Synthesis Of Coumarins Research Articles

Propylsulfonic acid grafted on mesoporous siliceous FDU-5 material: A high TOF catalyst for the synthesis of coumarins via Pechmann condensation

Abstract Coumarins and their synthetic derivatives are extensively used as base chemicals in diverse industrial applications in the fields of pharmaceutics, cosmetics, and agrochemicals, among others. Due to the growing number of applications, the need for new methods of coumarins synthesis has gained importance worldwide. In this sense, the use of propylsulfonic acid supported in FDU-5 (FDU-5-Pr-SO3H) as a catalyst for the synthesis of coumarins via Pechmann condensation in solvent free medium was investigated. FDU-5-Pr-SO3H was synthesized by co-condensation of MPTES and TEOS. FDU-5-Pr-SO3H was used as catalyst for the synthesis of 7-hydroxy-4-methylcoumarin and reaction conditions were optimized. The optimization process involved the study of the influence of the catalyst load, Resorcinol:EAA molar ratio, reaction temperature and reaction time. The optimal conditions were: catalyst load of 1.65 mol %, reactants molar ratio of 1:1.5, temperature 130 °C and 60 min of reaction time. Under these conditions, the FDU-5-Pr-SO3H material showed excellent yield (96.5%) and turn over frequency (59 h−1). Finally, the synthetized material was assessed as a catalyst with other phenolic compounds with ethyl acetoacetate and with ethyl benzoylacetate. The obtained products were isolated and identified by comparison of their spectral data with those reported in literature; from these results can be concluded that the catalyst is active with a wide range of phenolic substrates.

Polyphosphoric acid-promoted synthesis of coumarins lacking substituents at positions 3 and 4

Coumarins have recently emerged as a hot topic of research due to their diverse pharmacological properties. This work described a method for the synthesis of 3,4-diunsubstituted coumarins promoted by polyphosphoric acid (PPA) from salicylaldehydes and acetic anhydride. Various coumarins were produced in good to excellent yields.

Design and Synthesis of Novel Coumarin Conjugated Acetamides as Promising Anticancer Agents: An In Silico and In Vitro Approach.

Coumarin and benzophenone possess a vast sphere of biological activities, whereas thiazoles display various pharmacological properties. Hence, present study focused on the incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity, anticipating their interesting biological properties. The objective of the current work is the synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. A novel series of coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by a multistep reaction sequence and were characterized by the FT-IR, LCMS, and NMR spectral techniques. The newly synthesized compounds were screened for anti-cancer activity by in silico and in vitro methods. The cytotoxicity of the synthesized unique compounds was executed for two different cancer cell lines, MCF-7 (Breast cancer) and KB (Oral cancer), in comparison with standard paclitaxel by MTT assay. The compound 7f is a potent motif with an acceptable range of IC50 values, for anti-cancer activity, i.e., 63.54μg/ml and 55.67μg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids, MET 769, ARG 817, and LYS 721. Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.

Synthesis, characterization, molecular docking, and biological activities of coumarin-1,2,3-triazole-acetamide hybrid derivatives.

Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin-1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin-1,2,3-triazole-acetamide hybrids showed Ki values in the range of 483.50-1,243.04 nM against hCA I, 508.55-1,284.36 nM against hCA II, 24.85-132.85 nM against AChE, 27.17-1,104.36 nM against BChE,590.42-1,104.36 nM against α-Gly,and 55.38-128.63 nM against α-Amy. The novel coumarin-1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin-1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.

Synthesis of coumarins modified with cobalt bis (1,2-dicarbolide) and closo-dodecaborate boron clusters

Synthesis and characterization of novel coumarins containing carborane units were described. The breakdown reactions of cyclic oxonium derivatives of cobalt bis (1,2-dicarbollide) and closo-dodecaborate anions with a series of 7-hydroxy-3-substituted coumarins led to conjugates attached via C-7 position of the coumarin unit. The corresponding reactions of cobalt bis (1,2-dicarbollide) anion with 3-(4-hydroxybenzoyl)-7-methoxy-2H-chromen-2-one led to conjugates attached via C-3 position. Novel conjugates were isolated in the form of alkali metal salts. Therefore, these conjugates are of interest for the fluorescent study in aqua media.

A green and chemoselective synthesis of coumarins via Pechmann condensation using recoverable heterogeneous catalyst (Au@pSiO2)

Nano Au@porous SiO2 as a heterogeneous catalyst was prepared and characterized by Fourier transform infrared, X‐ray powder diffraction, transmission electron microscopy, thermogravimetric analysis and inductively coupled plasma–atomic emission spectroscopy techniques and then used as an efficient catalyst in the condensation of various phenols with ethyl acetoacetate for the preparation of coumarin derivatives through the Pechmann reaction. The combined merits of chemoselective and solvent free reaction conditions and the recyclability of the nanostructured catalyst make the condensation a safe operation, with low pollution, rapid access to products and simple workup.

Immobilized ionic liquid on the zeolite: its characterization and catalytic activity in the synthesis of coumarins via Pechmann reaction

In this work, in the first step, the 1-methyl-3-(3-trimethoxysilylpropyl) imidazolium chloride ([MTMSPIm]Cl) is immobilized on HY and NaY zeolites as an acidic catalyst. The synthesized catalysts were well characterized by different methods such as FTIR, TGA, XRD, BET, SEM, EDX and ICP. The characterizations of catalysts indeed show the ionic liquid supported on amine-functionalized zeolites. Also, the result shows the micro-/mesoporous structure for catalysts which have been emerged as an important class of catalytic materials. The micro-/mesocatalyst ([MTMSPIm]Cl@zeolite) was used as an acidic catalyst to synthesize coumarins via Pechmann reaction in solvent-free condition. The effect of different factors such as catalyst amount, solvent and time was investigated. Finally, catalyst can be easily separated and reused for the next reactions at least for five runs without any significant changes in yield and structure of the catalyst. Comparison of modified zeolite with [MTMSPIm]Cl shows higher yield and selectivity and mild condition related to other works.

Theoretical study of rhodium(III)-catalyzed synthesis of benzoxepine and coumarin.

The mechanisms of the rhodium-catalyzed cycloaddition of 2-vinylphenol with diphenylacetylene and carbon monoxide have been studied using density functional theory calculations at the B3LYP/6-31G (d, p) (Lanl2dz for Rh) level of theory. The SMD solvation model was used in MeCN solvents at M06-2X/6-311 ++ G (d, p) (Lanl2dz (f) for Rh) levels using a single-point calculation to consider the solvent effect. The calculation results show that there are two competitive reaction pathways for the cycloaddition reaction of rhodium-catalyzed synthesis of benzohexine and coumarin. Starting from the precursor reaction complex, the reaction channel is more favorable for the carbon atoms of diphenylacetylene and carbon monoxide to attack the Rh-C bond (the barriers of 9.88 and 10.01kcal/mol) rather than attack the Rh-O bond (the barriers of 15.37 and 30.17kcal/mol), and carbon monoxide in two different reaction channels has a greater energy difference than diphenylacetylene. The results show that the computational study of the rhodium-catalyzed cycloaddition reaction has a high catalytic activity consistent with the high yield of the experiment of Gulías et al.

An Extensive Study of Coumarin Synthesis via Knoevenagel Condensation in Choline Chloride Based Deep Eutectic Solvents.

In order to preserve the environment from harmful organic solvents, a synthesis of coumarin derivatives was performed in deep eutectic solvents, which are considered as "green" due to their characteristics. Choline chloride based deep eutectic solvents (DESs) were employed, both as solvents and as catalysts, in the synthesis of coumarin derivatives via Knoevenagel condensation. In order to find the best DES for coumarin synthesis, 20 DESs were tested for the reaction of salicylaldehyde and dimethyl malonate at 80 °C. Among the twenty tested deep eutectic solvents only five were adequate for this kind of synthesis. The best DES for this reaction was found to be the one composed of choline chloride:urea (1:2). Most coumarin compounds were obtained in good to excellent yield. Compounds 1g, 2g and 2p should be pointed out due to their yields of 85, 88 and 98 %, respectively. 3-Acetylcoumarins 5a, 5c, 5d, 5e, 5f and 5g were synthesized under ultrasound irradiation and were also obtained in excellent yields of 90, 95, 98, 93, 94 and 85 %, respectively. Series of coumarin derivatives were successfully synthesized, either in choline chloide:urea DES at 80 °C or in ultrasound-assisted reaction, from different salicylaldehydes and active methylene compounds. These "green" methods were found to be very effective in Knoevenagel condensation, while DES was recycled for several cycles without any significant influence on the product yield.

Synthesis and Antimicrobial Activity of Some New Coumarin and Dicoumarol Derivatives

Phase transfer catalysis reaction of 4-hydroxy-6-methyl-2H-chromen-2-one with alkyl halides afforded C4 oxygen alkylation products of 2H-chromen-2-one derivatives in appreciative yield, whereas with phenyl isothiocyanate gives the C3 addition product of 4-hydroxy-6-methyl-2-oxo-N-phenyl-2H-chromene-3-carbothioamide, also one pot three component phase transfer reaction was investigated. Treatment of 4-hydroxy-6-methyl-2H-chromen-2-one with aromatic aldehydes in different molar ratios gives 3‑arylidine and the dicoumarol derivatives. However pyrano chromene and pyrano pyridine were obtained by reaction of arylidine with ethyl acetoacetate through Michael cycloaddition reaction. The stability of pyrone ring in 3-arylidine and dicoumarol towards different nucleophilic reagents under reflux and/or fusion conditions has been studied by the action of, hydrazine hydrate, ammonium acetate, methyl amine and p-toluidine afforded compounds 1,2-bis(benzo[d][1,3]dioxol-5-ylmethylene)hydrazine, 1,2-bis(4-methoxybenzylidene)hydrazine and 2,6-bis((2,6-dihydroxy-3-methylphenyl)(hydroxy)methylene)-1-(4-methoxyphenyl)-4-(p-tolyl) piperidine-3,5-dione derivatives. The antimicrobial activity of some synthesized compounds has been investigated.

Synthetic studies toward novel pyrrolobenzodiazepine–coumarin hybrids

A comprehensive screening of known methods for the synthesis of coumarins was performed in order to obtain a new type of pyrrolobenzodiazepine–coumarin hybrids. A Pechmann condensation turned out to be the method of choice for successful synthesis of the desired hybrid starting from the corresponding phenol derivative and malic acid. Overall, the desired pyrrolobenzodiazepine–coumarin hybrid was obtained in a 3 step sequence starting from readily available starting materials – L-proline methyl ester and 4-methoxyanthranilic acid.

Design synthesis and anti-proliferative activity of some new coumarin substituted hydrazide–hydrazone derivatives

A series of 21 coumarin hydrazide–hydrazone derivatives were designed, synthesized and evaluated potential cytotoxicity effects at 25 μg/mL for 48 h against liver cancer (HepG2) cell line in vitro. Then, seven out of 21 compounds with % cell viability lower than 60% were selected for evaluation of in vitro anti-proliferative activity against liver cancer (HepG2), breast cancer (SKBR-3) and human colon cancer (Caco-2) cell lines. Among the test compounds, 5g, 6d and 6f showed potent activities against both Hep-G2 and SKBR-3 cell lines. More significantly, compound 6d, having a 4-bromophenyl moiety, exhibited best cytotoxic activity against Hep-G2 cell line with IC50 value of 2.84 ± 0.48 μg/mL which is comparable to the standard doxorubicin (IC50 = 2.11 ± 0.13 μg/mL). In addition, compound 6f, having 4-methoxyphenyl moiety, demonstrated the most potent activity (IC50 = 2.34 ± 0.68 μg/mL) against SKBR-3 cell line on comparison with other tested coumarin hydrazide–hydrazone derivatives. Unfortunately, all test compounds, as well as doxorubicin, showed no cytotoxicity toward drug-resistant cell line, Caco-2. Our preliminary results indicated that coumarin hydrazide–hydrazone derivatives could be exploited as leading structures for further anticancer-drug development.

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives

This review is a compilation of the green synthetic methods used in the synthesis of coumarin derivatives. Coumarins are a class of compounds with a pronounced wide range of biological activities, which have found their application in medicine, pharmacology, cosmetics and food industry. Their biological activity and potential application are highly dependent on their structure. Therefore, many researchers have been performing the synthesis of coumarin derivatives on a daily basis. High demands for their synthesis often result in an increased generation of different waste chemicals. In order to minimize the utilization and generation of toxic organic substances, green synthetic methods are applied in this manner. These methods are getting more attention in the last few decades. Green chemistry methods cover a wide range of methods, including the application of ultrasound and microwaves, ionic liquids and deep eutectic solvents, solvent-free synthesis, mechanosynthesis and multicomponent reactions. All typical condensation reactions for coumarin synthesis like Knoevenagel, Perkin, Kostanecki-Robinson, Pechmann and Reformansky reactions, have been successfully performed using these green synthetic methods. According to the authors mentioned in this review, not only these methods reduce the utilization and generation of toxic chemicals, but they can also enhance the reaction performance in terms of product yields, purity, energy consumption and post-synthetic procedures when compared to the conventional methods. Due to the significance of coumarins as biologically active systems and the recent demands of reducing toxic solvents, catalysts and energy consumption, this review provides a first full literature overview on the application of green synthetic methods in the coumarin synthesis. It covers a literature search over the period from 1995-2019. The importance of this work is its comprehensive literature survey on a specific class of heterocyclic compounds, and those researchers working on the coumarin synthesis can find very useful information on the green synthetic approaches to their synthesis. There are some reviews on the coumarin synthesis, but most of them cover only specific reactions on coumarin synthesis and none of them the whole range of green chemistry methods.

Antagonists of Vitamin K—Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives

Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.

Synthesis and characterization of some novel coumarin based various 2-aryl-pyrido [3,2-c] coumarins

A survey of the literature reveals that the number of coumarin derivatives having heterocyclic moieties either as substituent groups or fused with parent coumarin nucleus possesses a variety of functions and are widely used in drugs and dyes. Because of this wide utility, the synthesis of coumarin has remained a subject of active interest. Looking at the importance of these heterocoumarins and with a view to exploring new methods of their synthesis, the present work was undertaken and this synthesis deals with various 2-aryl-pyrido [3,2-c] coumarins. The compounds have been synthesized by reacting Mannich bases of various 4-hydroxy coumarins with pyridinium salts of various aroyl methyl bromides in the presence of ammonium acetate and acetic acid. All the compounds synthesized have been characterized by analytical and spectral data.
 Keywords: Pyrido, Coumarins, Krohanke’s reaction.

Design, synthesis and biological evaluation of coumarin linked 1,2,4-oxadiazoles as selective carbonic anhydrase IX and XII inhibitors.

A series of coumarin linked 1,2,4-oxadiazoles were synthesized and the synthesized compounds were subjected for evaluation against the four physiologically and pharmacologically relevant hCA isoforms, hCA I, II, IX and XII. Upon evaluation of the results, it was inferred that the coumarin linked 1,2,4-oxadiazoles showed selective hCA IX and XII inhibition (low to medium nanomolar range) over hCA I and II (>10000nM). The inhibition constants ranged from low nanomolar to moderately nanomolar. Compounds 6o, 6a, 6q and 6c elicited hCA XII inhibition, with Ki values lower than that of the standard, Acetazolamide (AAZ) with compound 6o exhibiting a Ki value of 1nM., against hCA IX, the compound 6c exhibited the most potent inhibition with a Ki value of 23.6nM. Hence, compound 6o can be taken as an effective lead compound for the development of hCA XII inhibitors and compound 6c can be taken as a lead compound for the development of dual hCA IX and XII inhibitors. To understand the molecular interactions, the two most potent compounds 6a and 6o were docked within the hCA XII catalytic cleft in order to study their binding modes with that isoform.

Recent Advances in the Synthesis of Coumarin Derivatives from Different Starting Materials.

The study of coumarin dates back to 1820 when coumarin was first extracted from tonka bean by Vogel. Compounds containing coumarin backbone are a very important group of compounds due to their usage in pharmacy and medicine. Properties and biological activities of coumarin derivatives have a significant role in the development of new drugs. Therefore, many different methods and techniques are developed in order to synthesize coumarin derivatives. Coumarin derivatives could be obtained from different starting materials with various methods but with big differences in yield. This review summarized various methods, techniques and reaction conditions for synthesis of coumarins from different compounds such as aldehydes, phenols, ketones and carboxylic acids.

Green synthesis, characterization, structure, biological activity, theoretical calculations and drug-likeness analysis of coumarins

Abstract Condensation of salicylaldehydes and 2-hydroxynaphthaldehyde with various β−dicarbonyl derivatives 2a-c, in the presence of KF-Al2O3, leads to the synthesis of a series of coumarins 3-8 and benzo[f]coumarins 10 respectively by a solvent free reaction under microwave irradiation. The catalyst is recovered by a simple filtration and reused in subsequent reactions. The structure of all synthesized compounds has been established by using analytical techniques such as IR, 1H and 13C NMR spectroscopic spectra and elemental analysis. Most of the coumarins exhibited significant antibacterial activity against S. aureus Gram-positive bacteria compared to Cefotaxime as positive control. The compounds 4a and 7a demonstrated moderate antimicrobial activity against compound 8a is extremely sensitive.. In addition, the compounds showed moderate to good antiradical (DPPH) activity. Theoretical calculations let us to confirm the reaction mechanism. Parameters drug-likeness and physicochemical properties including pharmacokinetic analysis of the synthesized compounds was performed using DruliTo program.

Synthesis and antimicrobial activity of some new coumarin and dicoumarol derivatives

AbstractPTC reaction of coumarin derivative 1 with alkyl halides afforded C4 oxygen alkylation products 2a‐d in appreciative yield, whereas with phenyl isothiocyanate gives the C3 addition product 4; also, one‐pot three‐component PTC reaction was investigated. Treatment of coumarin 1 with aromatic aldehydes in different molar ratios gives 3‐arylidene derivatives 7a,b and the dicoumarol derivatives 8a,b. Pyrano chromene 9 and pyrano pyridine 10 were obtained by reaction of arylidene 7a with ethyl acetoacetate through Michael cycloaddition reaction. The stability of pyrone ring in 3‐arylidene 7 and dicoumarol 8 towards different nucleophilic reagents under reflux and/or fusion conditions has been studied by the action of hydrazine hydrate, ammonium acetate, methyl amine, and p‐toluidine afforded compounds 11 and 13a‐c. The antimicrobial activity of some synthesized compounds has been investigated.

One-pot synthesis of coumarin derivatives via microwave assisted Pechmann reaction and biological activity of substituted coumarin derivatives

Pechmann reaction is mainly used for the synthesis of substituted coumarins as it can be executed with straight forward primary resources and gives coumarin derivatives with excellent yields. In the present work coumarin derivatives have been synthesized by condensation of β-ketoesters and substituted phenols under microwave irradiation in solvent free condition in which oxalic acid is used as catalyst. Oxalic acid is found to be a potential environment friendly catalyst for synthesis of coumarins. The new method of synthesis described here offers a number of advantages of being convenient, safe, gentle, shorter reaction time, high yield, and cleanness as compared to the conventional methods. The synthesized compounds have been systematically characterized by IR and MS analyses. All products are examined for antimicrobial activity against the Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram negative (Escherichia coli and Salmonella typhi) bacteria and antifungal activity against two fungal species (Aspergillus sp. and Fusarium graminearum). All the compounds inhibited the growth of bacteria as well as fungi.