate to excellent yields under mild conditions in one-pot. This finding provides a rapid and useful strategy for the synthesis of various functionalized 3-aminoindazole derivatives.

SYNTHESIS OF 1H-INDAZOLES USING LEMON PEEL POWDER AS A NATURAL, GREEN AND EFFICIENT CATALYST UNDER ULTRASOUND IRRADIATION

Bioactive 1 H -indazoles were synthesized from 2-substituted aromatic aldehyde and hydrazine hydrate using DMSO and Lemon peel powder as a green and efficient natural catalyst. Good yield of products were obtained in DMSO solvent using a catalytic amount of Lemon peel powder. In comparison to other reported conventional methods, this method affords good yield under ultrasonic irradiation.

A hydrogen bond and strong electron withdrawing group lead to the formation of surprisingly stable, cyclic hemiaminals

Hemiaminals are rarely stable, and usually arise during imine formation in the absence of acid using polar, aprotic solvents. Here, stable, cyclic hemiaminals from acidic or neutral ethanolic solutions are obtained. Using four 1,3-diketones (a–d) and four aromatic hydrazine derivatives (1–4), a hydrogen bond and strong electron withdrawing group (trifluoromethyl) are judged to be the two critical contributors to stability. Using resistance to dehydration as a surrogate for stability, these hemiaminals appear to be the most stable reported surviving in ambient, neat glacial acetic acid for long periods of time and requiring reflux for conversion to the corresponding pyrazole.

Synthesis, spectral analysis, anti-corrosive activity and theoretical study of an aromatic hydrazone derivative

An aromatic hydrazone derivative; namely (E)-1-(3-nitrobenzylidene)-2-(p-tolyl)hydrazine (E-NBPTH) has been synthesized by condensation of an aromatic hydrazine with an aromatic aldehyde in methanol at reflux. The molecular structure of E-NBPTH has been identified and analyzed by spectroscopic methods such as UV–vis, IR, 1H NMR and 13C NMR. The corrosion inhibition behavior of the prepared molecule in 0.5 M H2SO4 was investigated by gravimetric, electrochemical and theoretical methods. According to the polarization study, the E-NBPTH acts as a mixed type of inhibitor. The adsorption of E-NBPTH on the iron surface follows the Langmuir isotherm. The optimized molecular structure and some quantum chemical parameters of the synthesized compound have been calculated using the density functional method (DFT). The results obtained from theoretical study are well support the experimental results.

Chemical Tools for Targeted Amplification of Reactive Oxygen Species in Neutrophils.

A number of chemical compounds are known, which amplify the availability of reactive oxygen species (ROS) in neutrophils both in vitro and in vivo. They can be roughly classified into NADPH oxidase 2 (NOX2)-dependent and NOX2-independent reagents. NOX2 activation is triggered by protein kinase C agonists (e.g., phorbol esters, transition metal ions), redox mediators (e.g., paraquat) or formyl peptide receptor (FPR) agonists (e.g., aromatic hydrazine derivatives). NOX2-independent mechanisms are realized by reagents affecting glutathione homeostasis (e.g., l-buthionine sulfoximine), modulators of the mitochondrial respiratory chain (e.g., ionophores, inositol mimics, and agonists of peroxisome proliferator-activated receptor γ) and chemical ROS amplifiers [e.g., aminoferrocene-based prodrugs (ABPs)]. Since a number of inflammatory and autoimmune diseases, as well as cancer and bacterial infections, are triggered or enhanced by aberrant ROS production in neutrophils, it is tempting to use ROS amplifiers as drugs for the treatment of these diseases. However, since the known reagents are not cell specific, their application for treatment likely causes systemic enhancement of oxidative stress, leading to severe side effects. Cell-targeted ROS enhancement can be achieved either by using conjugates of ROS amplifiers with ligands binding to receptors expressed on neutrophils (e.g., the GPI-anchored myeloid differentiation marker Ly6G or FPR) or by designing reagents activated by neutrophil function [e.g., phagocytic activity or enzymatic activity of neutrophil elastase (NE)]. Since binding of an artificial ligand to a receptor may trigger or inhibit priming of neutrophils the latter approach has a smaller potential for severe side effects and is probably better suitable for therapy. Here, we review current approaches for the use of ROS amplifiers and discuss their applicability for treatment. As an example, we suggest a possible design of neutrophil-specific ROS amplifiers, which are based on NE-activated ABPs.

Multicomponent Tandem Polymerizations of Aromatic Diynes, Terephthaloyl Chloride, and Hydrazines toward Functional Conjugated Polypyrazoles

Multicomponent tandem polymerizations (MCTPs) of alkynes enjoying concise procedure, operational simplicity, synthetic efficiency, large structural diversity, high atom economy, and environmental benefit are recently developed as efficient strategies to synthesize functional conjugated polymers, which have attracted much attention from polymer scientists. In this work, through combination of Sonogashira coupling–Michael addition–cyclocondensation reactions in a one-pot procedure, an efficient three-component tandem polymerization of alkyne, carbonyl chloride, and hydrazine hydrate was reported to proceed smoothly under mild conditions at room temperature, affording polypyrazoles with high molecular weights (Mw up to 19 400 g/mol) in excellent yields (up to 95%). This MCTP also applies to various aromatic diynes and aromatic hydrazines, producing polypyrazoles with improved solubility and processability, higher Mws of up to 30 700 g/mol, and high yields. Structural characterization of the polymers such as ...

KMnO4-mediated direct C2-selective C−H arylation of quinoline N-oxides with aromatic hydrazines

An efficient protocol for the synthesis of 2-arylquinoline N-oxides has been developed via KMnO4-mediated cross-coupling reaction of quinoline N-oxides with aromatic hydrazines in moderated to good yields. The reactions proceeded efficiently over a broad range of substrates with excellent regioselectivity and functional group tolerance.

Synthesis of Tetrasubstituted Pyrazoles from Substituted Hydrazines and β‐Keto Esters

Herein we report the synthesis of tetrasubstituted pyrazoles from simple hydrazines and β‐keto esters under mild, basic conditions. This reaction enables the selective synthesis of pyrazolones, alkoxypyrazoles, and tetrasubstituted pyrazoles for a large variety of aromatic hydrazines and substituted β‐keto esters with high yields and selectivities. This method permits access to highly complex pyrazole scaffolds with four orthogonal diversification groups.

Alumina-promoted synthesis of N-aryl-1,2,4-triazoles from substituted hydrazines and imides

Herein we report the highly efficient, environmentally friendly alumina-promoted synthesis of N-aryl-1,2,4-triazoles with a wide variety of substitution patterns from commercially available hydrazines with symmetrical and unsymmetrical imides. Aromatic hydrazines with a variety of substitution patterns provided the corresponding 1,2,4-triazoles in very high yields. Unsymmetrical imides with a wide variety of functional groups also provide the respective triazoles with high yield and complete regioselectivities. The high productivity and mild conditions allow for the large-scale preparation of 1,2,4-triazoles.

Assessment of Antimicrobial Activity, Reactivity and Non‐Linear Optical Properties of New Pyrazoline Derivatives having Pyrrole moiety

AbstractThe purpose of this work is to study antimicrobial activity, chemical reactivity and non‐linear optical properties of newly synthesized and characterized 2‐pyrazoline derivatives having pyrrole moiety (4a–d). 1,3,5‐trisubstituted pyrazoline derivatives (4a–c) and 3, 5‐di‐aryl N‐substituted carbonyl pyrazoline derivative (4 d) were synthesized by simple and efficient approach using cyclization reaction of chalcones (3a–c) and aromatic hydrazine (AH) / aromatic acid hydrazide (AAH) in the presence of acid catalyst. The conformational investigation has been performed with the help of potential energy surface scan to understand and find out the stable conformers. All synthesized compounds have been characterized by spectroscopic (1H and 13C NMR, UV–Visible, FT–IR) techniques. Using self‐consistent reaction field (SCRF) method, the solvent‐induced effects on dipole moment (μ0), mean polarizability (|α0|), anisotropy of polarizability (Δα) and the first hyperpolarizability were studied for all compounds and found that the β0 values increase monotonically as the polarity increases. The β0 values of compounds are higher than the standard p‐nitroaniline (p‐NA) in solvent as well as in gas phase. The screening of the synthesized compounds for antimicrobial activity was performed against S. aureus, E. coli, C. Albicans and A. niger. The assayed compounds showed a good antibacterial (against gram positive and negative bacteria) and antifungal activity.

Abstract 4858: LADR™: A novel linker activated drug release technology for drug delivery

Abstract Drug delivery systems in oncology for treating cancer are based on different drug release mechanisms at the tumor site including primarily hydrolytic, reductive, enzymatic and/or acid-sensitive cleavage. Drug carrier conjugates that incorporate an acid-sensitive breaking-point exploit the extra- and intracellular acidic environment of the tumor. Important requirements for acid-sensitive bonds are high stability of the carrier-bound drug in the blood circulation and an effective or sustained release of the active drug in the acidic tumor interstitium and acidic endosomes/lysosomes of tumor cells. In addition, sufficient stability of the acid-sensitive bond is a prerequisite for galenic formulation and reconstitution. As a continuation of our development of aldoxorubicin, an acid-sensitive albumin-binding drug of doxorubicin, which is being clinically assessed in advanced clinical trials (www.cytrx.com), we have set out to design a novel acid-sensitive drug release platform that is applicable to carriers such as serum proteins and antibodies. The key components of this specific drug delivery system are linkers containing a thiol-binding maleimide group and a substituted aromatic hydrazine to form an acid-cleavable hydrazone bond with suitable carbonyl-containing drugs. For establishing and fine-tuning the pH-dependent release profiles, the aromatic moiety of the linker was substituted with a spectrum of electron-withdrawing groups, and reacted with the anthracyclines doxorubicin and nemorubicin. The resulting hydrazone derivatives were conjugated to the cysteine-34 position of albumin as a model protein. Subsequently, the drug release was determined at physiological and acidic conditions as well as in human plasma. It was discovered that by variation of the electron-withdrawing groups, the pH dependent release of the drug could be substantially varied between 1-50 h in the pH range of 4-5. The technology using these linkers was coined LADR™ (Linker Activated Drug Release) and has the additional advantage that the galenic formulation and reconstitution of LADR™-based drugs is facilitated. We have applied the LADR™ technology to several anticancer drugs such as vinblastine and gemcitabine. In summary, LADR™ is an innovative and versatile linker technology creating a platform for developing acid-sensitive drug carrier conjugates that allow the carrier-bound drug to be released in a controlled manner resulting in sustained exposure to cancer cells. Citation Format: Khalid Abu Ajaj, Stephan David Koester, Friederike Inga Nollmann, Simon Waltzer, Olga Fuchs, André Warnecke, Felix Kratz. LADR™: A novel linker activated drug release technology for drug delivery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4858.

ChemInform Abstract: Synthesis and Site‐Specific Incorporation of Red‐Shifted Azobenzene Amino Acids into Proteins.

AbstractThe CAN‐catalyzed reaction of quinonoidal spirolactones with various aromatic hydrazines afford the title amino acids in moderate to excellent yields.