Chapter One - Pechmann Reaction in the Synthesis of Coumarin Derivatives

This reaction is an acid‐promoted synthesis of coumarin derivatives from the condensation of phenols and β‐ketoesters or β‐keto carboxylic acids and is generally known as the Pechmann reaction. This reaction, under acidic conditions, involves an esterification or transesterification, followed by a cyclization and dehydration. It has been found that the outcome of this reaction depends on the nature of phenols, β‐keto esters, and condensation reagents. The study finds that only phenols with electron‐donating groups at themeta‐position of the hydroxy group readily undergo the Pechman condensation. On the other hand, the α‐substituents and γ‐substituents on β‐keto esters retard this reaction. This reaction has general application in the preparation of coumarin derivatives.

Review: various aspects, issues, and applications of this reaction; 199 refs.

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.

The reaction of phenols with ethyl acrylates in the presence of a Pd(OAc)2 catalyst in trifluoroacetic acid did not yield dihydrocoumarins but gave coumarins, in contrast to the reaction of phenols with propiolates. The addition of K2S2O8 as an oxidant increased the yield of coumarins. The reaction of several phenols with ethyl cinnamate, ethyl crotonate, or ethyl acrylate gave the corresponding coumarin derivatives in moderate to good yields. The coumarin formation competed with the oxidative coupling of electron-rich phenols, which reduced the product yield.

A suitable methodology of synthesis of coumarin derivatives by Pechmann reaction over heterogeneous solid acid catalysts in a free solvent media under microwave irradiation is described. Resorcinol, phenol and ethyl acetoacetate were selected as model reactants in the Pechmann condensation. The catalytic activity of several materials—Amberlyst-15, zeolite β and sulfonic acid functionalized hybrid silica—in solvent-free microwave-assisted synthesis of the corresponding coumarin derivatives has been investigated in detail. 7-Hydroxy-4-methylcoumarin and 4-methylcoumarin were obtained in 97% and 43% yields, respectively, over Amberlyst-15. This was the most active catalyst in the Pechmann reaction under studied conditions.

Herein, we report the fabrication of biomass rice husk‐derived chemically activated carbon (RCAC) sheets which are self‐assembled to 2D hollow porous materials and demonstrated their catalytic efficiency in the domino Knoevenagel−Michael addition reaction for the synthesis of various bio‐active coumarin derivatives in excellent yields under metal‐free conditions mild reaction conditions. Particularly, we have illustrated a facile, eco‐friendly, economical, and sustainable method for the synthesis of bis‐(4‐hydroxycoumarin)methanes, bis‐dimedones, and 4‐hydroxy‐3‐thiomethylcoumarins, via three‐component reactions of 4‐hydroxy coumarin/demedone, aldehydes and or thiophenols. Moreover, the Michael addition of 4‐hydroxy coumarin and chalcone derivatives leading to the synthesis of warfarin derivatives has also been demonstrated using RCAC as a catalyst. The cytotoxicity potential has been performed against human liver cancer cell line Hep‐G2 cancer cells for all the synthesized products by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The cytotoxicity study against Hep‐G2 results indicates that all compounds are capable of killing the liver cancer cell line. The most potent anti‐proliferative activity was observed in compounds 3 g , 5 b , 5 c , 5 a , and 9 b against liver cancer cells.

Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD. The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors. The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D]. The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

Coumarin derivatives were prepared by the von Pechmann reaction of PEG‐bound acetoacetate reagent with phenols in the presence of TiCl4 in excellent yield and purity with a facile workup procedure. The polymer reagent could be recycled two to four times without diminishing the yield or purity.

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.

The catalytic performance of highly active cobalt(II) supported on mesoporous SBA-15 materials for the Pechmann reaction was investigated. SBA-15 supported cobalt(II) nanocatalyst was found to be efficient and easily recoverable in the Pechmann reaction of phenols and β-ketoesters to their corresponding coumarin derivatives under solvent-free conditions. The supported cobalt catalyst could be easily recovered after reaction completion and reused twelve times with an excellent durability and without any noticeable loss in activity.

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Based on the pharmaceutical potentials of coumarins, which have antitumor activity, we synthesized new coumarin derivatives and evaluated their biological activities. The new coumarin derivatives were chemically synthesized from 4-hydroxycoumarin, and their structures were confirmed by nuclear magnetic resonance data. Ten of the synthesized compounds were investigated for antimetastatic activity against lung carcinoma cells. Several of the tested compounds showed good to mild inhibitory effects on lung cancer cell motility. There were no cytotoxic effects related to the use of these compounds. 4-Hydroxycoumarin derivatives, 4h and 4i, elicited the significant inhibitory effect on lung cancer cell motility by suppressing expression of the epithelial–mesenchymal transition markers N-cadherin, Snail, and Twist.

To expand the range of daphnetin-based inhibitors/activators used for targeting G protein-coupled receptors (GPCRs) in disease treatment, twenty-five coumarin derivatives 1–25, including 7,8-dihydroxycoumarin and 7-hydroxycoumarin derivatives with various substitution patterns/groups at C3-/4- positions, were synthesized via mild Pechmann condensation and hydroxyl modification. The structures were characterized by 1H NMR, 13C NMR and ESI-MS. Their inhibition or activation activities relative to GPCRs were evaluated by double-antibody sandwich ELISA (DAS–ELISA) in vitro. The results showed that most of the coumarin derivatives possessed a moderate GPCR activation or inhibitory potency. Among them, derivatives 14, 17, 18, and 21 showed a remarkable GPCR activation potency, with EC50 values of 0.03, 0.03, 0.03, and 0.02 nM, respectively. Meanwhile, derivatives 4, 7, and 23 had significant GPCR inhibitory potencies against GPCRs with IC50 values of 0.15, 0.02, and 0.76 nM, respectively. Notably, the acylation of hydroxyl groups at the C-7 and C-8 positions of 7,8-dihydroxycoumarin skeleton or the etherification of the hydroxyl group at the C-7 position of the 7-hydroxycoumarin skeleton could successfully change GPCRs activators into inhibitors. This work demonstrated a simple and efficient approach to developing coumarin derivatives as remarkable GPCRs activators and inhibitors via molecular diversity-based synthesis.

Coumarins possess a broad spectrum of biological activities and are important pharmacophores in drug developments. Since aberrant upregulation of PI3K/Akt signaling is related to uncontrolled tumor cell proliferation, enhanced migration, and adhesion-independent tumor growth, it is of interests to find novel coumarin derivatives as anticancer agents targeting the PI3K/Akt signaling pathway. A variety of coumarin derivatives possessing the pyridinylurea units were designed to increase their potency and isoform selectivity against PI3Ks. Novel coumarin analogs 4a-m were were prepared from 5-methylpyridin-2-ylamine in a straightforward way and their growth inhibitory activity against tumor cells was evaluated by a MTT assay. The inhibitory activity against PI3Kα, β, δ and γ was measured by luminescent assay. Akt phosphorylation inhibition and caspase 3 and PARP activation were measured by Western blot analysis. Apoptosis was measured by staining cells with annexin V-FITC and 7-AAD. In general, these coumarin analogs exhibited good in vitro growth inhibitory activities against tumor K562, Hela, A549 and MCF-7 cells. Some of them showed comparable or better potency than BENC-511. Compounds 4b and 4h were much more potent PI3K inhibitors than S14161 or BENC-511. In addition, 4b was more selective to PI3Kα/β over PI3Kδ/γ, while 4h was a selective PI3Kα/β/δ inhibitor. Moreover, 4h could suppress the phosphorylation of Akt and induce K562 cell apoptosis. Coumarin derivatives possessing the pyridinylurea units are potential PI3K inhibitors and anticancer agents. These findings will be helpful for the future design of more potent and selective PI3K inhibitors.

To shift from a petroleum-based to a biomass-based economy will require the development not only of biofuels, but also of biorenewable replacements for petroleumderived chemicals. In this regard, environmentally friendly biomass-derived esters may serve as alternatives to fossil-derived chemicals such as toxic halogenated solvents and glycol ethers. Therefore, esterification of various carboxylic acids that find significant applications in the chemical, pharmaceutical, petrochemical, food, and cosmetic industries has been initiated by the chemical industry. At atmospheric condition, esterification is a reversible reaction limited by the low equilibrium conversion and slow reaction rate, and has recently been performed with excess alcohol to shift the equilibrium conversion. Heterogeneous or homogeneous acid catalysts are used to achieve acceptable reaction rates. The conventional acid-catalyzed process has been extensively developed; but it suffers from problems associated with the generation of side reactions, corrosion of equipment, expensive purification procedures, long reaction times and discharge of acidic wastes. Various attempts on esterification of carboxylic acids with ethanol have previously addressed important issues concerning product distribution, catalyst activity, and kinetics of acid-catalyzed esterification at lower reaction temperatures, but kinetics of uncatalyzed esterification at elevated reaction temperatures are still very limited. It is thus of great interest from a practical viewpoint that more information such as kinetic and thermodynamic parameters are required to develop a possible esterification process without using any catalyst. In this work, therefore, a fundamental study on the uncatalyzed esterification of different aliphatic carboxylic acids with stoichiometric amounts of ethanol was