Synthesis of 1 H ‐pyrazole frameworks from chalcones using p ‐toluenesulfonic acid as an efficient catalyst

The pyrazole nucleus is present in a wide variety of biologically interesting compounds, which exhibit antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial, hypoglycemic, sedative-hypnotic activity. Thus, continuous efforts have been devoted to the development of more general and versatile synthetic methodologies to this class of compounds. Recently we have reported on the regio-selective synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives from the reaction of Baylis-Hillman adducts of alkyl vinyl ketone and hydrazine derivatives (Scheme 1). During the continuous studies on the chemical transformations of Baylis-Hillman adducts including the synthesis of pyrazoles we presumed that we could synthesize 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and acyloxiranes, which could be synthesized easily from Baylis-Hillman adducts (Scheme 2). According to the reported method, the required acyloxiranes 2a-e were synthesized in moderate yields from the corresponding Baylis-Hillman adducts 1 by NaOCl in the presence of silica gel in acetonitrile. With these acyloxiranes 2a-e in our hands, we examined the synthesis of corresponding pyrazoles under a variety of conditions, and we found that the reaction of 2a-e and various hydrazine hydrochlorides in 1,2-dichloroethane at refluxing temperature afforded the best results. As shown in Table 1, the reaction of 2a with phenylhydrazine hydrochloride, tertbutylhydrazine hydrochloride, 2,4-difluorophenylhydrazine hydrochloride afforded 3a-c in moderate yields (39-75%). In the reaction of 2,4-dinitrophenylhydrazine (entry 4), we used p-toluenesulfonic acid as the acid catalyst. Other acyloxiranes 2b-e showed similar results in the reactions of phenylhydrazine hydrochloride (36-71%, entries 5-8). Although we isolated the products in moderate yields in most cases, however, the yields of 3b and 3f were relatively low due to the formation of many intractable side products. In summary, we disclosed an expeditious synthesis of 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and the acyloxiranes, which were prepared from Baylis-Hillman adducts.

This research involved the conversion of sulfadiazine into compound 2-chloro-N-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) acetamide [A] through the reaction of sulfadiazine with chloroacetyl chloride in the presence of diethylamine in dimethylformamide as solvent. Then prepared the hydrazine derivative of sulfadiazine 2-hydrazinyl-N-(4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) acetamide [B] through the interaction of compound [A] with hydrazine in dimethylformamide as solvent. Followed by chalcones preparation [C1, C2, C3, C4, and C5] from the reaction of 4-aminoacetophenone with some aromatic aldehydes in a basic medium in absolute ethanol using an ice bath. Pyrazoline derivatives [BC1, BC2, BC3, BC4, and BC5] were prepared from the reaction of the hydrazine derivative of sulfadiazine [B] with chalcones in a basic medium in the presence of absolute ethanol. The pyrazole derivatives [IBC1, IBC2, IBC3, IBC4, and IBC5] were prepared from the reaction of the hydrazine derivative of sulfadiazine [B] with chalcones in the presence of glacial acetic acid and then the product was oxidized using Iodine. Synthesized compounds have been studied by their melting points, and characterized by C.H.N.S analysis, FT-IR and 1H-MNR spectroscopy and studied of biological activity.

Background: Antioxidants are developed to assist the immune system and overcome oxidative stress, the aggression of cellular constituents due to imbalance between reactive oxygen species and the inner antioxidant system. The main objective of this study was to search for new and potent antioxidants to protect humans against diseases associated with oxidative stress. Methods: In this study, three pyrano-[2,3-c]-pyrazole derivatives were synthesized via Multicomponent Reaction (MCR) approach and were characterized, using a melting point, High-Performance Liquid Chromatography (HPLC), and spectroscopic analyses (IR; 1H-NMR; 13C-NMR). All of the generated compounds were screened for their antioxidant properties in vivo, using ciliate “Tetrahymena” as a model organism exposed to oxidative and nitrative stress. They were then studied in vitro by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Results: The results demonstrated that the three compounds (5a, b, c) are biologically active and possess potent antioxidant activities, especially the 5a and 5b derivatives. On the other hand, the in vitro bioassays revealed that the 5a derivative possessed a significant antioxidant activity much greater than ascorbic acid. Accordingly, the in silico data are consistent with the experimental data. Conclusion: These findings confirmed the potent antioxidant property of the synthesized compounds, providing us with new inspiration and challenges to design a library of pharmaceutical compounds with strong activity and low toxicity in the future.

Dihydropyrano[2,3-c]pyrazole annulated heterocyclic compounds with diverse substituents on the 4H-pyran ring were efficiently prepared via a one-pot and four-component reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehyde, and malononitrile. The procedure proceeds without utilization of any catalyst or solvent using ball milling technique at ambient temperature to afford desired medicinally important dihydropyrano[2,3-c]pyrazole derivatives. This protocol offers several advantages such as avoiding the use of any toxic and hazardous catalyst or solvent, mild reaction conditions, high to quantitative yields of products, low cost, and straightforward work-up.

A novel and efficient one-pot synthesis of furo[3′,4′:5,6]pyrido[2,3- c]pyrazole derivatives using organocatalysts

Five membered heterocyclics derivatives were synthesized in this work by three routes. The first route includes the synthesis of N-benzoic acid 1,2,3,-triazole derivatives (3),(4) by diazotation of methyl-2-amino benzoate and treating the resulted salt (1) with sodium azide and ethyl acetoacetate or acetyl acetone, respectively. In the second route, derivatives of pyrazole (8) pyrazolin-5-one (9), (10) were prepared by the reaction of the salt (1) with some active methylene compounds to give the corresponding hydrazones derivatives (5-7) which then they were treated with hydrazine hydrate. The third route afforded the synthesis of three derivatives (12), (15a), (15b) of thiazolidinone by two different methods. AII compounds were confirmed by their melting points, FTIR, U.V-vis spectra and 1 H-NMR spectra for some of them.

We report a new pathway to synthesize pyrano[2,3-c]pyrazoles and their binding mode to p38 MAP kinase. Pyrano[2,3-c]pyrazole derivatives have been prepared through a four-component reaction of benzyl alcohols, ethyl acetoacetate, phenylhydrazine, and malononitrile in the presence of sulfonated amorphous carbon and eosin Y as catalysts. All products were characterized by melting point, 1H and 13C NMR, and HRMS (ESI). The products were screened in silico for their binding activities to both the ATP-binding pocket and the lipid-binding pocket of p38 MAP kinase, using a structure-based flexible docking provided by the engine ADFR. The results showed that eight synthesized compounds had a higher affinity to the lipid pocket than to the other target site, which implied potential applications as allosteric inhibitors. Finally, the most biologically active compound, 5, had a binding affinity comparable to those of other proven lipid pocket inhibitors, with affinity to the target pocket reaching −10.9932 kcal/mol, and also had the best binding affinity to the ATP-binding pockets in all of our products. Thus, our research provides a novel pathway for synthesizing pyrano[2,3-c]pyrazoles and bioinformatic evidence for their biological capability to block p38 MAP kinase pockets, which could be useful for developing cancer or immune drugs.

Microwave-assisted condensation of acetophenone 1 and aromatic aldehydes 2 gave chalcone analogs 3, which were cyclized to pyrazole derivatives 6a-f via the reaction with hydrazine hydrate and oxalic acid in the presence of the catalytic amount of acetic acid in ethanol. The structural features of the synthesized compounds were characterized by melting point, FT-IR, 1H, 13C NMR and elemental analysis. The antibacterial activities of the synthesized pyrazoles were evaluated against three gram-positive bacteria, such as Enterococcus durans, Staphylococcus aureus, Bacillus subtilis and two gram-negative bacteria such as Escherichia coli and Salmonella typhimurium. All the synthesized pyrazoles showed relatively high antibacterial activity against S. aureus strain, and none of them demonstrated antibacterial activity against E. coli.

In this study, three different catalysts were applied as catalysts for esterification of benzoic acid with ethanol, butanol and hexanol. These catalysts are ionic liquid, deep eutectic solvent, ion exchange resin. Amberlyst 15, ion exchange resin, was used as control catalyst to observe the catalytic activity of new generation solvent, deep eutectic solvent. Deep eutectic solvents show the similar properties with ionic liquids and have great attraction due to ease of preparation, low cost and environmentally friendly nature. They have many advantages such as reusability, stability, catalytically activity and removal of the reaction mixture. Deep eutectic solvents (DES) are composed hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA). It has lower freezing point than that of individual constituents. In this study, p -toluene sulfonic acid (p-TSA) was used as HBD, benzyl tri-ethyl ammonium chloride (BTEAC) was used as HBA. DES formed by p-TSA and BTEAC was used as dual solvent-catalyst for esterification of benzoic acid with different alcohols. DES gave high catalytic activity among three different catalysts, 88.3, 87.8 and 67.5% conversion of benzoic acid for ethanol, butanol and hexanol, respectively. The effects of time, temperature, alcohol type and catalyst type were investigated in a batch reactor at specified conditions. It was found that DES provided the simple, efficient and environmentally friendly method for the synthesis of benzoic acid ester.

Traditional I-line resists commonly use novolak as matrix resin and diazonaphthoquinone as photosensitizer. Novolak resins, however, can not be used in Deep-UV resist formulations because of their high optical absorption at 248 nm. When the lithography migrated to Deep-UV technology, polyvinylphenols (PVP), which has a low absorption at 248 nm, became the resin of choice. Styrene maleic anhydride polymers also have a low optical absorption at 248 nm and are commercially available with relatively lower cost than current polyvinylphenols. Therefore, we felt that styrene maleic anhydride polymers would be of interest for DUV resist applications. In our investigation, the styrene maleic anhydride copolymer was first reacted with methanol to form the half ester then was protected with tetrahydropyranyl and tetrahydrofuranyl groups using p- toluene sulfonic acid as catalyst. Since the protected polymers have no base soluble component, they exhibit high inhibition in TMAH developer. TGA analysis also shows these polymers having reasonable thermal stability with the onset of decomposition at temperature above 150 degree C. However the resists formulated with these polymers showed poor adhesion property. By blending PVP with these polymers in resist formulation, the adhesion problem was resolved and reasonable lithographic performance was obtained.

Current research had focused on the synthesis of the novel pyrazole ethanone linked compounds with improved biological activity. In this synthetic process 1st step was to synthesize the intermediate chalcone and 2nd step was the synthesis of final compound pyrazole derivative containing ethanone moiety. This procedure is the type of cyclization reaction using proton transfer mechanism. By using this method 8 derivatives synthesized. After synthesis these were subjected to identification tests by using various methods like melting point study, thin layer chromatography, solubility study and characterization by using UV, IR and NMR Spectroscopy.
 Keywords: Selective COX-2 inhibitor, anti-inflammatory, pyrazole ethanone linked compounds, pyrazole derivatives, inflammation

A highly regioselective route was established to 2-aryl-, 2-cyclohexyl-, and 2-(2-arylethyl)4-alkylthiophenes, which are potential candidates as liquid crystalline compounds of low viscosity. The key synthetic intermediates, 2-substituted-4-(chloromethyl)thiophenes 6, 14, and 20 were prepared respectively from the reactions of β, γ-epoxycarbonyl compounds 5, 13, and 19 with Lawesson's reagent in the presence of a catalytic amount of p -toluenesulfonic acid. The epoxycarbonyl compounds were obtained from the TiCl4-mediated reactions of 2-(chloromethyl)-3-(trimethylsliyl)propene (10) with acid chlorides followed by epoxidation with m-chloroperoxybenzoic acid, or from prior epoxidation followed by oxidation with pyridinium dichromate of homoallylic alcohols 3. The homoallylic alcohols 3 were synthesized from the reactions of 2-(chloromethyl)-3-(trichlorosilyl)propene (2) with aldehydes in N, N-dimethylformamide. Copper (I) catalysed cross-coupling reactions of 2-substituted-4-(bromomethyl)thiophenes (which were prepared by transhalogenation of 2-substituted-4- (chloromethyl)thiophenes with NaBr in acetone) with Grignard reagents afforded 2,4-disubstituted thiophenes. Using this method, eleven 2,4-disubstituted thiophenes were synthesized and their potentials as liquid crystalline compound of low viscosity were examined. The synthesized 2-(4-cyanophenyl)-4-pentylthiophene was observed to have a lower melting point than the corresponding 2,5-disubstituted thiophene. This observation is consistent with the expectation from the basis of molecular linearity which can affect the viscosity and/or melting point of crystalline compounds.

The main objective of the current research, 3-amino-1H‐1,2,4‐triazole immobilized on 3-chloropropyl joined SiO2 nanoparticles as a recyclable, environment-friendly, and novel heterogeneous base catalyst. It was characterized by fourier transform infrared, X-ray diffraction patterns, field emission scanning electron microscopes, and energy-dispersive X-ray spectroscopy. This new material as a green and efficient catalyst was used for the synthesis of pyrano [2,3-c]pyrazoles derivatives through the reaction of aromatic aldehydes, malononitrile, and 3-methyl-1-phenyl-2-pyrazoline-5-one. The reactions did in solvent-free conditions at 60°C and the related pyran derivatives prepared in excellent yields. Also, this catalyst could be used several times without decreasing the activity.

A mild and versatile method for the synthesis of substituted dihydro- and tetrahydro­isoquinolines using an intramolecular Friedel-Crafts reaction of propargylic alcohols is reported. The propargylic alcohols are readily synthesized from aromatic aldehydes, benzyl amines, or benzylic alcohols in 3-4 steps (V. Terrasson et al. Adv. Synth. Catal. 2006, 348, 2063). The cyclization is effected by catalytic amounts of a Lewis acid, a number of which gave comparable yields; the choice for the use of FeCl3 was based on its low cost. A Brønsted acid, such as p-toluene sulfonic acid (PTSA) did not yield the desired isoquinoline but instead afforded a Meyer-Schuster rearrangement product (an open-ring ene-ketone, see: C. Y. Lorber et al. Tetrahedron Lett. 1996, 37, 853). In general, tetrahydroisoquinolines A were formed in moderate to excellent yields although in two cases the isomerized dihydroisoquinolines B were obtained. The allene products A were isomerized into the dihydroisoquinolines B by treatment with PTSA. The substrate scope was moderately studied but not tested thoroughly in terms of R1 = EWG effects.

We have developed an efficient and sustainable approach for the synthesis of 4,4′‐bipyrazole derivatives from spirocyclopropanyl‐pyrazolone and hydrazine under mild conditions. This methodology is catalyst‐free, operating effectively in both batch and continuous flow processes. The flow synthesis allows the production of products up to 110 mg/h which provides industrial applicability and scalability. Additionally, 4,4’‐bipyraole has been transformed into a triphenyl‐substituted pyrazole derivative.