Products 3a Research Articles

Zirconocene-mediated selective synthesis of 1,4-bis(alkynyl)benzenes

A series of novel 1,4-bis(alkynyl)benzene derivatives were synthesized from trimethylsilyl-substituted alkynes by the mediation of zirconocene with excellent regioselectivity in high yields. The 3,6-bis(trimethylsilyl)-4,5-dialkylphthalic acid dimethyl esters were prepared by cycloaddition of 2,5-bis(trimethylsilyl)zirconacyclopentadienes to dimethyl acetylenedicarboxylate. After iodination with iodine monochloride, 3,6-diiodo-4,5-dialkylphthalic acid dimethyl esters reacted with terminal alkynes to prepare the corresponding 1,4-bis(alkynyl)benzene derivatives by Sonogashira coupling reactions. After removal of trimethylsilyl, 4,5-dibutyl-3,6-bis(ethynyl)phthalic acid dimethyl ester (compound 3) reacted with 4-iodobenzoic acid ethyl ester and 2-iodothiophene, respectively, to obtain the corresponding products 4a and 4c. Compound 3 can be extended to higher oligomers, which reacted with 1-bromo-4-iodobenzene and phenylacetylene in a stepwise manner under Sonogashira conditions to give the phenylene-ethynylene oligomer 5 in an isolated yield of 85%. The structures of the products were confirmed by 1H NMR spectroscopy, 13C NMR spectroscopy, and MS. The optical properties of the 1,4-bis(alkynyl)benzene derivatives were studied by UV-Vis spectroscopy and fluorescence spectra. The results indicated that some can be developed into potential photovoltaic materials.

Synthesis of new cyclotriphosphazene derivatives bearing Schiff bases and their thermal and absorbance properties

In this study, a series of cyclotriphosphazene derivatives containing a Schiff base (3a–3d) were synthesized by the reactions of hexachlorocyclotriphosphazene (1) with bis-aryl Schiff bases ( 2a – 2d ) having different terminal groups (H, F, Cl, and Br). The products ( 3a – 3d ) were characterized by elemental and mass analyses, FT-IR, and 1 H, 13 C, and 31 P NMR spectroscopies. Furthermore, the structure of compound 3a was also determined by X-ray crystallography. The thermal behaviors and the spectral properties of the new cyclotriphosphazene compounds ( 3a – 3d ) were investigated and the results were compared in the series.

Synthesis of Novel Benzodifuranyl; 1,3,5-Triazines; 1,3,5-Oxadiazepines; and Thiazolopyrimidines Derived from Visnaginone and Khellinone as Anti-Inflammatory and Analgesic Agents.

Novel (4-methoxy or 4,8-dimethoxy)-3-methyl-N-(6-oxo-2-thioxo-1,2,3, 6-tetrahydro- pyrimidin-4-yl) benzo [1,2-b: 5, 4-b’] difuran-2-carboxamide (5a–b) has been synthesized by the reaction of visnagenone–ethylacetate (2a) or khellinone–ethylacetate (2b) with 6-aminothiouracil in dimethylformamide or refluxing of benzofuran-oxy-N-(2-thioxopyrimidine) acetamide (4a–b) in sodium ethoxide to give the same products (5a,b) in good yields. Thus, compounds 5a–b are used as an initiative to prepare many new heterocyclic compounds such as 2-(4-(3-methylbenzodifuran- 2-carbox-amido) pyrimidine) acetic acid (6a–b), N-(thiazolo[3, 2-a]pyrimidine)-3-methylbenzo- difuran-2-carboxamide (7a–b), N-(2-thioxopyrimidine)-methylbenzodifuran-2-carbimidoylchloride (8a–b), N-(2-(methyl-thio) pyrimidine)-3-methylbenzodifuran-2-carbimidoylchloride (9a–b), N-(2, 6 -di(piperazine or morpholine)pyrimidine)-1-(3-methylbenzodifuran)-1-(piperazine or morpholine) methanimine(10a–d), 8-(methylbenzodifuran)-thiazolopyrimido[1,6-a][1,3,5]triazine-3,5-dione (11a –b), 8-(3-methyl benzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-trione (12a–b), and 2,10 -di(sub-benzylidene)-8-(3-methylbenzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-3,5,11- trione (13a–f). All new chemical structures were illustrated on the basis of elemental and spectral analysis (IR, NMR, and MS). The new compounds were screened as cyclooxygenase-1/ cyclooxygenase-2 (COX-1/COX-2) inhibitors and had analgesic and anti-inflammatory activities. The compounds 10a–d and 13a–f had the highest inhibitory activity on COX-2 selectivity, with indices of 99–90, analgesic activity of 51–42% protection, and anti-inflammatory activity of 68%–59%. The inhibition of edema for the same compounds, 10a–d and 13a–f, was compared with sodium diclofenac as a standard drug.

Microwave Assisted Synthesis and Antimicrobial Activity of Novel Pyrrolidine Derivatives

Microwave assisted synthesis of 1-acetyl-2-benzylpyrrolidine-2-carboxylic acid and its derivatives has been developed with highly encouraging yields. 2-Benzyl-tert-butylpyrrolidine-1,2-dicarboxylate is used as an initial compound in the four steps synthesis of the target compounds. Structures of the products 5a–5h have been confirmed by spectroscopic methods. According to antimicrobial tests 1-acetyl-2-benzylpyrrolidine-2-carboxamide 5c is determined to be the most potent product.

Facile synthesis, crystal growth, characterization and computational study of new pyridine‐based halogenated hydrazones: Unveiling the stabilization behavior in terms of noncovalent interactions

The pyridine‐based halogenated hydrazone derivatives (E)‐N′‐benzylidene‐2‐[(6″‐chloroazin‐2″‐yl)oxy]acetohydrazide (6a), (E)‐N′‐(3′‐chlorobenzylidene)‐2‐[(6″‐chloroazin‐2″‐yl)oxy]acetohydrazide (6b) and (E)‐N′‐(3′‐bromobenzylidene)‐2‐[(6″‐chloroazin‐2″‐yl)oxy]acetohydrazide (6c) have been obtained using 6‐chloro‐2‐hydroxypyridine. The structure of the products (6a–c) has been verified using X‐ray crystallography and spectroscopic approaches. A single‐crystal X‐ray diffraction (SC‐XRD) investigation showed that the structures are stabilized by intermolecular attractive forces. Additionally, density functional theory (DFT) has been adopted to explore the structural properties, vibrational spectra, noncovalent interactions and frontier molecular orbitals using the B3LYP/6‐311 + G(d,p) level. The nonlinear optical properties of the title compounds were calculated using the CAM‐B3LYP/6‐311 + G(d,p) level. Frequency analysis confirmed the stability of the molecules, and an excellent correlation was observed between the DFT‐ and SC‐XRD‐based structural parameters. The SC‐XRD analysis confirmed that the dimers of 6a, 6b and 6c are linked by hydrogen‐bonding interactions. Natural bond orbital (NBO) analysis also reconfirmed the strength of intermolecular hydrogen‐bonding and hyperconjugative interactions. NBO investigation was also utilized to analyze the atomic charges. Moreover, Fourier transform infrared and natural population analyses endorsed that there are significant N&bond;H⋅⋅⋅O&dbond;C hydrogen‐bonding linkages in dimeric structures of the compounds. The hydrogen‐bonding network and different sorts of hyperconjugative interactions are the main reasons for the stability of the products in the solid state. The highest occupied and lowest unoccupied molecular orbital energies and first‐order nonlinear optical properties of these molecules are reported. The quantum chemical parameters were derived using frontier molecular orbital energies.

Selective C-C Bond Scission of Ketones via Visible-Light-Mediated Cerium Catalysis

Summary Here, we report a general catalytic manifold for the selective C–C bond scission of ketones via the exploitation of the ligand-to-metal charge transfer (LMCT) excitation mode. Through a cooperative utilization of Lewis acid catalysis and LMCT catalysis, the C–C bond of ketones could be selectively and effectively cleaved, enabling the installation of different functionalities at each carbon of the cleaved C–C bond through a sequential and orthogonal manner. This reaction manifold serves as a photocatalytic alternative to the Norrish type I reaction with the combination of visible light and inexpensive cerium salts. Under operationally simple conditions, a wide range of acyclic and cyclic ketones, from simple strained cyclobutanones to complex androsterone with less strained cyclopentanone moiety, could be successfully transformed into versatile chemical building blocks.

In situ vinylindole synthesis: Diels–Alder reactions with N-phenylmaleimides, 1-tetralones and 4-chromanones to give annulated tetrahydrocarbazoles

An acid-catalyzed condensation of indole 4 with 1-tetralones 5a–f formed a vinylindole which reacted in situ with N-phenylmaleimides 7a–g. This cascade of condensation and Diels–Alder reaction was performed in IPA (isopropyl alcohol) and in presence of p-TsOH (p-toluenesulfonic acid) at reflux to produce annulated tetrahydrocarbazoles 8a–g and 10a–e. Similarly, 9a–g were synthesized by substituting 4-chromanone 6 for 5a–f. The 1-tetralone derived products 8a–g and 10a–e were obtained in higher yields (19–79%) compared to 4-chromanone derived 9a–g (6–28%), likely due to additional side reactions in case of chromanones. To establish the structure and stereochemistry of products, the crystal structure of 10c was obtained, confirming endo-Diels–Alder addition.

From Isocyanides to Iminonitriles via Silver-mediated Sequential Insertion of C(sp3)-H Bond.

SummaryHeterocycles are prevalent constituents of many marketing drugs and biologically active molecules to meet modern medical challenges. Isocyanide insertion into C(sp3)–H bonds is challenging especially for the construction of quaternary carbon centers. Herein, we describe an efficient strategy for the synthesis of α-iminonitrile substituted isochromans and tetrahydroisoquinolines (THIQs) with quaternary carbon centers through silver-triflate-mediated sequential isocyanide insertion of C(sp3)–H bonds, where isocyanide acts as the crucial “CN” and “imine” sources. The produced α-iminonitriles have extensive applications as valuable synthetic building blocks for pharmacologically interesting heterocycles. This protocol could be further applied for the synthesis of iminonitrile-decorated phenanthridines and azapyrene. Interestingly, a remarkable aggregation-induced emission (AIE) effect was first observed for an iminonitrile-decorated pyrene derivative, which may open a particular area for iminonitrile applications in materials science.

Alkynyl Fischer Carbenes as a Platform for the Production of Difluorodiazaborinine Complexes via β‐Amino‐azadienes

The results of a study of the reactivities of alkynyl Fischer carbenes in the syntheses of diazaborinine derivatives 7a‐i are reported. The strategy employed included the use of β‐amino‐α,β‐unsaturated carbenes (3a–j) with different amines in order to determine the scope of a previously unknown catalytic reaction in the presence of copper salts and anilines. The reaction was highly stereoselective, yielding (Z)‐isomers of the β‐amino‐1‐azadiene framework as the main products (4a–o). As an extension of this research, the compounds 4a–o proved to be suitable precursors for the syntheses of diazaborinine scaffolds in good yields (7a‐i).

Synthesis of Quaternary Carbon-Centered Benzoindolizidinones via Novel Photoredox-Catalyzed Alkene Aminoarylation: Facile Access to Tylophorine and Analogues

Photoredox-catalyzed aminoarylation and thioamination of unactivated alkenes have been developed, providing novel synthetic routes to access synthetically challenging quaternary carbon-centered ben...

Copper-Catalyzed Asymmetric Formal Hydroaminomethylation of Alkenes with N,O-Acetals to Access Chiral β-Stereogenic Amines: Dual Functions of the Copper Catalyst

Chiral amines are synthetically versatile intermediates used for the preparation of a wide range of biologically active compounds and drugs. Compared with the well-developed synthesis of α-stereoge...

Design, efficient synthesis and molecular docking of some novel thiazolyl-pyrazole derivatives as anticancer agents

Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides 3a,b (obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates 1a,b with thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives 6a–h, 10a–c, 15a–c, 17, 19 and 21 via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities (10a: − 3.4 kcal/mol, 6d: − 3.0 kcal/mol, 15a: − 2.2 kcal/mol, 3a: − 1.6 kcal/mol, and 21: − 1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products 3a, 6d, 10a, 15a, and 21 was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.

Highly Efficient [3 + 2] Cycloaddition: Click Synthesis of Novel 1H‐indol‐3‐yl‐benzo[d]imidazole Bis‐triazoles

A series of novel 1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐2‐(1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐5‐substituted‐1H‐indol‐3‐yl)‐6‐substituted‐1H‐benzo[d]imidazoles 5a–i have been prepared using click chemistry as an ideal strategy where [3 + 2] cycloaddition of azides with terminal alkynes has been developed as the target compounds. In route‐II, 5‐substituted‐1H‐indole‐3‐carbaldehydes 1a–c react with 5‐substituted orthophenylenediamine 8 to give desired products, that is, 6‐substituted‐2‐(5‐substituted‐1H‐indol‐3‐yl)‐1H‐benzo[d]imidazole 6a–i. Here, 6a–i react with 2 equiv of propargylbromide 7 to give novel 6‐substituted 2‐(5‐substituted‐1‐(prop‐2‐yn‐1‐yl)‐1H‐indol‐3‐yl)‐1‐(prop‐2‐yn‐1‐yl)‐1H‐benzo[d]imidazole 4a–i. 4a–i were reacted with 2 equiv of NaN3 in t‐butanol/water (1:2) and add catalytic amount of CuSO4.5H2O. Stir the reaction mixture at room temperature to get the target products 5a–i. Here, obtained products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages of this method are short reaction times, easy workup, higher yields (88–92%), and no by‐products formation.

Corrigendum: Branched C=C and C−N Bond Cleavage on Enaminones toward the Synthesis of 3‐Acyl Quinolines

In the original paper, we proposed that the enaminone participates in the construction of the quinoline ring by acting as the C4-source via C=C double-bond cleavage (Scheme 1).1 Based on two recent publications on the synthesis of the same type of quinolines,2, 3 the construction of the quinoline ring involves the participation of DMSO as the C4 source. We then further checked the model reaction by varying the reaction medium to para-xylene, and no product 3a was observed therein. In combination with the data from the reactions in toluene and ethyl lactate in our original paper,1 where only traces of the product were obtained, it is more reasonable that DMSO also acts as the major C4-carbon source in our work (Scheme 2). Originally proposed mechanism for the quinoline construction involving an enaminone C=C bond cleavage. DMSO involvement in the synthesis of quinolines.

An Efficient Synthesis of Pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori Reaction

An efficient synthetic strategy has been developed for the synthesis of pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori cyclization reaction. The reaction of various pyrazolyl‐phenylethanones with semicarbazide hydrochloride in the presence of sodium acetate/methanol gave the corresponding semicarbazones (3a–i). These semicarbazones were further reacted with thionyl chloride via the Hurd–Mori cyclization conditions to accomplish the title products (4a–i). The present protocol favored for the formation of both pyrazolyl semicarbazone derivatives and pyrazolyl‐1,2,3‐thiadiazole derivatives by forming C─S, N─S, and C═N bonds in excellent yields with variety of substrates. The final compounds were characterized by analytical and spectral studies.

Molybdenum and rhenium carbonyl complexes containing thiolato ligands

The reaction of fac-[M(OTf)(CO)3(N–N)](M = Mn, Re; N–N = 2,2′-bipyridine, 1,10-phenanthroline) complexes with in situ generated LiSEt afforded immediately, in THF at low temperature, the corresponding mononuclear terminal thiolato complexes fac-[M(SEt)(CO)3(N–N)](1-2a,b). Using an analogous synthetic strategy, tungsten and molybdenum (II) alkyl- and arylthiolatos of formula cis-[M(SR)(η3-allyl)(CO)2(N–N)] (3-6a,b) have been obtained. Preliminary reactions of the more reactive molybdenum thiolato complexes towards dimethylacetylenedicarboxylate led to Z-alkenyl products (7a,b), resulting from the insertion of the organic unsaturated electrophile into the Mo–S bond. For each new type of compound, one representative has been characterized in the solid state by X-ray diffraction.

Oxidative coupling of coumarins catalyzed by laccase

Laccase (LAC) belongs to the blue multi‑copper lignolytic oxidase enzymes, and has been regarded as an important tool to produce some important dimers in the application of biotechnology. In this study, sixteen coumarins 1–16 were screened to investigate the catalytic ability of LAC, and three coumarins 6, 7, and 16 could be catalyzed to produce three coumarin derivative coupling with acetone 6a, 7a, and 16a. The potential interaction mechanisms of three coumarins 6, 7, and 16 with LAC were analyzed by molecular docking. The kinetic analyses of catalytic reactions for coumarins 6, 7, and 16 with LAC were performed by using the transformed products 6a, 7a, and 16a as standard substances. Km values of coumarins 6, 7, and 16 were ranged from 0.87 ± 0.07 μM to 2.74 ± 0.29 μM, respectively. This finding suggested that LAC was a reliable method to catalyze oxidative coupling.

Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2.

Traumatic spinal cord injury (SCI) triggers an acute-phase response that leads to systemic inflammation and rapid mobilization of bone marrow (BM) neutrophils into the blood. These mobilized neutrophils then accumulate in visceral organs and the injured spinal cord where they cause inflammatory tissue damage. The receptor for complement activation product 3a, C3aR1, has been implicated in negatively regulating the BM neutrophil response to tissue injury. However, the mechanism via which C3aR1 controls BM neutrophil mobilization, and also its influence over SCI outcomes, are unknown. Here, we show that the C3a/C3aR1 axis exerts neuroprotection in SCI by acting as a physiological antagonist against neutrophil chemotactic signals. We show that C3aR1 engages phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, to restrain C-X-C chemokine receptor type 2-driven BM neutrophil mobilization following trauma. These findings are of direct clinical significance as lower circulating neutrophil numbers at presentation were identified as a marker for improved recovery in human SCI. Our work thus identifies C3aR1 and its downstream intermediary, PTEN, as therapeutic targets to broadly inhibit neutrophil mobilization/recruitment following tissue injury and reduce inflammatory pathology.

Synthesis, crystal structure, spectroscopic characterization, Hirshfeld surface analysis, molecular docking studies and DFT calculations, and antioxidant activity of 2-oxo-1,2-dihydroquinoline-4-carboxylate derivatives

A series of hydroquinolines derivatives (2a-2c) have been achieved by a cyclocondensation reaction. The synthesis of 2-oxo −1,2-dihydroquinoline-4-carboxylic acid derivatives (3a-3c) has been carried out using alkylation reactions under phase transfer catalysis (PTC) conditions. The prepared products were characterized through spectroscopic NMR 1H and 13C, IR and single crystal X-ray diffraction techniques. 2D and 3D Hirshfeld surfaces (for 3a and 3b) studies were realized to understand non-bonding intermolecular interactions in solid phase crystal packing of the compound. With the optimized structures, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and clouds were obtained and evaluated. Good agreement was found between the calculated results and experimental data. Furthermore, the molecular docking study is performed to investigate binding patterns of the synthesized molecules (3a and 3b) into 1M17 inhibitor using Auto-Dock Vina program. The antioxidant activity of compounds (3a-3c) has been evaluated using DPPH free radical scavenging, ferric reducing (FRAP) power and β-carotene kinetic blanching assays. Both DPPH and FRAP methods confirmed that 3b had the best antioxidant activity followed by 3c. On the other hand, β-carotene bleaching assay showed the high activity of the product 3a.

Synthesis and evaluation of some new 1,3,4-oxadiazoles bearing thiophene, thiazole, coumarin, pyridine and pyridazine derivatives as antiviral agents.

In an attempt to produce heterocyclic compounds based on 1,3,4-oxadiazole derivatives with potential antiviral activity, synthesis of compound 1 [2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile] was performed through the reaction of cyanoacetic acid hydrazide with carbon disulfide in alcoholic potassium hydroxide. Compound 1 has an activating methylene group, so it was directed toward some specific reactions. Thus, aryldiazonium chlorides reacted with compound 1 affording hydrazono derivatives 2a-c. Also, aromatic aldehydes reacted with compound 1 to produce compounds 3a,b. Furthermore, cyclic ketones were subjected to the synthesis of fused thiophene derivatives 4a,b via reaction with compound 1 in the presence of elemental sulfur. In addition, 1,3,4-oxadiazole derivative 1, when reacted with isothiocyanates, salicylaldehyde or 1,3-dicarbonyl compounds, formed thiazole derivatives 5a,b, coumarin derivative 6 and alkenyl derivatives 7a,b resp. Compound 7b underwent cyclization to afford pyridine derivative 8. Arylhydrazono derivatives 9a,b were produced through the reaction of compound 7a with aryldiazonium chlorides. Products 9a,b underwent cyclization to produce pyridazine derivatives 10a,b. Finally, 1,3,4-oxadiazole derivative 1 was directed toward reaction with hydrazine derivatives, bromoacetophenone and ethylchloroacetate affording compounds 11a,b, 12 and 13, resp. Fused thiophene derivatives 14a,b were produced via reaction of compounds 4a,b with a mixture of malononitrile and ethylorthoformate. Antiviral activity of the synthesized products showed that 5-(4-amino-3-ethyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5a) and 5-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5b) acted as the most active agents against Feline herpes virus, Feline corona virus, Herpes simplex virus-1 and Herpes simplex virus-2, whereas compound 2-(5-(2-phenylhydrazono)-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile (11b) was the most effective against Vaccinia virus, Herpes simplex virus (TK-KOS-ACVr), Coxsackie virus B4 and Vesicular stomatitis virus.