Skraup Reaction Research Articles

Insight into the Various Approaches Undertaken for the Synthesis of Quinoline Hybrids Imparting Diverse Therapeutic Activities

Abstract: Quinoline is one of the promising and prominent biologically active N-based heterocyclic compounds. This review paper aims to discuss the synthetic approaches, summarized from various research articles on the preparation of quinoline derivatives intended for different therapeutic activities like antifungal activity, anticancer activity, anticonvulsant activity, antitubercular activity, antimalarial activity, anti-Alzheimer activity and so on. The comprehensive study complies with all related publications and trademark publications demonstrating the synthesis and biological aspects of quinoline derivatives. Various types of quinoline hybrids were synthesized and treated for therapeutic activity, including anticancer, antitubercular, anti-Alzheimer, antioxidant, and antifungal activity, which have been analyzed. Quinoline is a planner hetero-aromatic compound with the chemical formula C9H7N. Several wellknown synthetic routes to the quinoline skeleton include Friedlander synthesis, Knorr quinoline synthesis, and Skraup reaction. Researchers may use other techniques or alter current strategies to reach their objectives, depending on what exact structure and therapeutic action they are investigating. The availability of starting materials, reaction conditions, scalability, desired regioselectivity, and functionalization of the quinoline core all have a role in the choice of synthetic method. This review covers the latest literature and knowledge on the synthetic procedures for numerous quinoline and its derivatives and their biological and pharmacological application.

Chemistry of Thieno [2,3-h]-/[3,2-h] Quinoline and Thieno [2,3-f]-/[3,2-f] Quinoline Derivatives Part (x), Reactivities, and Biological Activities

Abstract: Several thieno [2,3-h] /[3,2-h] quinolines and thieno [2,3-f] /[3,2-f] quinolines (TQs) are discussed in this review from a few perspectives, including various preparation and processing methods employing cutting-edge machinery. The preparation of (TQs), from 4-(5)aminobenzothiophene, 2(3)chloromethylthiophene, 2(3)thienylboric acid, and other chemical reagents is illustrated via a number of chemical procedures in this review. The formation of (TQs) was clarified using the Michael addition, Photocyclization, Skraup reaction, Ullmann-Fetvadjian process, Suzuki-Miyaura and Sonogashira reaction, aza-Diels-Alder reaction, and Friedel-Crafts reaction.

Influence of Granulated Hierarchical Zeolite ZSM-5 Physicochemical Properties on Its Catalytic Performance in Skraup Synthesis of Quinolines

Influence of Granulated Hierarchical Zeolite ZSM-5 Physicochemical Properties on Its Catalytic Performance in Skraup Synthesis of Quinolines

Synthesis of Quinolines by the Skraup Reaction: Hierarchical Zeolites vs Microporous Zeolites

AbstractThe activity, selectivity, and stability of microporous highly dispersed zeolites (H‐Y, H‐ZSM‐5) and granulated hierarchical zeolites (H‐Yh and H‐ZSM‐5h) were studied in the synthesis of quinolines by the Skraup reaction. Texture, porous structure, morphology of crystals, acidic properties were characterized by XRD, XRF, N2 adsorption‐desorption, SEM, NH3‐TPD methods. It was found that quinoline, 2‐ and 4‐methylquinolines are the main products in the reaction of aniline with glycerol in the presence of the studied catalysts. H‐ZSM‐5h and H‐Yh catalysts are more efficient than catalysts H‐ZSM‐5 and HY and provide a yield of quinolines to 72.4 (H‐ZSM‐5h) and 60.2 % (H‐Yh) at 450 °C, 0.2 h−1, the molar ratio of aniline:glycerol=1 : 3. The high activity and selectivity of hierarchical zeolites are due to the presence of meso‐ and macropores, as well as nanocrystals of 15–100 nm size. It was reported that hierarchical catalysts exhibit higher stability in the reaction compared with microporous zeolites.

Deep eutectic solvents used as catalysts for synthesis of 1,10-phenanthroline by improved Skraup reaction

In this study, three different choline chloride-based deep eutectic solvents were synthesized. And it is the first time to synthesize 1,10-phenanthroline through an improved Skraup reaction using deep eutectic solvent as the new catalyst from acrolein and 8-aminoquinoline. The deep eutectic solvents were characterized by Fourier transform infrared (FT-IR), 1H nuclear magnetic resonance (1H NMR), pH/mV meter, and thermogravimetric analysis (TGA). The research results show that the deep eutectic solvent formed by sulfanilic acid and choline chloride has the strongest acidity and highest catalytic active among the three deep eutectic solvents. Besides, the impacts of reaction parameters and molar ratio of raw materials on the reaction were also investigated. Under the optimized reaction conditions, the maximum selectivity and yield of 1,10-phenanthroline were achieved as 84.6 and 75.6%, respectively. The synthesis method, meanwhile, also has simple preparation process and low cheaper catalyst raw. Replacing traditional sulfuric acid and hydrochloric acid with deep eutectic solvents (DESs) as new catalysts provides a more efficient, greener and more economical strategy for the synthesis of 1,10-phenanthroline by a new improved Skraup reaction.

Synthetic and medicinal perspective of quinolines as antiviral agents.

In current scenario, various heterocycles have come up exhibiting crucial role in various medicinal agents which are valuable for mankind. Out of diverse range of heterocycle, quinoline scaffold have been proved to play an important role in broad range of biological activities. Several drug molecules bearing a quinoline molecule with useful anticancer, antibacterial activities etc have been marketed such as chloroquine, saquinavir etc. Owing to their broad spectrum biological role, various synthetic strategies such as Skraup reaction, Combes reaction etc. has been developed by the researchers all over the world. But still the synthetic methods are associated with various limitations as formation of side products, use of expensive metal catalysts. Thus, several efforts to develop an efficient and cost effective synthetic protocol are still carried out till date. Moreover, quinoline scaffold displays remarkable antiviral activity. Therefore, in this review we have made an attempt to describe recent synthetic protocols developed by various research groups along with giving a complete explanation about the role of quinoline derivatives as antiviral agent. Quinoline derivatives were found potent against various strains of viruses like zika virus, enterovirus, herpes virus, human immunodeficiency virus, ebola virus, hepatitis C virus, SARS virus and MERS virus etc.

Zeolites in the synthesis of quinolines by the Skraup reaction

A novel heterogeneous catalytic method for the synthesis of quinoline (1) and a mixture of 2- and 4-methylquinolines (2) by Skraup reaction in the presence of H-Y, H-MOR, H-Beta, H-ZSM-5 zeolite catalysts has been proposed. H-Beta and H-ZSM-5 zeolite catalysts demonstrated the highest activity, selectivity and stability: the total selectivity to 1 and 2 was up to 74% with a dominance of quinoline in the fraction, the conversion of aniline was 88–100%.

Glycerol and Q-Tubes: Green Catalyst and Technique for Synthesis of Polyfunctionally Substituted Heteroaromatics and Anilines.

The role of glycerol as a green bio-based solvent, reactant, and/or a catalyst in the synthesis of novel heterocycles, under pressure, is studied. Synthesis of novel quinolines in good yields using a new modified Skraup synthesis, utilizing glycerol and pressure Q-tubes, is demonstrated. Novel aniline trimers are prepared using glycerol, and substituted anilines under pressure, in acidic medium and water. Glycerol was employed as a catalyst and a green solvent in the synthesis of novel pyridazines 13a–c. The mechanisms of the reactions and the catalytic effect of glycerol in protic and aprotic media are fully discussed. The structures of the synthesized compounds were determined via X-ray crystallography and spectroscopic methods.

Experimental and theoretical study of quinoline derivatives obtained by slight modifications of the standard skraup reaction

In order to explore the role of glycerol in the Skraup reaction, in producing complex structure quinolines, synthesis of some quinoline-5-carboxylic acid glycerol esters from the commercially available anilines (3-aminobenzoic acid derivatives) has been carried out using a slightly modified Skraup reaction. It has been found that the reaction of an excess of glycerol with 3-aminobenzoic acid with I2 as oxidant in concentrated H2SO4, results in the formation of two acyclic isomers (a, b) of the corresponding glycerol ester, one of them (a) is predominant and a third cyclic isomer (c) obtained in the form of traces. Among the final products, isomer (a) has been purified by flash chromatography and analyzed by IR, 1H NMR, 13C NMR and Mass spectroscopy and isomers (b) and (c) (R = OMe, R’ = H) were identified by 1H NMR. While obtaining the acyclic isomers is quite expected, the cyclic isomer (c), which was previously isolated in traces and characterized, failed to be formed again despite various attempts. To support the experimental results, theoretical computations have been carried out at DFT level and using the B3LYP/6-31++G(d,p) method. Calculations of the activation energies corresponding to the transition states of proposed ways to give isomer (c) show that the formation of this isomer is possible. However, this later is probably obtained from the less predominant isomer (b) which is not an energetically favorable product according to the theoretical calculations. This explains the small amount of isomer (c). Furthermore, the regioselectivity of the esterification reaction has been also assessed by conceptual DFT descriptors.

Synthesis, Structural Characterization and Antinociceptive Activities of New Arylated Quinolines via Suzuki-Miyaura Cross Coupling Reaction.

The quinoline ring system is one of the most commonly encountered heterocycles in medicinal chemistry, due to the pharmaceutical and medicinal uses of derivatives containing this ring. These quinoline-based compounds have remarkable biological activity, as they are employed as antimalarial, antibacterial, antifungal, and antitumor agents. The quinoline nucleus can be synthesized by various traditional methods such as the Skraup reaction, Friedlaender synthesis, Combes quinoline synthesis, Larock quinoline synthesis, among others. The aim of the present work is to synthesize a number of new arylated quninolines having significant antinoceciptive effect through the Suzuki-Miyaura cross coupling reaction using 3- bromoquinoline as a starting material. A number of new quinoline derivatives have been synthesized. Structures of the newly synthesized compounds were confirmed by means of IR, NMR, and mass spectrometry, and by elemental analysis. In addition, the molecular structures of two representative derivatives were determined with the aid of X-ray crystallography. Additionally, the antinociceptive activity of the prepared compounds was evaluated in vivo; results revealed that most of the tested compounds exhibited a dosedependent antinociceptive effect. Prepared compounds were found to exhibit significant antinociceptive activities and could be used as potential analgesic agents. Further work, however, may be required to establish the safety and efficacy of these compounds.

Continuous niobium phosphate catalysed Skraup reaction for quinoline synthesis from solketal

Solketal is derived from the reaction of acetone with glycerol, a by-product of the biodiesel industry. We demonstrate the use of NbOPO4 as a catalyst for the conversion of solketal and anilines to quinolines.

Synthesis of fluorine-containing 1,10-phenanthrolines using mild versions of Skraup and Doebner-von Miller reactions

A versatile route for the synthesis of new 1,10-phenanthroline derivatives with fluorine-containing groups is described. Skraup reactions were performed with yields of 19 up to 48% and overall yields of 5 up to 13% based on different fluorinated anilines as starting materials. Ten formerly unknown derivatives were synthesized and characterized by NMR spectroscopy (1H, 13C, 19F), ESI mass spectrometry and elemental analysis.

Proton and Hydride Transfer in the Skraup Reaction

AbstractThe Skraup reaction affording quinoline was investigated computationally by the use of a model consisting of aniline, glycerol (HO‐CH2‐CH(OH)‐CH2OH) and H3O+ (H2O)7. First, two reaction channels up to the 1,2‐dihydroquinoline were considered. One is the traditional one involving acrolein. The other is for the direct linkage of aniline and glycerol. The channel without acrolein was calculated to be more likely. Second, the oxidation process of 1,2‐dihydroquinoline to quinoline was examined with and without the oxidizing agent, nitrobenzene. With it, the hydride‐shift path was obtained and it is likely energetically. Without it, while the process is feasible in accord with a microwave‐irradiation study, the large activation energy was required in the acid catalyzed either (1,2‐dihydroquinoline + glycerol) or (1,2‐dihydroquinoline + acrolein) reaction. The proton transfer was found to be primary driving force of the Skraup reaction.

A Systematic Study on the Synthesis of n‐Butyl Substituted 8‐Aminoquinolines

A systematic study on the synthesis of 8‐aminoquinoline derivatives with an n‐butyl group at each alternate position of the quinoline ring was carried out. Skraup Reaction and its Doebner–von Miller variation were used to obtain most of the quinoline ring except for the 2‐butyl‐8‐aminoquinolines and 4‐butyl‐8‐aminoquinolines where the commercially available methylquinoline derivatives were used as precursors. The structures of the synthesized compounds were characterized by FTIR, 1H‐NMR, COSY, 13C‐NMR and HRMS spectra.

Properties and structure of two fluorinated 1,10-phenanthrolines

Abstract We report the synthesis, X-ray structure, absorbance and emission of 4,7-bis(4-fluorophenyl)-1,10-phenanthroline and 4,7-bis-(4′-trifluoromethyl-biphenyl-4-yl)-1,10-phenanthroline. 4,7-Bis(4-fluorophenyl)-1,10-phenanthroline was synthesized by successive Skraup reactions and features absorbance at 274 nm and emission at 384 nm while 4,7-bis-(4′-trifluoromethyl-biphenyl-4-yl)-1,10-phenanthroline featured absorbance at 283 nm and emission at 400 nm. The structures show molecular stacking of the phenyl groups and phenanthroline structure and longitudinal fluorine atom associations within the crystal lattice. Furthermore, the three fused rings of the 4,7-bis(4-fluorophenyl)-1,10-phenanthroline unit exhibited torsion up to 13.97(9)° throughout the crystal lattice whereas no torsion is observed for 4,7-bis-(4′-trifluoromethyl-biphenyl-4-yl)-1,10-phenanthroline.

A Mild and Efficient Synthesis of Substituted Quinolines via a Cross‐Dehydrogenative Coupling of (Bio)available Alcohols and Aminoarenes

AbstractA ruthenium‐catalysed dehydrogenative cross‐coupling of primary alcohols and imines in the presence of TFA provided a library of differently substituted quinolines. Imines can be prepared in situ from various anilines and several benzyl alcohols using a ruthenium‐catalysed hydrogen‐transfer procedure. Without changing the catalyst, quinolines can be obtained in moderate to good yields by adding various primary alcohols in the presence of TFA (30 mol%) via a “telescopic” protocol. The use of alcohols, the absence of strong oxidants and the diversity of potential starting materials make this modern version of the Skraup reaction superior to most of the conventional quinoline syntheses.magnified image

Microwaves under pressure for the continuous production of quinoline from glycerol

Microwave heating is an interesting technology for chemical engineering, since it can provide effective volumetric heating of the reaction medium and reduce energy costs. Many commercially available laboratory-scale microwave reactors have already been used to carry out chemical reactions on a small scale (a few milliliters), and at high temperatures and pressures. Some research has been undertaken to scale-up microwave processes and make them suitable for a larger scale production.Indeed, combining wave propagation through the walls of a reactor with resistance toward high pressure and temperature as well, is not an easy task. For these reasons, this work focuses on the development of a pilot scale microwave apparatus used for the heating of larger reaction volumes under pressure, and under controlled conditions. The specially designed microwave apparatus allows chemical reactions in batch or continuous mode. The applicator operates in single mode enabling a uniform electromagnetic field, and well controlled operating conditions. The main advantage of the setup is the quite large reactor volume that permits either relatively long residence times or relatively high mass flowrates (up to 1kg/h). The developed microwave apparatus was then used for quinoline synthesis from glycerol via a modified Skraup reaction. The major advantage of our system is the ability to carry out continuous chemical synthesis, at a large pilot scale, and high temperatures (200–220°C), while ensuring a better control of the pressure (max. 19bar) through the control of the power absorbed by the reaction medium.

ChemInform Abstract: Quinoline and Phenanthroline Preparation Starting from Glycerol via Improved Microwave‐Assisted Modified Skraup Reaction.

AbstractMicrowave‐assisted modified Skraup reaction of anilines with glycerol provides access to quinoline derivatives.

ChemInform Abstract: 1‐(1‐Alkylsulfonic)‐3‐methylimidazolium Chloride Broensted Acidic Ionic Liquid Catalyzed Skraup Synthesis of Quinolines under Microwave Heating.

AbstractThe ionic liquid promoted Skraup synthesis of quinolines involving the in situ formation of acrolein by dehydration of glycerol under microwave conditions.

1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquid catalyzed Skraup synthesis of quinolines under microwave heating

1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquids are shown as excellent catalysts and reaction mediums for Skraup synthesis of quinolines under microwave conditions without the use of nitrobenzene as an oxidant and metal catalysts.