Highly functionalized calix[4]arenes via multicomponent reactions: synthesis and recognition properties

Multicomponent reactions (MCRs) include several aspects of green chemistry principles, so it is obvious that chemists in different areas are increasingly interested in providing their product by multicomponent approaches. MCRs can be very useful in supramolecular chemistry, especially to produce novel supramolecular derivatives. Therefore, there are several reports of highly-functionalized calix[4]arene derivatives obtained by MCRs instead of conventional stepwise protocols during the last decade. In this paper, we have particularly focused on the exploitation of upper rim and lower rim substituted calix[4]arenes in multicomponent approaches as a facile and convenient synthetic strategy. The value of this method lies in its operational simplicity, mild reaction conditions and structural diversity of the products. Interestingly, in most cases the products afforded by this method offer unique features and applications which are highlighted in the following sections.

Multicomponent reactions (MCRs) include several aspects of green chemistry principles, so it is obvious that chemists in different areas are increasingly interested in providing their product by multicomponent approaches.     

Synthesis of functionalized benzo[1,3]dioxin-4-ones from salicylic acid and acetylenic esters and their direct amidation

Direct synthesis of 4H-benzo[d][1,3]dioxin-4-one derivatives from salicylic acids and acetylenic esters (both mono- and disubstituted) has been described. The reaction is mediated by CuI and NaHCO₃ in acetonitrile. Room temperature amidation of the synthesized 1,3-benzodioxinones with primary amines readily afforded the corresponding salicylamides in moderate to good yields.

An efficient method for the synthesis of the active core 4H-benzo[d][1,3]dioxin-4-one followed by its direct room temperature amidation is reported.

Heterocycles and their derivatives play a pivotal role in natural products and synthetic organic chemistry. Isolation, bio and chemical synthesis, and investigation of pharmacological and biological properties of diverse heterocycles have attracted both organic and medicinal chemists.¹ It is a highly vibrant and ever-expanding field of research. Besides, heterocycle scaffolds contribute significantly towards the development of novel organic materials for luminescent applications due to their unique photophysical properties, which can be tuned to suit diverse applications.² Benzodioxans are oxygen-based isomeric heterocycles with various applications in medicinal, agricultural, and synthetic chemistry. Among the isomeric benzodioxans, 1,3-benzodioxane and its derivatives are used in medicinal and agrochemicals chemistry research.³ In addition, they are potential synthetic intermediates in multistep organic synthesis.⁴ Among the various 1,3-benzodioxane derivatives, 4H-benzo[d][1,3]dioxin-4-one has been identified as an active core in many biologically active molecules such as nucleoside base transport inhibitor, topoisomerase I inhibitor, antiplasmodial and cytotoxic drugs, etc., and its thio derivatives find applications as an insecticide, crop protection agents, and fungicides.⁵ Few examples have been shown in Fig. 1.Open in a separate windowFig. 1Bioactive molecules with 1,3-benzodioxinone or benzoxathiinone core.Salicylic acid and its derivatives are widely used to access the 4H-benzo[d][1,3]dioxin-4-one scaffolds, and several approaches have been reported in the literature.⁶ In a similar line, reports in which thiosalicylic acid yielding the corresponding benzo-1,3-oxathiine derivatives are also reported.⁷ For example, conversion of salicylic acid to benzo[d][1,3]dioxin-4-ones using dichloromethane as the methylene donor was reported by Xiuling Cui under catalyst-free condition using potassium phosphate.⁸ Later, Liu et al. developed a Cu(OAc)₂ catalyzed approach based on ortho-halobenzoic acid, KOH, and NaHCO₃.⁹ Morpholine catalyzed conversion of salicylic acid to the benzodioxinone scaffold was reported by Qiu and co-workers treating with ynones.¹⁰ In 2017, Kawatsura et al. reported the synthesis of 1,3-oxathiine derivatives via an iron-catalyzed intermolecular reaction between thiosalicylic acid and internal alkynes.¹¹ Very recently, Muthusamy et al. reported a catalyst-free synthesis of 1,3-oxathiine derivatives by treating thiosalicylic acid and substituted propargylic alcohols.¹² Due to our continued interest in the development of novel and modified synthetic routes to heterocycles,¹³ we herein report a modified route to synthesize benzo[d][1,3]dioxin-4-ones from salicylic acid and acetylenic esters. To the best of our knowledge, this is the first report on the synthesis of benzo[d][1,3]dioxin-4-ones from salicylic acid and acetylenic esters though the corresponding benzo-1,3-oxathiine route has already been documented.¹¹ Interestingly, both mono- and disubstituted acetylenic esters were equally effective in the reaction. The benzo[d][1,3]dioxin-4-ones derivatives synthesized further readily converted to amides when treated with primary amines at room temperature.From the literature, we understand that the reaction between salicylic acid and acetylenic esters is not yet explored in detail though the analogous thiosalicylic acid-based methods have been well documented. We started our investigations using the salicylic acid 1a and dimethyl acetylenedicarboxylate (DMAD) 2a as the model substrates and the reaction optimization observations of the pilot experiment are summarized in

Third-generation ionic liquids with N-alkylated 1,4-diazabicyclo[2.2.2]octane cations and pelargonate anions

Ionic liquids that belong to the third-generation designs due to their intended biological activity are compounds with high potential applications as plant-protection products. The present study describes the synthesis and characterization of novel ionic liquids with cations based on the alkyl derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and an anion derived from naturally occurring pelargonic acid. The developed synthesis method allowed obtaining products with a high yield (≥96%), and the liquids were characterized as high-viscosity liquids at room temperature. This allowed classifying the products as ionic liquids (ILs). The structures of the obtained ILs were confirmed on the basis of their NMR and IR spectra as well as by elemental analysis. All the products exhibited surface activity and were capable of partially wetting a hydrophobic surface. The tested ionic liquids exhibited higher herbicidal activity against winter oilseed rape (Brassica napus L.) and common lambsquarters (Chenopodium album L.) at a lower dose compared to a commercial preparation in greenhouse studies. The studied ionic liquids also exhibited different effects as antifeedants on various insect species. The best results were obtained against beetles belonging to the granary weevil species (Sitophilus granarius L.). The relation between the surface-tension-reduction efficiency pC₂₀ and biological activity was investigated. The herbicidal activity was also correlated with the value of the contact angles for the studied pelargonates. All the obtained results indicate that the designed and synthesized ionic liquids possess double biological functions: herbicidal activity and deterrent activity.

Novel ionic liquids with cations based on alkyl derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and an anion derived from naturally occurring pelargonic acid possessed double biological functions: herbicidal and deterrent activity.     

Multisulfonate hyperbranched polyglycerol functionalized graphene oxide as an efficient reusable catalyst for green synthesis of benzo[a]pyrano-[2,3-c]phenazines under solvent-free conditions

A novel acid catalyst was prepared based on growing hyperbranched polyglycerol (HPG) on the surface of graphene oxide. Then, the hydroxyl groups of HPG on graphene oxide were functionalized by sulfonate groups to form an acid catalyst. The catalyst displayed a good loading level of acidic groups on the surface because of coating graphene oxide with HPG. This new catalyst is demonstrated to be highly effective in the preparation of benzo[a]pyrano[2,3-c]phenazine dyes.

A novel acid catalyst was prepared based on growing hyperbranched polyglycerol (HPG) on the surface of graphene oxide. Then, the hydroxyl groups of HPG on graphene oxide were functionalized by sulfonate groups to form an acid catalyst.     

Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram

Piclamilast is a type 4 phosphodiesterase (PDE4) inhibitor with equal affinity for the high-affinity rolipram binding site (HARBS) and low-affinity rolipram binding site (LARBS). The binding of [(3)H]piclamilast to preparations of rat brain and peripheral tissue was investigated and compared with that of [(3)H]rolipram. [(3)H]piclamilast binding was high-affinity, saturable, reversible, and partially Mg(2+)-dependent. Binding was detected both to membrane and soluble fractions, with K(d) values of 3.1 and 4.5 nM, respectively. The B(max) values for [(3)H]piclamilast were about 1.5-fold greater than that of [(3)H]rolipram binding, suggesting that [(3)H]piclamilast, but not [(3)H]rolipram, binds to LARBS as well as the HARBS. The HARBS was present in all the brain regions examined, but not in peripheral tissues. All PDE4 inhibitors tested were potent competitors for [(3)H]piclamilast binding; the competition curves for rolipram, desmethylpiclamilast, ICI 63,197, and Ro 20-1724 were better described by a two-site model, while the competition curves for piclamilast, cilomilast, roflumilast, and CDP 840 were adequately described by a one-site model. Inhibitors of other PDE families were much less potent. The inhibition of [(3)H]piclamilast was further tested in the presence of 1 microM rolipram to isolate the LARBS. Under this condition, the competition curves for all the inhibitors were adequately described by a one-site model, with K(i) values close to that for the LARBS. The results indicated that [(3)H]piclamilast is a useful tool to directly study inhibitor interaction with the HARBS and the LARBS in rat brain.     

Optical studies and dielectric response of [DMA]2MCl4 (M = Zn and Co) and [DMA]2ZnBr4

[DMA]₂ZnCl₄, [DMA]₂CoCl₄ and [DMA]₂ZnBr₄ crystallized in the monoclinic system, in the P2₁/n, P2₁/n and P2₁/c space groups, respectively. The optical properties of [DMA]₂MCl₄ (M = Zn and Co) and [DMA]₂ZnBr₄ were studied using ultraviolet-visible (UV-Vis) spectroscopy in the range of 200–800 nm. The Tauc model was used to determine the band gap energy of each hybrid compound. The calculated values of the direct and indirect band gaps (E_gd, E_gi) for all samples were found to be in the range of 1.91 eV to 4.29 eV for [DMA]₂ZnCl₄, 4.76 eV to 5.34 eV for [DMA]₂ZnBr₄ and 1.77 eV to 3.84 eV for [DMA]₂CoCl₄. The Urbach energy (E_u), extinction coefficient (k) and refractive index (n) of each compound was calculated. On the other hand, the dispersion of (n) is discussed in terms of the single oscillator Wemple–DiDomenico model. The single oscillator energy (E₀), the dispersion energy (E_d), and both the real ε_r and imaginary parts ε_i of the dielectric permittivity were estimated. The variation of optical conductivity with the incident photon energy has also been studied. We employed impedance spectroscopy to thoroughly investigate the dipolar dynamics in the prepared materials. The evolution of the dielectric loss, as a function of frequency, showed a distribution of relaxation times, which probably could be of a Maxwell–Wagner type interfacial polarization relaxation, possibly attributed to grain boundary effects or blocking at the contacts. In fact, the current work opens an efficient path to high quality organic–inorganic halide perovskites with good optical properties, which makes them suitable for application in nonlinear optoelectronic devices.

[DMA]₂ZnCl₄, [DMA]₂CoCl₄ and [DMA]₂ZnBr₄ crystallized in the monoclinic system, in the P2₁/n, P2₁/n and P2₁/c space groups, respectively.     

Synthesis and structural characterization of CO2-soluble oxidizers [Bu4N]BrO3 and [Bu4N]ClO3 and their dissolution in cosolvent-modified CO2 for reservoir applications

CO₂ utilization in upsteam oil and gas applications requires CO₂-soluble additives such as polymers, surfactants, and other components. Here we report the facile synthesis of CO₂-soluble oxidizers composed of judiciously selected organic cations paired with oxidizing anions. [Bu₄N]BrO₃ and [Bu₄N]ClO₃ are prepared using a double displacement synthetic strategy, whereby the crystalline product is readily obtained in high yield and structurally characterized using single-crystal X-ray diffraction. The facility of the approach is demonstrated through the preparation of several additional alkylammonium bromate compounds. Static solubility studies using a high-pressure cell with viewing windows showed that tetrabutylammonium compounds could be solubilized using cosolvent-modified CO₂. Using 4 mol% ethanol as cosolvent, >3 mM [Bu₄N]BrO₃ could be dissolved in CO₂, while ∼0.75 mM [Bu₄N]ClO₃ could be dissolved in the same solvent system. The solubility properties of [Bu₄N]BrO₃ along with its thermal stability up to ∼200 °C suggest that it is a promising oilfield oxidizer that can be utilized in subterranean CO₂ applications.

Bromate and chlorate salts were hydrophobically modified with tetrabutylammonium to yield oxidizers that are soluble in CO₂-cosolvent mixtures.     

Tissue distribution and functional correlation of [3H]leukotriene C4 and [3H]leukotriene D4 binding sites in guinea-pig uterus and lung preparations

To determine the distribution of leukotriene (LT) C4 and LTD4 receptors and functional significance of each receptor, we used [3H]LTC4 and [3H]LTD4 to measure the binding activity in various tissue homogenates and to correlate the relative ability of the LT agonists to inhibit binding with their contractile responses in guinea-pig uterine or lung parenchymal preparations. Guinea-pig brain contained the highest binding activity of 1 to 2 nM [3H] LTC4 followed by small intestine, heart, lung, kidney, uterus, etc., whereas guinea-pig lung had at least 2.7-fold greater [3H] LTD4 binding activity than any other tissues tested. In the brain and uterine homogenates, the rank order of potency for the compounds in competing with [3H]LTC4 for binding sites was LTC4 much greater than LTD4 greater than LTE4 greater than FPL-55712 = arachidonic acid. The in vitro functional study showed that the ability of the LT agonists to produce uterine contraction was in the order of LTC4 greater than LTD4 greater than LTE4, which is compatible with their relative effect for inhibition of uterine or brain [3H]LTC4 binding. In the lung homogenate, either LTC4, LTD4 or LTE4 inhibited effectively [3H]LTD4 binding and the potency order for the [3H]LTD4 competition study was LTD4 greater than LTE4 greater than LTC4 much greater than FPL-55712 greater than arachidonic acid. These LT agonists also produced lung contraction effectively and the difference among their contractile ability was not significant. We conclude that 1) there are distinct functional LTC4 and LTD4 receptors, 2) activation of the LTC4 receptor could account for the uterine contraction due to the LT agonists and 3) the lung contraction induced by LTC4, LTD4 and LTE4 is at least mediated partly by the LTD4 receptor.     

3-(Propylthio)propane-1-sulfonic acid immobilized on functionalized magnetic nanoparticles as an efficient catalyst for one-pot synthesis of dihydrotetrazolo[1,5-a]pyrimidine and tetrahydrotetrazolo[5,1-b]quinazolinone derivatives

An efficient and reusable catalyst, which is 3-(propylthio)propane-1-sulfonic acid immobillized on functionalized magnetic nanoparticles [PTPSA@SiO₂–Fe₃O₄], has been synthesized. For the first time, it is highlighted under solvent-free conditions for the catalytic activity in multicomponent synthesis of dihydrotetrazolo[1,5-a]pyrimidines, dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylates and tetrahydrotetrazolo[5,1-b]quinazolinones. The structure of the catalyst was well confirmed by characterization techniques, such as FT-IR, TGA, SEM-EDX, elemental mapping, TEM, VSM and elemental analysis. Besides, this unique catalyst was found to be effectual up to six cycles, which made it spotlighted. Recyclability of catalyst, excellent yield of the products, short reaction time and clean reaction profile are the advantages of the present protocol.

A novel method for the synthesis of dihydrotetrazolo[1,5-a]pyrimidine and tetrahydrotetrazolo[5,1-b]quinazolinone derivatives using [PTPSA@SiO₂–Fe₃O₄] as a green and reusable catalyst under solvent-free conditions is reported.     

Polymorphisms in the IL-4 and IL-4R [alpha] genes and allergic asthma.

Allergic asthma is caused by genetic and environmental factors that interact to determine disease susceptibility and severity. Several lines of evidence suggest that the interleukin (IL-4 gene and the IL-4-receptor alpha (IL-4Ralpha) gene are involved in the development of atopic diseases. We sought to determine whether two polymorphism sites in IL-4 and IL-4Ralpha chain were associated with allergic asthma in a Chinese population. We obtained DNA and clinical data from allergic asthma patients, which were compared with those of a group of healthy control subjects. The subjects were genotyped for the IL-4 C-590T promoter polymorphism and the IL-4R alpha chain Q576R by polymerase chain reaction-restriction fragment length polymorphism. The results showed that the IL-4 C-590T was not associated with allergic asthma in a Chinese population. However, the IL-4R alpha chain 576R/R was significantly increased in allergic asthma patients compared with control subjects (chi2 = 21.16; p < 0.01), and also total plasma immunoglobulin E (IgE) level was increased in allergic asthma patients. These data suggest that the IL-4R alpha chain 576R/R genotypes confer genetic susceptibility to allergic asthma in Chinese.     

Correction: Synthesis and structural characterization of CO2-soluble oxidizers [Bu4N]BrO3 and [Bu4N]ClO3 and their dissolution in cosolvent-modified CO2 for reservoir applications

Correction for ‘Synthesis and structural characterization of CO₂-soluble oxidizers [Bu₄N]BrO₃ and [Bu₄N]ClO₃ and their dissolution in cosolvent-modified CO₂ for reservoir applications’ by Katherine L. Hull et al., RSC Adv., 2020, 10, 44973–44980, DOI: 10.1039/D0RA09563J.

The authors regret that the value for the solubility of [Bu₄N]BrO₃ in the last sentence of the Results and discussion section was given incorrectly.In the sentence beginning “Notably, the solubility of [Bu₄N]BrO₃ achieved…” on page 44978, the corrected sentence should read “Notably, the solubility of [Bu₄N]BrO₃ achieved (>0.12 wt%) with ethanol cosolvent significantly exceeds the typical concentrations utilized in the application (∼0.03 wt%)”.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Visible light enabled [4+2] annulation reactions for anthracenone-furans from 2,3-dibromonaphthoquinone and phenylbenzofurans

A facile visible light promoted approach to anthracenone-furans from readily available 2,3-dibromonaphthoquinones and phenylbenzofurans via a formal Diels Alder reaction is reported. This reaction involves wavelength-selective agitation of 4CzIPN, energy transfer to quinones, recombination of 1,6-biradicals and elimination to give anthracenone-furans in good to excellent yields in one pot.

A facile visible light promoted [4 + 2] annulation reaction from readily available starting materials using an organo-photocatalyst gave anthracenone-furans with up to 95% yield in one-pot.     

Sonochemistry in an organocatalytic domino reaction: an expedient multicomponent access to structurally functionalized dihydropyrano[3,2-b]pyrans,spiro-pyrano[3,2-b]pyrans,and spiro-indenoquinoxaline-pyranopyrans under ambient conditions

A highly convenient and sustainable one-pot approach for the diversely-oriented synthesis of a variety of medicinally privileged amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives on the basis of a domino three-component reaction of readily available carbonyl compounds including aryl aldehydes or isatins, active methylene compounds, and kojic acid as a Michael donor using secondary amine catalyst l-proline under ultrasound irradiation in aqueous ethanolic solution at ambient temperature has been developed. This methodology can involve the assembly of C–C, C C, C–O, C–N bonds via a one-pot operation, and following this protocol, a series of novel amino-substituted spiro[indeno[1,2-b]quinoxaline-11,4-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylates have been synthesized. The practical utility of this method was found to be very efficient for scale-up reaction and other useful transformations. The methodology provides significant advantages including mild reaction conditions, energy-efficiency, short reaction time, fast reaction, simple work-up procedure, broad functional group tolerances, utilization of reusable catalyst, green solvent system, being metal-free, ligand-free, waste-free, inexpensive, etc. Excellent chemical yields have been achieved without using column chromatography. To address the issues of green and more sustainable chemistry, several metrics including Atom Economy (AE), Reaction Mass Efficiency (RME), Atom efficiency, E-factor, Process Mass Intensity (PMI), and Carbon Efficiency (CE) have been quantified for the present methodology that indicates the greenness of the present protocol.

Amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives has been synthesised under ultrasound irradiation in aqueous ethanolic solution at rt.     

Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes. Under similar conditions, the one-pot reaction of tryptamines, alkyl propiolates and β-nitroalkenes resulted in functionalized tetrahydroindolizino[8,7-b]indoles. The reaction mechanism involved sequential generation of β-enamino ester, Michael addition, Pictet–Spengler reaction and annulation process. The reaction showed high atomic economy and met the goals of sustainable chemistry.

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes.     

Structure-based discovery and bio-evaluation of a cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one as a phosphodiesterase 10A inhibitor

Phosphodiesterase10A (PDE10A) is a potential therapeutic target for the treatment of several neurodegenerative disorders. Thus, extensive efforts of medicinal chemists have been directed toward developing potent PDE10A inhibitors with minimal side effects. However, PDE10A inhibitors are not approved as a treatment for neurodegenerative disorders, possibly due to the lack of research in this area. Therefore, the discovery of novel and diverse scaffolds targeting PDE10A is required. In this study, we described the identification of a new PDE10A inhibitor by structure-based virtual screening combining pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation. Zinc42657360 with a cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one scaffold from the zinc database exhibited a significant inhibitory activity of 1.60 μM against PDE10A. The modelling studies demonstrated that Zinc42657360 is involved in three hydrogen bonds with ASN226, THR187 and ASP228, and two aromatic interactions with TYR78 and PHE283, besides the common interactions with the P-clamp residues PHE283 and ILE246. The novel scaffold of Zinc42657360 can be used for the rational design of PDE10A inhibitors with improved affinity.

Phosphodiesterase10A (PDE10A) is a potential therapeutic target for the treatment of several neurodegenerative disorders.     

Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-free and solvent-free conditions for minimizing waste generation

Brønsted acidic ionic liquid was found to be an efficient and recyclable catalyst for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under an atom-economical pathway. The low-cost recyclable catalyst, metal- and solvent-free conditions, and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

A facile, efficient, and atom-economic method for preparing benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal- and solvent-free condition has been developed.     

CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology

CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.     

Acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition for the synthesis of quinolines under air

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Acetic acid was the best cocatalyst for the cycloaddition of N-alkyl anilines with alkenes or alkynes under air. Various quinoline derivatives were obtained in satisfactory-to-excellent yields, and no other byproducts besides water were produced in the reaction. The zebrafish model has become an important vertebrate model for evaluating drug effects. We tested the activity of 3n in zebrafish. The test results showed that 1 μg mL⁻¹3n treatments resulted in morphological malformation, and 0.01–0.1 μg mL⁻¹3n treatments led to potent angiogenic defects in zebrafish embryos. The results of this study will be of great significance for promoting drug research in cardiovascular and cerebrovascular diseases.

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Various quinoline derivatives were obtained, and no other byproducts besides water.

The construction of quinoline motifs has received intensive attention owing to their potential application in photovoltaic devices¹ and pharmaceuticals,² such as anticancer, antiviral, antifungal, antiplatelet aggregation, antimalarial, antibacterial, antileishmanial and anti-inflammatory medicine.³ Because of their importance, many methods have been reported for the synthesis of quinolines.⁴ Among them, the most attractive strategy for the synthesis of these compounds is the dehydrogenative [4 + 2] cycloaddition through transition-metal catalysis and Lewis/Bronsted acid catalysis. In its most general and classical form, dehydrogenative [4 + 2] cycloaddition catalysed by transition metals such as Fe,⁵ Cu,⁶ Pd,⁷ and others,⁸ has been used as a potent tool for the synthesis of quinolone derivatives (Scheme 1a). However, these methods require the presence of excess peroxides, chloranil, potassium persulfate or other oxidants to promote the cycloaddition reaction and to obtain good product yields. Furthermore, in these processes, the formation of stoichiometric amounts of acid or tetrachlorohydroquinone waste as byproducts is a substantial problem that has limited their use. To overcome these drawbacks, several methods that utilise oxygen as a terminal oxidant have been reported.⁹ However, in many cases, the industrial use of these methods is problematic owing to operational difficulty. Therefore, the development of more efficient and economical synthetic methods is still necessary. Undoubtedly, the use of air as a terminal oxidant is the best choice. In addition, in the field of transition-metal catalysis, iron is one of the most commonly used base metals and has been widely applied in various coupling reactions.¹⁰ Therefore, it is desirable to develop an iron-catalysed dehydrogenative cycloaddition for the synthesis of quinoline under air.Open in a separate windowScheme 1Different strategies for [4 + 2] cycloaddition of N-alkyl anilines and alkenes or alkynes by transition-metal catalysis.Herein, we report the first acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition of N-alkyl anilines with alkenes or alkynes using air as a terminal oxidant (Scheme 1b). Iron-catalysed cycloaddition reaction for the synthesis of quinolines under air has always been a challenge because of metal deactivation after the end of the catalytic cycle. We commenced our studies by treating N-benzylaniline (1a) and styrene (2a) with 5 mol% iron as a catalyst. Initially, we tried to use a variety of iron catalysts to catalyse the cycloaddition of N-alkyl anilines and olefins under air ( EntryCatalyst (5 mol%)Acid (0.3 mmol)Solvent T (°C)Yield^a (%)1Fe(OTf)₂NoToluene120Trace2FeCl₂NoToluene120Trace3FeCl₃NoToluene120284Fe₂O₃NoToluene120Trace5Fe₂(SO₄)₃NoToluene120Trace6Fe(OTf)₃NoToluene120337Fe(OTf)₃NoEthanol12008Fe(OTf)₃NoMysitylene120269Fe(OTf)₃NoDioxane120010Fe(OTf)₃NoNitrobenzene1202811Fe(OTf)₃NoAcetonitrile1202312Fe(OTf)₃NoToluene1504213Fe(OTf)₃NoToluene1404914Fe(OTf)₃NoToluene1001615Fe(OTf)₃NoToluene80816Fe(OTf)₃NoToluene60Trace17Fe(OTf)₃NoToluene40018Fe(OTf)₃H₂SO₄Toluene140019Fe(OTf)₃TfOHToluene140020Fe(OTf)₃TFAToluene1406521Fe(OTf)₃PTSAToluene1406122^bFe(OTf)₃BNPAToluene1405723Fe(OTf)₃HCOOHToluene1404224Fe(OTf)₃BzOHToluene14050 25 Fe(OTf) ₃ AcOH Toluene 140 82 26Fe(OTf)₃PhB(OH)₂Toluene1403527Fe(OTf)₃B(OH)₃Toluene1401528Fe(OTf)₃PhenolToluene1405429^cFe(OTf)₃AMSAToluene1405130NoAcOHToluene140TraceOpen in a separate window^aIsolated yields.^bBNPA = 1,1′-binaphthyl-2,2′-diylhydrogen-phosphate.^cAMSA = aminomethanesulfonic acid.The optimal solvent for the reaction was toluene (Scheme 2), could be formed in the reaction from the interaction of the imine intermediate and FeL₃, which could not catalyse the conversion of imines to quinoline. Critically, the FeL₂ species was difficult to oxidize to FeL₃ under air conditions. Inspired by Birk''s work,¹¹ we envisaged that the addition of an acid may promote the oxidation of Fe(ii) to Fe(iii) under air. Based on this assumption, we proposed that FeL₃ can undergo ligand exchange with HL′ to generate the active catalytic species L₂FeL′. A subsequent oxidation reaction provided LFeL′, which was easier oxidize to L₂FeL′ than FeL₂ under air, enabling the next catalytic cycle.Open in a separate windowScheme 2Proposed strategy.Based on this hypothesis, we investigated some strong acids and moderate acids. Trifluoroacetic acid (TFA) was a cocatalyst that promoted the Fe-catalysed [4 + 2] cycloaddition of N-alkyl anilines and alkenes to deliver 2,4-diphenylquinoline in 65% yield (Scheme 3, entries 21–22). For further improvement of the reaction, other acid such as formic acid (HCOOH), benzoic acid (BzOH), acetic acid (AcOH), phenylboronic acid, boric acid, phenol and carbamic acid were tested (Open in a separate windowScheme 3Reaction conditions: substrate 1 (0.2 mmol), aryl olefin (0.4 mmol), Fe(OTf)₃ (10 μmol), AcOH (0.3 mmol), toluene (1.0 mL), at 140 °C under air for 24 h, and isolated yields of the products.With the optimized reaction conditions in hand, a series of aryl ethylenes were investigated for extending the substrate scope (Scheme 3). This acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction displayed good functional group tolerance. Aryl ethylenes with electron-neutral or electron-donating groups on the aryl rings, such as alkyl, phenyl and naphthyl, all gave the corresponding 2,4-diarylquinoline with high selectivity in good yields. Aryls containing an electron-withdrawing group such as fluoro, chloro, bromo and ester were also tolerated and afforded the corresponding 2,4-diarylquinolines 3e–3n in moderate to good yields. Moreover, the reaction of N-benzylaniline 1b containing a substituent (MeO) at the para-position of the aniline ring also produced the corresponding quinoline products 3o in 79% yield. These results indicated that different groups, such as methyl, phenyl, fluoro, chloro, bromo and methoxyl on benzene rings, were tolerated under the optimized reaction conditions. Notably, the retention of the F, Cl and Br atoms in the structures of the products should make the products considerably useful in organic transformations. Unfortunately, the current method could not be applied to olefins containing N heteroatoms, which was likely because of the strong coordination of N atoms with iron.Next, the scope of arylacetylenes was also investigated, and the results are summarized in Scheme 4. Arylacetylenes could be used instead of arylethylenes for the synthesis of 2,4-diarylquinoline under the optimized reaction conditions. Similar good results were obtained, as shown in Scheme 4. Quinoline derivatives 3a–3g, 3i, 3k–3m and 3o were obtained in satisfactory to good yields (63–96%).Open in a separate windowScheme 4Reaction conditions: substrate 1 (0.2 mmol), aryl alkyne (0.4 mmol), Fe(OTf)₃ (10 μmol), AcOH (0.3 mmol), toluene (1.0 mL), at 140 °C under air for 24 h, and isolated yields of the products.To test the synthetic utility of the current method, a gram scale dehydrogenative [4 + 2] cycloaddition reaction of N-benzyl-4-methoxyaniline with methyl-2-vinylbenzoate was conducted under the optimal conditions, providing the target 3n in 45% yield. To demonstrate the potential of our approach, we conducted molecular docking studies of human phenylethanolamine N-methyltransferase (hPNMT) and the quinoline derivatives. The studies were performed to help visualize possible interactions between hPNMT and the quinoline derivatives. The results showed that methyl-2-(6-methoxy-2-phenylquinolin-4-yl)benzoate 3n may have π–π interactions with ARG 90, and π–cation interactions with TYR 27 in hPNMT. Based on this docking result, 3n is highly likely to be a potent inhibitor of hPNMT. The results of the docked poses of hPNMT and 3n are shown in the ESI.^† The zebrafish model has become an important vertebrate model for evaluating drug effects. ¹² To demonstrate the drug effect of 3n on the vascular system in the trunk of zebrafish embryos, we tested the activity of 3n in zebrafish. The test results showed treatment of zebrafish embryos with 1 μg mL⁻¹3n resulted in morphological malformation, and treatment with 0.01–0.1 μg mL⁻¹3n led to potent angiogenic defects (Scheme 5b). The results of this study will be of great significance for promoting drug research in cardiovascular and cerebrovascular diseases.Open in a separate windowScheme 5Gram-scale synthesis and the drug effect of 3n treatment on vascular in the trunk of Tg(kdrl:EGFP) zebrafish embryos at 48 hpf. (A–D) control group and 1, 0.1, 0.01 μg mL⁻¹3n treated groups. Scale bar, 75 μm.To gain a better understanding of the role of the acid, air and iron in the current cycloaddition reaction, additional experiments were conducted. First, control experiments showed that the absence of any of the three components, air, AcOH and Fe(OTf)₃, significantly reduced the reaction yield, implying that each of the components was essential to this reaction. To clarify that the reaction was undergoing the production of an imine intermediate, we employed N-benzylideneaniline as a substrate to test if 2,4-diphenylquinoline could be obtained (Scheme 6). To our great surprise, 3a was obtained in 99% yield. The results showed that a cycloaddition reaction occurred after N-benzylaniline was oxidized to an imine. Based on these results, we proposed the following catalytic cycle: FeL₃ first underwent ligand exchange with AcOH to generate an active catalytic species L₂FeOAc, leading to subsequent oxidative dehydrogenation to provide the imine intermediate and intermediate LFeOAc while releasing HL. The imine intermediate can then undergo a [4 + 2] cycloaddition with an alkyne or alkene, forming the desired 2,4-diarylquinoline or dihydroquinoline. A subsequent dehydrogenation reaction of dihydroquinoline provided the target product. The intermediate LFeOAc underwent an oxidation reaction in the presence of air to regenerate the catalytic species L₂FeOAc.Open in a separate windowScheme 6Mechanistic experiments.     

The cyclooxygenase-2 inhibitor GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] is effective in animal models of neuropathic pain and central sensitization

The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.