Pyrazole Skeleton Research Articles

Selected Electrosynthesis of 3-Aminopyrazoles from α,β-Alkynic Hydrazones and Secondary Amines.

An available and simple electromediated cyclization method for 3-amino-substituted pyrazoles by using α,β-alkynic hydrazone and secondary amine is described. The strategy utilizes KI as an electrolyte in an undivided cell with a constant current, generating the desired products in moderate-to-good yield. The method features selective amination at the 3-position of the pyrazole skeleton. The results indicate that α,β-alkynic hydrazones functionalized with aromatic groups and secondary amines functionalized with electron-rich groups were better tolerated in this transformation.

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl2 and NH4SCN/KSeCN.

A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NH4SCN/KSeCN as thio/selenocyanogen sources and PhICl2 as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl-SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.

Switchable synthesis of natural-product-like lawsones and indenopyrazoles through regioselective ring-expansion of indantrione

Lawsones and indenopyrazoles are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules, but their synthesis has always remained challenging as no comprehensive protocol has been outlined to date. Herein, a metal-free, ring-expansion reaction of indantrione with diazomethanes, generated in situ from the N-tosylhydrazones, has been developed for the synthesis of lawsone and indenopyrazole derivatives in acetonitrile and alcohol solvents, respectively. It provides these valuable lawsone and pyrazole skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials. DFT calculations were used to explore the mechanism in different solutions. The synthetic application example also showed the prospects of this method for the preparation of valuable compounds.

Intramolecular integration of pyrazole-triazine-triazole heterocyclic skeletons: A novel 5/6/5 fused energetic framework with high energy and low sensitivity

Currently, the research in energetic materials focuses on exploring new design strategies to seek the ideal balance between high performance and molecular stability. In this work, the intramolecular integration strategy with the introduction of 1,2,4-triazine between triazole skeleton and pyrazole skeletons to develop the advanced 5/6/5 fused energetic materials is proposed. The six-membered skeleton 1,2,4-triazine in three-membered fused rings is rarely constructed with the N-NH2 group on the ring and the N− on the γ-position of the adjacent ring via cyanogen bromide. By employing the above strategy, an advanced energetic molecule 9,10-dinitropyrazolo[1,5-d][1,2,4]triazolo[3,4-f][1,2,4]triazine-3,6-diamine (4) and its derivatives (5–7) with the excellent overall performance is prepared. These compounds all have high density (ρ > 1.80 g cm−3), good thermal stability (Tdec > 210 °C except 5), excellent detonation performance (Dv > 8841 m·s−1), and low sensitivity (IS > 30 J; Fs > 300 N). These favorable energetic properties are obviously superior to those of the extensively used high explosive RDX (ρ = 1.805 g cm−3; Dv = 8801 m s−1; Tdec = 204 °C; IS = 7.4 J; FS = 120 N). Among them, the perchlorates 7 has an excellent and comprehensive performance with high density 1.945 g cm−3, high energy (Dv = 9046 m s−1) comparable to HMX (Dv = 9144 m s−1), low sensitivity (IS = 35 J; FS = 310 N) comparable to TNT (IS = 15 J; FS = 353 N) and good decomposition temperature 212 °C, which make it potentially candidates for the novel HEDMs.

Iodine‐Promoted Tandem Pyrazole Annulation and C−H Sulfenylation for the Synthesis of C4‐Sulfenylated Pyrazoles

AbstractCascade reactions of 1,3‐diarylpropane‐1,3‐dione or unsaturated ketones with arylsulfonyl hydrazide have been achieved in the presence of iodine source. Fully substituted C4‐sulfenylated pyrazoles were synthesized via the tandem pyrazole annulation and C(sp2)−H sulfenylation. This approach is efficient and practical. The starting materials are readily available, while also providing a useful strategy for the construction of different arylthio‐substituted pyrazole skeletons.

Catalytic asymmetric synthesis of 3,4′-indole–pyrazole derivatives featuring axially chiral bis-pentatomic heteroaryls

We reported the catalytic asymmetric construction of the axially chiral 3,4′-indole–pyrazole skeleton, a bis-pentatomic heteroaryl scaffold in many bioactive molecules.

Regio- and stereoselective synthesis of spiro-heterocycles bearing the pyrazole scaffold via [3+2] cycloaddition reaction

Herein we reported the utility of one-pot multicomponent based [3+2] cycloaddition reaction transformation to prepare a new two hybrids of spirooxindoles engrafted with pyrazole skeleton. Upon treatment of the electron-deficient olefins based pyrazole motif with in situ the generated azomethine ylides (AY) of sarcosine with the 6-chloro-isatin afforded spiroadducts. To enlighten the regio- and diastereo-selectivity of these spiroheterocycles, single crystal X-ray diffraction analysis was presented. Using Hirshfeld calculations, many short distance contacts such as O…H, Cl…H, N…H, H…C, C…C and Cl…S have a great impact on the molecular packing and the crystal stability of 8a and 8b. The latter showed some Cl…Cl inter halogen interactions (Cl1…Cl3; 3.358 Å). In addition, DFT calculations were used to compute the electronic properties as well as the 1H- and 13C-NMR spectra of the studied systems. Both compounds are polar where 8b (3.995 Debye) has higher dipole moment than 8a (3.414 Debye). The NMR chemical shifts were calculated and found in excellent correlations between the calculated and experimental data were obtained (R2 = 0.94–0.98).

Intramolecular integration of multiple heterocyclic skeletons for energetic materials with enhanced energy & safety

The research for new generations of high explosives with the remarkable overall performance has always been a challenging task. Currently, the research priority of energetic materials is to explore new design strategies to balance and/or break the energy-safety limits. In this study, an intramolecular integration of various heterocyclic skeletons based on the unique superiority of each heterocycle was developed. By employing this approach, an advanced energetic molecule integrating 1,2,5-oxadiazole, 1,2,4-oxadiaozle and pyrazole skeletons, 5-(3,4-dinitro-1H-pyrazol-5-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole (6), was designed and prepared. The energy level (e.g., detonation velocity: 9094 m s−1) of 6 is approaching that of the extensively used high explosive, RDX (8801 m s−1), while its safety (impact sensitivity: IS = 24 J; thermal stability: Tdec = 265 °C) are obviously superior to that of RDX (IS = 7.4 J; Tdec = 204 °C). These favorable energetic properties demonstrate the outstanding overall performance of 6. Moreover, the variation of sensitivities and thermal stabilities were further investigated through the quantum chemistry methods based on the single-crystal data. Our study is anticipated to attract more in-depth study on the promising intramolecular integration approach and accelerate the development of the advanced energetic materials.

Synthesis of some heterocyclic of expected bioactivity via reactions of thiazine derivatives: Thesis Abstract

Thesis Abstract: 2-acetylphenothiazine plays an important role in organic chemistry. The behavior of 2-acetylphenothiazine towards various reagents was carried out. Thus, the aim of the present work is to design and synthesize some of heterocyclic nuclei through the reaction of phenothiazine derivatives as scaffold moiety with different reagents. α,β-Unsaturated ketones containing phenothiazine moiety 4, 5, 7 were synthesized by condensation of 2-acetylphenothiazine with different aryl aldehydes 2, 3, and (DMFDMA). Pyrazole skeletons were also synthesized by 1,3-dipolar cycloaddition reactions of α,β-unsaturated ketones with different nucleophilic reagents. Formylpyrazole derivative 36 was synthesized through the Vilsmeier-Haack reaction of phenylhydrazone 35b. Azines derivatives of phenothiazines were synthetically constructed from one-pot multicomponent reactions of 1-(4a, 10a-dihydro-10H-phenothiazine-2-yl) ethan-1-one with various reagents. Newly synthesized compounds were screened as antioxidant agents. The sequence of these reactions that adopted for the synthesis of the designed compounds in this thesis is summarized into two sections. Furthermore, studying of the biological activity of the newly synthesized compounds as antioxidants properties were performed.

Copper(ii) facilitated decarboxylation for the construction of pyridyl–pyrazole skeletons

Pyridyl–pyrazole carboxylic compounds were synthesized in one step by Cu(ii) facilitated decarboxylation of H3pdc and activation of pyridine in water.

Pyrazole: A potent drug candidate with various Pharmacological activities

Aromatic organic heterocycle containing pyrimidine scaffolds. Pyrazole possess, a five-membered hetero aromatic ring with two nitrogen atoms. Presence of this nucleus in these Pyrazole skeletons comprise various ranges of pharmacological activities viz. analgesic, antipyretic, anticancer, antiviral, anti-Inflammatory, antioxidants, antimicrobial, anti-diabetic, anticonvulsant &antiarrhythmic. Pyrazole is a multipurpose lead compound which is developed by chemical architecture for effective molecules which are mostly biologically active. Several synthetic routes are accorded for the development of pyrazole containing reactions to afford a novel molecule.

A combined experimental and DFT investigation of disazo dye having pyrazole skeleton

Disazo dye containing pyrazole skeleton has been synthesized. The structure of the dye has been confirmed by using FT-IR, 1H NMR, 13C NMR, HRMS spectral technique and elemental analysis. The molecular geometry and infrared spectrum are also calculated by the Density Functional Theory (DFT) employing B3LYP level with 6-311G (d,p) basis set. The chemical shifts calculation for 1H NMR of the title molecule is done by using by Gauge-Invariant Atomic Orbital (GIAO) method by utilizing the same basis sets. The total density of state, the partial density of state and the overlap population density of state diagram analysis are done via Gauss Sum 3.0 program. Frontier molecular orbitals such as highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and molecular electrostatic potential surface on the title molecule are predicted for various intramolecular interactions that are responsible for the stabilization of the molecule. The experimental results and theoretical values have been compared.

Radical Addition of Hydrazones by α-Bromo Ketones To Prepare 1,3,5-Trisubstituted Pyrazoles via Visible Light Catalysis.

A novel efficient tandem reaction of hydrazones and α-bromo ketones is reported for the preparation of 1,3,5-trisubstituted pyrazoles by visible light catalysis. In this system, the monosubstituted hydrazones show wonderful reaction activity with alkyl radicals, generated from α-bromo ketones. A radical addition followed by intramolecular cyclization affords the important pyrazole skeleton in good to excellent yields. This efficient strategy under mild conditions with wide group tolerance provides a potential approach to the 1,3,5-trisubstituted pyrazoles.

Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity.

A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4.

Structure elucidation of the designer drug N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide and the relevance of predicted (13) C NMR shifts - a case study.

The detailed structure elucidation process of the new cannabimimetic designer drug, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide, with a highly substituted pyrazole skeleton, using nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric (MS) techniques is described. After a first analysis of the NMR spectra and comparison with 48 possible pyrazole and imidazole structures, a subset of six positional isomeric pyrazoles and six imidazoles remained conceivable. Four substituents of the heterocyclic skeleton were identified: a proton bound to a pyrazole ring carbon atom; a 5-fluoropentyl group; a 4-fluorophenyl substituent; and a carbamoyl group, which is N-substituted with a methyl residue carrying a tert.-butyl and a carbamoyl substituent. The 5-fluoropentyl residue is situated at the nitrogen ring atom. Additional NMR experiments like the (1) H,(13) C HMBC were performed, but due to the small number of signals based on long-range couplings, the comparison of predicted and observed (13) C chemical shifts became necessary. The open access Internet shift prediction programs NMRDB, NMRSHIFTDB2, and CSEARCH were employed for the prediction of (13) C shift values which allowed an efficient and unambiguous structure determination. For the identified N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide, the best agreement between predicted (13) C shifts and the observed chemical shifts and long-range couplings for the pyrazole ring carbon atoms, with a standard error of about 2 ppm, was found with each of the predictions. For the comparison of measured and predicted chemical shifts model compounds with simple substituents proved helpful. The identified compound is a homologue of AZ-037 which is offered by Internet suppliers. Copyright © 2015 John Wiley & Sons, Ltd.

Copper-catalyzed aerobic cascade cycloamination and acyloxylation: a direct approach to 4-acyloxy-1H-pyrazoles.

A novel direct transformation of hydrazones to acyloxylated pyrazoles by copper-catalyzed regioselective olefinic C(sp(2))-H bond cycloamination and acyloxylation was performed under mild conditions, which combines the formation of the pyrazole skeleton and installation of an acyloxyl group in a single step, using facile carboxylic acids as the acyloxylation reagents.

ChemInform Abstract: TEMPO‐Mediated Aliphatic C—H Oxidation with Oximes and Hydrazones.

AbstractThis method opens access towards highly substituted isoxazole and pyrazole skeletons under transition metal‐free conditions.

Enantioselective Michael Addition of 1,3-Diketones to Arenesulfonylalkylindoles: A Flexible Gateway to Optically Active 3-sec-Alkyl-Substituted Indoles Containing a Pyrazole Skeleton

Enantioselective Michael addition of 1,3-diketones to alkylideneindolenines generated in situ from arenesulfonylalkylindoles is described, and a series of optically active C3-alkyl-substituted indole derivatives has been obtained. The resulting adducts can be readily converted into 3-sec-alkyl-substituted indoles containing a pyrazole skeleton, with direct connection between the α- and 4-positions, without decrease of the enantioselectivity.

TEMPO-Mediated Aliphatic C–H Oxidation with Oximes and Hydrazones

A method for aliphatic C-H bond oxidation of oximes and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) has been developed, which enables the concise assembly of substituted isoxazole and pyrazole skeletons.

Identification of novel 3,5-diarylpyrazoline derivatives containing salicylamide moiety as potential anti-melanoma agents

There is an accumulating body of experimental evidences validating oncogenic BRAFV600E as a therapeutic target and offering opportunities for anti-melanoma drug development. Encouraged by the positive results of pyrazole derivatives as BRAFV600E inhibitors, we sought to design diverse novel potential BRAFV600E inhibitors as antitumor agents based on pyrazole skeleton. In silico and in vitro screening of our designed pyrazole derivatives has identified Hit 1 as BRAFV600E inhibitor. Based on its structure and through further structure modification, compound 25, which exhibited the most potent inhibitory activity with an IC50 value of 0.16μM for BRAFV600E and GI50 value of 0.24μM for mutant BRAF-dependent melanoma cells, was obtained. The 3D-QSAR models and the molecular docking simulation were introduced to analyze the structure–activity relationship.