Synthesis of coumarin-based derivatives from different starting materials: A review of ongoing developments

Objective: This brief review highlights the recent advances in the synthesis of coumarin-based derivatives from phenols, aldehydes, ketones, and various other functional group-containing starting compounds. Also, the recent developments in the conditions of several original synthetic methods involving Pechmann and Knoevenagel reactions are being revised. Conclusion: It is critical to decreasing energy consumption, prevent hazardous chemicals, and get pure molecules in high yields during synthesis. Scientists working in this sector will be able to utilize this comparison of reaction conditions and compound yields to create new efficient procedures.


INTRODUCTION
oumarins are abundantly expressed in nature and may be found as secondary metabolites in many plant sections involving the seeds, roots, leaves, peels, flowers, and fruits 1 . Because the majority of recovered coumarins exhibit various biological activities 2-4 , coumarin derivatives are increasingly being synthesized. As the extraction of coumarins from the plants is time-consuming and unprofitable (several processing steps to the last product) 5 .
Coumarin derivatives can be synthesized via a range of methodologies, including the Baylis-Hillman, Perkin condensation, Vilsmeier-Haack, Knoevenagel condensation, Claisen rearrangement, Pechmann condensation, Wittigreaction, and Suzuki cross-coupling reaction 6 . C Their findings on the coumarins' therapeutic potentials 7 . Some of these results indicated that many synthetic coumarins have antimicrobial properties, including anti-HIV, antiviral, antituberculosis, antibacterial, and antifungal impacts 8 . Also, several coumarin compounds were shown to have strong antioxidant properties and some of them are being evaluated as acetyl cholinesterase (AchE) inhibitors, with the potential to be used as medications for treating Alzheimer's disease 9,10 . Additionally, other coumarin derivatives have a variety of biological effects, such as anti-hyperglycemic, anticancer, antiinflammatory, and anticoagulant actions 11 .
Since the coumarin chemical nucleus has been established as a functional pharmacophore, the demand for synthesizing compounds derived from this backbone is increasingly grown 12 . Many coumarin synthetic methods have been employed using starting materials with various functional groups and reaction experimental parameters 13 . The present brief review article summarizes the results of the recently reported research papers regarding the synthesis of coumarin derivatives from various precursors via various experimental methods.

Synthesis of coumarin derivatives from aldehyde functionalized compounds
Keshavarzipour and Tavakol reported the facile green synthesis of coumarin derivatives via the Knoevenagel condensation reaction phenotype using a deep eutectic solvent. This dissolving agent that also acts as a catalyst was prepared by mixing, at 100°C, one mole of choline chloride and two moles of zinc chloride. The starting materials utilized in this synthesis, as shown in Scheme 1, included simple or functionalized salicylaldehydes and methylene involving compounds, such as ethyl 3-oxo-3-phenylpropanoate, ethyl cyanoacetate, and dimethyl malonate. The incomes were significant ranged between 61% and 96% 14 . Scheme 1. Synthesis of coumarin derivatives from various aldehydes and active methylenes as described by Keshavarzipour and Tavakol.
Mi and colleagues administrated the metal-free tandem oxidative acylation and cyclization, as shown in Scheme 2, various 3-acyl-4-aryl coumarin derivatives were synthesized by coupling alkynoates with aldehydes. For optimizing the reaction conditions, the condensation between diethyl-ptolualdehyde and phenyl 3phenylpropionate was performed as a reaction model in the locked environment under nitrogen gas using an oil bath for one day . Through the optimization process, the incoming factors have been modulated: catalyst (Et4NBr, n-Bu4NI , n-Bu4NBr, n-Bu4NCl, n-Bu4NF, and pivalic acid), oxidizing agent ((NH4)2S2O8, Na2S2O8,K2S2O8, and tert-butyl hydroperoxide), solvent (H2O, ACN, CH3CH2Cl2, dioxane, and toluene), and activating temperature (80, 90 and 100°C). Based on the acquired results, the authors concluded that the best reaction factors are the K2S2O8 as an oxidizing agent, n-Bu4NBr as a catalyst, ClCH2CH2Cl as a solvent, and 90°C as an activating temperature 15 .
Scheme 2. Metal-free tandem oxidative acylation and cyclization for the synthesis of various 3-acyl-4-aryl coumarin derivatives, as demonstrated by Mi and colleagues.
Brahmachari recorded the synthesis of various coumarin-3-carboxylic acid derivatives at room temperature in an aqueous medium using a one-pot Knoevenagel condensation reaction. To recognize the catalytic agent afforded the best yield, a model reaction between Meldrum's acid and salicylaldehyde was conducted. The results reported that the best catalytic agents were NaN3 and K2CO3 indicated the reaction yields of 99% and 92%, respectively. Subsequently, the condensations between different functionalized salicylaldehydes and Meldrum's acid were conducted using the detected catalytic agents resulting in different functionalized coumarin-3-carboxylic acid derivatives, as shown in Scheme 3, in the yields ranged between 73% and 99%. Since the NaN3 is a highly toxic reagent especially at the employed concentration (50 mol%), the author recommended the utilization of K2CO3 in the concentration of 20 mol% as a preferred catalytic agent 16 .

Scheme 3. Synthesis of various coumarin-3-carboxylic acid derivatives via a one-pot
Knoevenagel condensation reaction as described by Brahmachari.

Scheme 14.
A two-step one-pot synthesis of 4-methylcoumarin based derivatives substituted at 3-position with various aryl moieties as described by Phakhodee et al.
Sharma and Makrandi described the onepot synthesis of 3-cyano4methylcoumarin compounds under conventional heating and microwave irradiation. This synthesis, as depicted in Scheme 15, proceeded in DMF by condensing malononitrile with various ortho-hydroxy acetophenone derivatives employing iodine as a catalytic agent.
From the obtained results, the authors concluded that there are no significant differences in the %yields among the utilized activating energy sources. Despite this, the basic merit of using microwave irradiation as activating energy was the reduction in the reaction interval 28 .

Synthesis of coumarin derivatives from carboxylic acid functionalized compounds
Li et al. demonstrated a specific method for synthesizing various 4phenylcoumarins from carboxylic acidfunctionalized compounds under microwave irradiation conditions, as shown in Scheme16. During the course of the reaction, the optimization process was conducted using various phenyl acrylic acid-based derivatives, solvents (EtOH, ACN, DMF, toluene, DCM, and TFA), catalysts (I2, LiBr, BF3.Et2O, and TFA), and oxidants (phenyliodine diacetate that symbolized as PIDA and bistrifluoroacetate that symbolized as PIFA). From the obtained outcomes, the authors identified the best reaction parameters that were DCM, I2, and PIDA as a solvent, catalyst, and oxidizing agent, respectively. By applying the aforementioned reaction parameters, a series of neoflavonoids (4phenylcoumarins) was prepared in goodto-excellent outcomes ranged between 41% to 92% 29 .
Scheme 16. Microwave-aided synthesis of 4-phenylcoumarin as described by Li et al.
Yan et al. developed a novel and practical method for the synthesis of trisubstituted coumarin derivatives. This silver-promoted radical cyclization method involved the coupling between various alkynoates and α-ketoacids, as shown in Scheme 17. The coupling between phenylglyoxylic acid and 3phenylpropiolate was used as a model reaction and accomplished in varied conditions. The variables included the change in the solubilizing agent (DMF:H2O, H2O, and ACN:H2O), oxidant (K2S2O8, O2, TBHP, (NH4)2S2O8, and Na2S2O8), and catalyst (AgOAc, Ag2CO3, Ag2O, AgNO3, and catalystfree). From the afforded results, the researchers reported that the best outcome (75%) was arisen from applying the following reaction parameters: ACN:H2O, K2S2O8, and AgNO3 as a solvent mixture, oxidant, and catalyst, respectively 30 . , and neutralizing-(KOH, KHCO3, NaOAc, and Na2CO3) agents. The researcher concluded from the afforded results that the highest outcome (74%) was arisen from applying the following reaction parameters: ACN:H2O, K2S2O8, Ag2CO3, and NaOAc as a solvent mixture, oxidant, catalyst, and base, respectively 31 .