Knoevenagel-Doebner Reaction Research Articles

Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Tranilast Analogs as Anticancer Agents

Abstract: Developing new agents with higher therapeutic potential and less toxicity to overcome the limitations of chemotherapy in cancer treatment has been identified as an urgent need and priority. Recent studies have shown promising anticancer activities of tranilast when used alone or in combination with other chemotherapeutic agents. This research aims to synthesize tranilast analogs, evaluate in vitro anticancer activity, and dock into the TGFβ1 target to find stronger anticancer agents. Tranilast (5a) and analogs (5b–f) were synthesized from anthranilic acid derivatives, Meldrum’s acid, and benzaldehydes based on the Knoevenagel-Doebner reaction. The compounds were evaluated for in vitro cytotoxicity activity by MTT assay and docked into the TGFβ1 target using AutoDockTools–1.5.6. Tranilast (5a) and seven analogs (5b–h) were successfully synthesized and analyzed for their structures. Four analogs (5b–d, 5f) possessed stronger effects on both HepG2 and MCF-7 cell lines with proliferation inhibitions at concentrations of 100 μg/mL in the range of 41 to 95% compared to tranilast (16.95% and 22.64%). Compound 5f exhibited the most potent analog with IC50 = 27.57 μg/mL (HepG2) and 16.67 μg/mL (MCF-7) compared to tranilast (IC50 > 100 μg/mL) and had good binding affinity on TGFβ1 target (docking score ˗7.35 Kcal/mol). Four of seven tranilast analogs possessed stronger cytotoxicity activity on both HepG2 and MCF-7 cell lines compared to that of the parent compound, tranilast. Notably, compound 5f displayed the most potent activity and good binding affinity on the TGFβ1 target, indicating the potential for further study as an anticancer agent.

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.

Pore size engineering of hexagonal mesoporous carbon nitride (HMCN) for high catalytic performance in the synthesis of α, β-unsaturated acid and its derivatives

The pore size of hexagonal mesoporous carbon nitride (HMCN) materials were engineered with different pore sizes of 3.5, 4.7, 5.9, 7.1, 7.9 and 9.2 nm using SBA-15 hard template synthesised at 80, 100, 120, 150, 160 and 180 °C, respectively. HMCN (x) and SBA-15 (x) materials were characterized by XRD, N2 sorption, FESEM, CHN, FTIR, Raman and DR UV–Vis spectroscopy. N2 sorption isotherms of HMCN (x) and SBA-15 (x) samples showed a type IV isotherm with H1 hysteresis loop having a region of steep increase due to capillary condensation. The catalytic performance of HMCN (x) catalysts were studied on the synthesis of α, β-unsaturated carboxylic acid and its derivatives via Knoevenagel-Doebner reaction in metal/pyridine-free, azeotropic conditions (Dean-Stark apparatus) by an environmental friendly approach. Among the HMCN (x) catalysts studied, HMCN (5.9) showed an excellent performance of 94.5% p-hydroxybenzaldehyde conversion with 100% selectivity of p-hydroxycinnamic acid (91% isolated yield) within 60 min. The reaction parameters of temperature, time and catalyst amount were studied on p-hydroxycinnamic acid synthesis. The derivatives of α, β-unsaturated carboxylic acid were synthesised under optimized reaction parameters. The experimental results of our study proved that the pore size engineering of HMCN is important for the catalytic reaction to get maximum product yield for the reactants with different molecular dimensions.

Synthesis and characterization of nanostructured Cu-ZnO: An efficient catalyst for the preparation of (E)-3-styrylchromones

We have explored nanocrystalline ZnO and Cu-ZnO catalyst for the preparation of 3-styrylchromones with trans selectivity derived from 3-formylchromones. Synthesis of ZnO and Cu-ZnO nano flakes (NFs) was carried by precipitation technique. The analytical techniques such as UV-Visible spectroscopy, X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), field emission scanning electron microscopy (FESEM) and energy-dispersive analysis X-ray spectroscopy (EDAX) were used to characterize the catalysts. The XRD pattern showed highly pure wurtzite ZnO and Cu-ZnO. The FESEM images showed nano flakes such as sunflower seed morphology in the range width of 9–34nm and length 90–180nm. Doping of copper in ZnO was employed to study the selectivity of Knoevenagel and Knoevenagel-Doebner reactions. Knoevenagel condensation was catalyzed efficiently by pure ZnO nano flakes, whereas the Cu-ZnO nano flakes facilitate the Knoevenagel-Doebner reaction. Present synthetic protocols are novel, very clean and high yielding for synthesis of 3-styrylchromones. Almost same yield was observed to the recycled catalyst up to four runs.

β‐Alanine‐DBU: A Highly Efficient Catalytic System for Knoevenagel‐Doebner Reaction under Mild Conditions

AbstractA mild and efficient Knoevenagel‐Doebner reaction from malonic acid and a wide range of aldehydes was catalyzed by a catalytic system consisting of β‐alanine and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), affording the corresponding (E)‐α,β‐unsaturated carboxylic acids in good to excellent yields and with high stereoselectivity. The advantage of the method is that the reaction could proceed smoothly at ambient temperature so that it can tolerate a variety of functional groups and avoid unnecessary side reactions.

Organocatalyzed Decarboxylation of Naturally Occurring Cinnamic Acids: Potential Role in Flavoring Chemicals Production

The mechanism and the final outcome of the Knoevenagel-Doebner reaction are discussed. The condensation reaction between different hydroxy-substituted aromatic aldehydes and malonic acid is performed using piperidine as organocatalyst. The key role of the catalyst is clearly pointed out during the decarboxylation of ferulic acid, without the use of a strong decarboxylating agent, leading to a 4-vinylphenol derivative. Based on the results obtained, the studied pathway may be important in the understanding of vinylphenol production during malting and brewing of wheat and barley grains. Finally, changing the solvent of the reaction from pyridine to water in the Knoevenagel-Doebner reaction of 4-hydroxybenzaldehydes, dimerization of resulting styrene derivatives is observed. These results can be of interest also in the field of food chemistry, since cinnamic acids are frequently found in fruits and vegetables used for human consumption.

The Knoevenagel-Doebner Reaction on 1,2-O-(2,2,2-Trichloroethylidene) Derivatives of D-Gluco- and D-Manno- furanose

The synthesis of new α,β-unsaturated furanuronic acid derivatives of α-gluco- (3), β-gluco- (6) and β-manno-chloraloses (9) via a convenient one pot procedure using the Knoevenagel-Doebner reaction approach are described. The dialdofuranose derivatives were reacted with malonic acid under Knoevenagel-Doebner reaction conditions and (E)-α,β-unsaturated furanuronic acid derivatives were obtained.

Gem-Dibromomethyl Aromatics: Efficient Aldehyde Equivalents in the Knoevenagel-Doebner Reaction

A valuable variation of the Knoevenagel-Doebner reaction for the efficient synthesis of cinnamic esters is described. This reaction provides cinnamic esters in a single step from gem-dibromomethyl aromatics, which otherwise require the hydrolytic conversion of gem-dibromides into aldehydes, and demonstrates the use of an alternative reagent for noncommercial and expensive aldehydes. Further, the reaction of gem-dibromomethyl aromatics with malonic acid and di-tert-butyl dicarbonate for the one-pot synthesis of tert-butyl cinnamates is also described.

Gem-Dibromomethylarenes: A Convenient Substitute for Noncommercial Aldehydes in the Knoevenagel−Doebner Reaction for the Synthesis of α,β-Unsaturated Carboxylic Acids

A facile synthesis of alpha,beta-unsaturated carboxylic acids from gem-dibromomethylarenes is described. gem-Dibromomethylarenes are employed for the first time in the Knoevenagel-Doebner reaction as aldehyde equivalents for the efficient synthesis of alpha,beta-unsaturated carboxylic acids.

One‐Pot Two‐Step Synthesis of 4‐Vinylphenols from 4‐Hydroxy Substituted Benzaldehydes under Microwave Irradiation: A New Perspective on the Classical Knoevenagel—Doebner Reaction.

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One-pot two-step synthesis of 4-vinylphenols from 4-hydroxy substituted benzaldehydes under microwave irradiation: a new perspective on the classical Knoevenagel–Doebner reaction

The classical Knoevenagel–Doebner reaction is reinvestigated wherein the direct synthesis of substituted 4-vinylphenols instead of the expected 4-hydroxycinnamic acids is described. The condensation reaction is performed on 4-hydroxy substituted benzaldehydes and malonic acid with a mixture of acetic acid–piperidine as condensing agent under focused microwave irradiation. The occurrence of simultaneous condensation–double decarboxylation without the use of any decarboxylating agent is a new finding, the reaction being facilitated solely by the hydroxy substituent and microwave irradiation effect.

Combined microwave and ultrasound accelerated Knoevenagel–Doebner reaction in aqueous media: a green route to 3-aryl acrylic acids

The microwave and ultrasound combined aqueous Knoevenagel–Doebner reaction proves an efficient and eco-friendly route for preparing 3-aryl acrylic acids in good yields. This organic solvent-free protocol is valuable since rapid reaction rate, low energy consumption, waste minimization, simple operation and easier product work-up can be achieved.

Aromatic spiranes XX: Syntheses of dimethylsubstituted 2-carboxymethyl-indan-1-ones and benzylchlorides as synthones for syntheses of di- to tetramethylsubstituted spirobiindandiones

The isomeric dimethyl methylbenzoates5, obtained from the bromidesvia Grignard reactions with dimethylcarbonate, were reduced with LiAlH4 to the hydroxymethyl derivatives6. The latter were then transformed both to the benzylchlorides7 (with SOCl2) and to the aldehydes8 (with pyridinium chlorochromate).Knoevenagel-Doebner reaction of8 afforded the acrylic acids9 which (after hydrogenation to11) were cyclized to the desired indanones12 with polyphosphoric acid. On the other hand,12c and12e were prepared from dimethyl 3-chloropropiophenone (14) by warming with sulfuric acid. After NaH-catalyzed reaction with dimethylcarbonate, the indanones12 gave the ketoesters15 which then could be hydrogenated to the indanes16. All reactions proceeded with satisfactory to excellent yields (60–90%).

The Knoevenagel-Doebner reaction in the synthesis of branched-chain sugarderivatives

The Knoevenagel-Doebner reaction in the synthesis of branched-chain sugarderivatives

A comparison of the Wittig and Knoevenagel–Doebner reactions for the chain extension of aldoses

Reaction conditions are described for the chain extension of 2,3 : 5,6-di-O-isopropylidence-D-mannose (1) with a Wittig ylide (2) to give the acyclic manno-octenoate (3) or the C-glycofuranosides (4 and 5) and with the Knoevenagel–Doebner reaction to afford the isomeric gluco-octenoate (6); the isomerisation proved to occur in the latter reaction provides an explanation for an anomaly in the literature and indicates that the C-glycosides (4 and 5) are formed by a Michael-type ring closure rather than via a betaine intermediate.

The Reaction of Acetals with Malonic Acid and its Derivatives. A Contribution to the Knowledge of the Knoevenagel-Doebner Reaction

The Reaction of Acetals with Malonic Acid and its Derivatives. A Contribution to the Knowledge of the Knoevenagel-Doebner Reaction