Doebner Reaction Research Articles

Structural Elucidation of a New Puzzling Compound Emerged from Doebner Quinoline Synthesis

The quinoline ring is found in many biologically active natural alkaloids and is still being highly exploited by researchers due to its numerous potential applications in fields ranging from pharmacology to material science. During our synthetic attempts for new quinoline-4-carboxylic acids, using an extended version of the Doebner reaction, a new puzzling compound emerged when para-iodine aniline was reacted with salicylaldehyde and pyruvic acid in acetic acid as a reaction medium. The chemical structure of this new compound was established based on the information obtained from 1D and 2D NMR experiments (1H-, 13C-, and 15N-NMR), corroborated with MS spectrometry and IR spectroscopy. The photophysical properties (UV–vis and fluorescence) were also investigated. The proposed structure contains as the main elements a 1,4-dioxane-2,5-dione core symmetrically substituted with a propylidene chain that has attached to it a salicylaldehyde fragment and a pyrrole-2-one ring containing two 4-iodophenyl fragments. The isolation of this compound, reported here for the first time, is direct evidence that unexpected compounds can emerge from “classical” synthetic pathways when the right components are combined.

Pd NP-loaded covalent organic framework for pH-switched Pickering emulsion catalytic dechlorination.

Quinoline carboxylic acid-linked and Pd nanoparticle (NP)-loaded COF nanospheres were constructed via a three-component one-pot Doebner reaction and post-synthetic metalation. The obtained Pd@DhaTAPB-COOH solid stabilizer can greatly promote the pH-switched recyclable Pickering interfacial dechlorination reaction, which sheds light on the bright future of smart Pickering emulsion catalysis.

Constructing bifunctional and robust covalent organic frameworks via three-component one-pot Doebner reaction for Cr(VI) removal

The integral part of covalent organic frameworks (COFs) is covalent bonds. Thus, stable and functional links must be developed to expand the potential applications of COFs. Herein, in situ linkage functionalization using a three-component irreversible Doebner reaction was achieved to fabricate chemically stable carboxylic acid-bearing COFs (Tp-Tta-COOH and Tp-Tapb-COOH), which have abundant chelating groups and ordered electron donor–acceptor moieties facilitating charge separation for effective Cr(VI) adsorption and photoreduction, respectively. These functionalized COFs are more effective at Cr(VI) removal via adsorption and photoreduction than their unfunctionalized counterparts (Tp-Tta and Tp-Tapb). The synergy of adsorption and photocatalysis is crucial to effectively remove Cr(VI) from aqueous solutions. This synergy empowers Tp-Tta-COOH to be used continuously for Cr(VI) removal without any elution after each cycle. Furthermore, Tp-Tta-COOH exhibits high chemical stability, durability, and recyclability. This study will promote the development of durable and useful COF materials for real-world applications.

Synthesis of Copper (II) Oxide Nanoparticles using Vitis vinifera L. Leaf Ex-tract and its Application as a Catalyst in Doebner Reaction

Synthesis of Copper (II) Oxide Nanoparticles using Vitis vinifera L. Leaf Ex-tract and its Application as a Catalyst in Doebner Reaction

Three-Component Synthesis of Quinoline-4-carboxylic Acids Based on Doebner Hydrogen-Transfer Reaction.

The Doebner hydrogen-transfer reaction has been developed for the synthesis of substituted quinolines from anilines possessing electron-withdrawing groups, which are known to give products in low yields when used in the conventional Doebner reaction. This reaction can be applied to not only anilines having electron-withdrawing groups but also those having electron-donating groups and can be used in the large-scale synthesis of bioactive molecules.

Wound Gel with Antimicrobial Effects Based on Polyvinyl Alcohol and Functional Aryloxycyclotriphosphazene.

A silver-containing gel based on polyvinyl alcohol and aryloxycyclotriphosphazene containing β-carboxyethenylphenoxy and p-formylphenoxy groups has been developed. Phosphazene was synthesized via the Doebner reaction from hexakis[(4-formyl)phenoxy]cyclotriphosphazene and malonic acid and characterized by 1H, 13C, and 31P NMR spectroscopy and MALDI-TOF mass spectrometry. The study of the gel using scanning electron microscopy showed that the gel contains open pores and can absorb wound exudate. The maximum water absorption capacity of the gel was 272%, which was reached after 80 min of testing. The antimicrobial activity of the obtained silver-containing gel was evaluated using the diffusion method. The gel was found to inhibit the growth of the main microorganisms in contact with the skin: the bacteria S. aureus, P. aeruginosa, E. coli, B. subtilis, S. epidermidis, and C. stationis and the fungus C. albicans. The study of the wound-healing effect of the gel in vivo showed a decrease in the wound area of the rabbit hind limb by 91.43% (p < 0.05) on the 10th day of observation and a decrease in the content of C-reactive protein in the rabbit blood serum by 1.3 times (p < 0.05).

Integrating Bifunctionality and Chemical Stability in Covalent Organic Frameworks via One-Pot Multicomponent Reactions for Solar-Driven H2O2 Production

Multicomponent reactions (MCRs) can be used to introduce different functionalities into highly stable covalent organic frameworks (COFs). In this work, the irreversible three-component Doebner reaction is utilized to synthesize four chemically stable quinoline-4-carboxylic acid DMCR-COFs (DMCR-1-3 and DMCR-1NH) equipped with an acid-base bifunctionality. These DMCR-COFs show superior photocatalytic H2O2 evolution (one of the most important industrial oxidants) compared to the imine COF analogue (Imine-1). This is achieved with sacrificial oxidants but also in pure water and under an oxygen or air atmosphere. Furthermore, the DMCR-COFs show high photostability, durability, and recyclability. MCR-COFs thus provide a viable materials' platform for solar to chemical energy conversion.

Synthesis of highly deuterated coniferyl alcohol for silencing of NMR signals in the resulting dehydrogenative polymer

To establish a facile methodology for the elucidation of the lignin chain-growth mechanism, the preparation of monolignol that does not show NMR signals in the dehydrogenative polymer (DHP) was attempted. As a monolignol of which aliphatic moieties were deuterated, coniferyl alcohol-d7 was successfully synthesized from protocatechualdehyde and malonic acid via the modified Knoevenagel–Doebner reaction and the Luche reduction. The process achieved high to excellent deuteration efficiencies at the aimed positions (i.e., methoxy: > 99%D, α: > 99%D, β: 92%D, and γ: 98%D). DHP was prepared solely from coniferyl alcohol-d7, and its NMR spectra were compared with those from coniferyl alcohol. The results indicated that: (1) the deuterium atoms at methoxy group, α- and β-positions were highly retained even in the DHP, and their signals were effectively suppressed; (2) a part of the deuterium at γ-position was replaced with H through the reaction; (3) meanwhile, the formation of γ-CH2 was negligible. This study demonstrated that coniferyl alcohol-d7 could “silence” the majority of the signals even when converted to DHP. Highly deuterated monolignols can be a unique molecular tool that can differentiate the signals of interest from those derived from monolignols.

Constructing chemical stable 4-carboxyl-quinoline linked covalent organic frameworks via Doebner reaction for nanofiltration

Covalent linkages are the key component of covalent organic frameworks (COFs). The development of stable and functional linkages is essential to expand the COFs family and broaden their application prospects. In this work, we report the synthesis of crystalline and chemical stable 4-carboxyl-quinoline linked COFs (QL-COFs) via Doebner reactions in both one-pot (OP) and post-synthetic modification (PSM) methods. Both methods can be universally applied to most of the reported imine COFs family via bottom-up construction or linkage conversion. Owing to the contractive pore size, more hydrophilic structure and better chemical stability than the conventional imine COFs endowed by 4-carboxyl-quinoline linkage, QL-COFs are supposed to possess a wider application range. We further demonstrate the nanofiltration membrane (NFM) based on QL-COF exhibited a desirable separation capacity with high rejection for small dye molecules (> 90%), high water permeance (850 L m−2 h−1 MPa−1) and tolerance of extreme conditions (1 M HCl/NaOH), which were benefitted from the enhanced properties of QL-COFs. Additionally, efficient ion sieving properties were also achieved by QL-COF membrane. We anticipate that this work opens up a way for the construction of robust and functional COFs materials for practical applications.

One-Pot Synthesis of 2-Phenylquinoline-4-Carboxylic Acid: Iron(III) Trifluoromethanesulfonate Catalysed Doebner Reaction

Iron (III) trifluoromethanesulfonate [Fe (OTF)3] has been proven to be an effective catalyst in the synthesis of 2-phenylquinoline-4-carboxylic acid by the Doebner reaction using one-pot pyruvic acid, aniline, and benzaldehyde. This method shows attractive characteristics including concise one-pot conditions, high atom economy, very limited energy consumption, and the sequential catalytic process requires only a catalytic (15 mol%) amount of Fe (OTf)3 with short reaction periods (3 h) . Meanwhile, the catalyst was easily recovered from the reaction system and reused smoothly with only a little loss of activity.

Construction of acid-base bifunctional covalent organic frameworks via Doebner reaction for catalysing cascade reaction.

We report herein a series of quinoline-4-carboxylic acid linked COFs via the multicomponent one-pot in situ Doebner reaction. The obtained acid-base bifunctional COFs are chemically stable and can highly promote one-pot cascade deacetalization-Knoevenagel condensation reaction in a heterogeneous way under solvent-free conditions.

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound’s pharmacology and provide guidelines for further lead optimization.

Synthesis of novel 2-methyl-4-carboxyquinolines, the new by-products of the Doebner reaction

The Doebner reaction is the chemical reaction of an aniline with an aldehyde and pyruvic acid to form quinoline-4-carboxylic acids. Although Doebner reaction is a simple procedure for synthesis of 4-carboxyquinolines, which the product precipitates from the reaction mixtures with high purity, its yield is not high due to the formation of different reaction by-products. In the present study we found a new by-product (2-methylquinoline-4-carboxilic acid derivative), in Doebner reaction. We synthesized new 2-methylquinoline-4-carboxilic acid derivatives simply by stirring pyruvic acid and aromatic amine in ethanol with high purity. Generally, we found that aniline derivatives possessing electron donating groups are needed for the synthesis of 2-methylquinoline-4-carboxilic acid derivatives in ethanol. 1H-NMR data of products revealed that this reaction is regioseletive and ring closure occurs on the position with less steric hindrance. The order of mixing of the reactants plays a key role in determining the type of products in the Doebner reaction.

Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from −1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.

Development of Antimicrobial, Antimalarial and Antitubercular Compounds Based on a Quinoline-Pyrazole Clubbed Scaffold Derived via Doebner Reaction

In an effort for the development of novel antimicrobial, antimalarial and antitubercular agents, series of quinoline carboxylic acid derivatives bearing substituted pyrazole moiety were synthesized from derivatives of substituted pyrazole aldehydes, substituted aniline and pyruvic acid, through a one-pot Doebner reaction. Then the Carboxylic group was converted to an acyl chloride, N-(3-(dimethylamino) propyl) carboxamide, and alcohol functional groups. All the compounds were characterized by elemental analysis, MS, 1H NMR and 13C NMR spectroscopy and were screened against bacterial strains. Majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Compounds were also screened for antitubercular and antimalarial activities. Quinoline-Pyrazole clubbed derivative showed better results when compared with the reference drugs based on their MIC values. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antimicrobial, antimalarial, and antimycobacterial agents.

Synthesis of new 6-substituent 2-phenyl and 2-(furan-2-yl)-3-phenyl-quinoline-4-carboxylic acid derivatives

A synthesis of substituted quinolines has been achieved by the Doebner reaction which is a three component coupling of arylaldehyde, p-amino-acetophenone and phenyl pyruvic acid. The products of 2,3-diary-6-acetyl-quinoline-4-carboxylic acids were obtained by Claisen Schmidt condensation reaction with aldehydes in the presence of sodium hydroxide in order to give the corresponding α,β-unsaturated carbonyls. The substituted α,β-unsaturated carbonyls were condensed with urea, thiourea, hydrazine, phenyl hydrazine, semicarbazide hydrochloride and ethanolamine to synthesized 2-pyrimidinone, 2-pyrimidinethion, pyrazoline-1-phenyl, pyrazoline, pyrazoline-1-carboxamide and 1,4-oxazepines derivatives, respectively, with good yields. The purity and identities of products were elucidated through thin layer chromatography (TLC), melting point and spectroscopic data (IR, 1H NMR, 13C NMR and LC-Mass).

One Pot Synthesis of 6-(4-carboxy-3-methyl-2-phenylquinolin-6-ylsulfonyl)-3-methyl-2-phenylquinoline-4-carboxylic Acids from Dapsone and α-ketobutyric Acid by a Doebner Reaction

A series of new 6-(4-carboxy-3-methyl-2-phenylquinolin-6-ylsulfonyl)-3-methyl-2-phenylquinoline-4-carboxylic acids were synthesised by a one-pot reaction of dapsone, α-ketobutyric acid, and aromatic aldehydes in the presence of CuBr2 as a catalyst. Operational simplicity, mild reaction conditions, and eco-friendly procedure make this novel protocol a promising alternative for the preparation of quinoline-4-caboxylic acid derivatives. The structures of the products were established by elemental analyses and spectroscopic data. The biological activity of the new sulfone dimers was evaluated as having the potential for use as anticancer agents.

Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives.

A series of new 2-phenyl-quinoline-4-carboxylic acid derivatives was synthesized starting from aniline, 2-nitrobenzaldehyde, pyruvic acid followed by Doebner reaction, amidation, reduction, acylation and amination. All of the newly-synthesized compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The antibacterial activities of these compounds against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), as well as one strain of methicillin-resistant Staphylococcus aureus (MRSA) bacteria were evaluated by the agar diffusion method (zone of inhibition) and a broth dilution method (minimum inhibitory concentration (MIC)), and their structure-activity relationships were obtained and discussed. The results revealed that some compounds displayed good antibacterial activity against Staphylococcus aureus, and Compounds 5a4 and 5a7 showed the best inhibition with an MIC value of 64 μg/mL against Staphylococcus aureus and with an MIC value of 128 μg/mL against Escherichia coli, respectively. The results of the MTT assay illustrated the low cytotoxicity of Compound 5a4.

Recent Applications of Doebner, Doebner-von Miller and Knoevenagel-Doebner Reactions in Organic Syntheses

Quinolines as one of the most important classes of heterocyclic compounds are widely present as key structural motifs in many natural products, particularly in alkaloids and numerous bioactive drugs. Various name reactions for the syntheses of quinolines such as Skraup, Camps, Combes, Conrad-Lympach, Knorr, Gould-Jacobs, Povarov, Doebner and Doebner-von Miller, Pfitzinger and Niementowski, and Friedländer have already been discovered and extensively developed and modified. This review covers the most recent applications of Doebner and Doebner-von Miller reactions in organic syntheses. In addition the developments of the Knoevenagel- Doebner reaction in the synthesis of α,β-unsaturated carboxylic acids were demonstrated. In this paper we provide extensive compilation of the development of the Doebner reaction and variations for the synthesis of quinolines published from 2006 to 2013. Keywords: Doebner reaction, doebner-von miller, heterocyclic syntheses, Knoevenagel reaction, quinolines.

Synthesis, characterization and antimicrobial studies of some new quinoline incorporated benzimidazole derivatives

Two new series of quinoline incorporated benzimidazole derivatives (4a–i and 8a–f) were synthesized from substituted aniline and isatin through multi-step reaction. 6-substituted-4-carboxyquinolines (3a,b and 7) were synthesized by multi component one pot reactions (via Doebner reaction and Pfitzinger reaction respectively) and the targeted benzimidazole derivatives were obtained by the reaction of 6-substituted-4-carboxyquinolines (3a,b and 7) with substituted aromatic diamines in acidic media. All the newly synthesized compounds were characterized by IR, NMR mass spectral study and also by C, H, N analyses. The final compounds were screened for their in-vitro antibacterial and antifungal activity by well plate method (zone of inhibition). The results revealed that, compounds 4c, 4d, 8c and 8d showed significant antibacterial activity. The compound 8b was found to be potent antifungal agent. 4a, 8a and 8f showed moderate to good antimicrobial activity as compared to the standard drugs against all tested microbial strains.