**3.1 Microwave mediated innovative synthesis**

Recently, microwave-mediated organic synthesis has replaced conventional heating methods. In recent years, the synthesis of organic molecules has increasingly *Recent Methods for Synthesis of Coumarin Derivatives and Their New Applications DOI: http://dx.doi.org/10.5772/intechopen.108563*

**Figure 14.** *Baylis Hillman reaction for the synthesis of substituted coumarin.*

relied on the use of microwave energy to heat chemical reactions. In contrast to dramatically accelerating chemical reactions, direct microwave heating is known to reduce the formation of side products, increases yield, and improves the reproducibility. Various academic research institutions have already embraced microwave irradiation as a method for fast reaction in order to efficiently synthesize and discover new chemical substances [54].

In the year 2017, Brahmbatt and co-workers demonstrated the microwave- assisted preparation of 3-aryl-furo[3,2-c] coumarins **37**. The time required for the synthesis was just 2–4 minutes and the yield was also good (72–82%) as shown **Figure 15** [55].

In the same year, Desai et al. reported the preparation of 4-(substitutedphenyl)- 2-(furan-2-ylmethyleneamino)-6-(2-oxo-2*H*-chromen-3-yl)nicotinonitrile derivatives **42**. The reaction was carried out in a solvent-free condition, the reaction was performed with 2-amino-4-(substitutedphenyl)-6-(2-oxo-2*H*-chromen-3-yl) nicotinenitriles **41** and 2-furfuealdehyde and the microwaves (300 W) were irradiated for 8–10 min. in the presence of acetic acid and a catalytic amount of ZnCl2 (**Figure 16**) [56].

**Figure 15.** *Microwave assisted synthesis of 3-aryl-furo[3,2-c] coumarins.*

[3,4-d]triazole-fused coumarin derivatives were synthesized by Schwendt and coworkers. The yield obtained was best (63–94%) in the presence of DMF (solvent) and at 160°C for 1 min [57].

A variety of coumarin-carbonodithioate and coumarin-maltol derivatives were synthesized, showing antibacterial activity and antitumor in a relatively short period in the presence of microwave radiations. It was stated that this approach was 24 times faster than the traditional technology [58, 59].

Pyrido[3,2-c]coumarins were synthesized in the presence of ammonium acetate, the reaction was carried out with suitable starting materials. The yield obtained was good and the time required for the reaction was about 3–4 mins [60]. Synthesis of coumarin-thiazolidine-2,4-dione was carried out recently by Mangasuli and coworkers. The reaction was performed in the presence of K2CO3 (catalyst), the starting material utilized was coumarin and thiazolidinedione.

#### **3.2 Ultrasound helped synthesis**

Comparing ultrasonic irradiation to traditional energy sources, there are various benefits like heat, light, and electric potential) [61, 62]. The primary cause of the chemical reactions caused by ultrasound is acoustic cavitation, which is the formation, *Recent Methods for Synthesis of Coumarin Derivatives and Their New Applications DOI: http://dx.doi.org/10.5772/intechopen.108563*

**Figure 17.**

*Ultrasound assisted synthesis of 3-substituted coumarins.*

**Figure 18.** *Mechanism of the synthesis of 3-substituted coumarins.*

#### **Figure 19.**

*Synthesis of coumarin via ultrasonic/microwave radiation.*

development, and implosive bursting of bubbles. In many fields of chemistry research, including organic synthesis and solid-state materials, ultrasonic-assisted synthesis techniques have gained a lot of interest as shown **Figure 17** [63].

The 3-substituted coumarins **10** can be synthesized in the presence of MgFe2O4 nanoparticle, and the reaction can be carried out between salicylaldehyde **8** and 1,3 dicarbonyl compound **9** in the existence of the Ultrasound radiation. The mechanism for the syntheis of 3-substituted coumarin **10** was reported by Ghomi and co workers in 2018 and has been shown in the **Figure 18** [64].

The Pechmann condensation reaction for the synthesis of 3- substituted coumarin **5** in the presence of ultrasound radiation as well as in microwave radiation was carried out in the presence of catalyst FeCl3, it was found that the yield reported was better with the methodology used than the conventional method as mentioned in **Figure 19** [65].

Bis-coumarin derivatives have been synthesized in the presence of ultrasound radiation, the reaction was carried out between various aromatic aldehydes and 4-hydroxycoumarin [66].

#### **3.3 Solvent-free synthesis**

Large volumes of hazardous and volatile organic solvents are used in numerous conventional chemical reactions. Green chemistry's major objective is to replace such toxic reaction solvents. The design of solvent-free green processes has attracted

**Figure 20.** *Solvent-free synthesis of coumarin.*

**Figure 21.**

*Synthesis of substituted coumarin in solvent-free condition.*

noticeably more interest from researchers as environmental consciousness on a worldwide scale rises. Many researchers have reported the synthesis of coumarin in a solvent free condition. In the year 2014, Sabetpoor et al. reported the synthesis of simple coumarin analogs **5** in the solvent-free conditions in the presence of glutamic acid as a catalyst. The reaction was carried out between the reactant phenol **3** and keto-ester **4** (**Figure 20**). The yield obtained of the expected product was excellent, in ranging from 83 to 93% [67].

The solvent-free Knoevenagel and Pechmann preparation of coumarin **46** has been carried out by Sugino and Tanaka. Pechmann reaction was carried out between reactant substituted phenol **45** and keto-ester **4** utilizing *p*-toluenesulfonic acid (PTSA catalyst) at 60°C. The yield obtained was good ranging 66–98% with different substituents at Resorcinol **45** and ethyl acetoacetate **4** in **Figure 21**. After heating the mixture for 10 min, it was kept for cooling and then crystalline product was obtained after adding water to the reaction mixture, followed by recrystallization from EtOH [68]. In 2011, a similar type of method has been reported by Makrandi et al. [69].

The same authors have also demonstrated the Knovenagel reaction of salicylaldehyde **47** and β-keto ester **4**, in the presence of piperidine at room temperature for 5 min. The neutralization of the reaction mixture has been carried out using aq. HCl, followed by filtration and recrystallization from EtOH. The 3-ethoxycarbonylcoumarin **48** was obtained with a great yield up to 95%. As well as the other substituted coumarin was also obtained with a high yield [68] as given **Figure 22**.

#### **3.4 Light induced metal-free radical cyclization**

In 1912, at the start of the 19th century, Ciamician created a unique technique that used light as a natural source in a chemical reaction. Moreover, utilizing the irradiating method, several organic photochemical processes based on Ultra Violet were developed [70]. In this respect, MacMillan initially investigated in 2008 how a *Recent Methods for Synthesis of Coumarin Derivatives and Their New Applications DOI: http://dx.doi.org/10.5772/intechopen.108563*

**Figure 22.**

*Synthesis of coumarin via Knovenagel reaction in solvent-free condition.*

combination of an organocatalyst and a photosensitive catalyst could enhance the asymmetrical alkylation of aldehydes. Because of its unique single electron transfer (SET) path in very mild reaction circumstances, as well as the fact that it is a secure, economical, and sustainable energy source, visible light-irradiated photoredox catalysis has recently gained a lot of interest. By pairing visible light with metals such as Ruthenium, Iridium, Copper, Nickel, and others, many C-C and carbonheteroatom bonds can be created. Several studies about how to produce coumarins through metal-free/transition-metal catalyzed inter and intramolecular, radical and electrophilic cyclizations have indeed been reported in the literature, but their practical implementation is constrained by the requirement of a toxic metal, substance, or reagent. In order to synthesize coumarins and other compounds, it is crucial to develop simple, practical, and environmentally friendly techniques [71].

A novel photocatalytic technique to produce (3-acyl 4-arylcoumarin) **51** from aldehyde and aryl alkyne ester was reported in 2018 by Itoh et al. Using visible light, the reaction of phenyl 3-phenyl-2-propynate **49** with *p*-tolualdehyde **50** was conducted in the presence of a AQN catalyst (10 mol%), an oxidant like Bz2O2, and K2CO3. The necessary 1,2-ester compound was generated in good yields using *p*substituted phenoxy rings carrying either electron-donating substitution (CH3, OMe) or electron-poor groups (I, RCOOR', CH3CO, and OAc). It's noteworthy that the team performed a few straightforward control trials to demonstrate the molecular pathway (**Figure 23**). The method's appealing qualities also include mild reaction conditions, affordable catalysts, and readily available substrates [72].

**Figure 23.** *Synthesis of 3-acyl 4-arylcoumarin.*

**Figure 24.**

*Synthesis of iodo coumarins via light-assisted metal-free radical cyclization.*

**Figure 25.** *Synthesis of 3-arylacetylene coumarins.*

Li and colleagues described the straightforward photocatalyzed cyclization of alkynoates **49** to iodo coumarins in a THF solvent at 25°C and metal-free circumstances in 2019 (**Figure 24**). After examining the effects of various light sources on the procedure, it was discovered that visible light with a wavelength of 380–385 nm is the most effective. Iodo coumarins **53** were synthesized in high yields using substrates that had substitutions at the *p*-position of the benzene ring [71].

Wu and co-workers very recently reported, in 2020, a simple and practical one-pot reaction to synthesize 3-arylacetylene coumarins **55** from the precursor **54** using thermo-catalysis and photosensitizer-free photocatalytic activity. The basic and effective photocatalytic reactions of *p*-tolyl 3-phenylpropiolate and *N*iodosuccinimide (NIS) have been conducted in acetonitrile to carry out the one-pot process as given **Figure 25** [73].

#### **3.5 Metal-mediated radical cyclization**

Metal-catalyzed reactions have established themselves as one of the crucial steps in the synthesis of organic compounds. There is various methodology reported by chemists for the construction of coumarin derivatives via metal-assisted Radical cyclization reaction. Sulfonyl coumarins **58** can be synthesized from phenyl 3*Recent Methods for Synthesis of Coumarin Derivatives and Their New Applications DOI: http://dx.doi.org/10.5772/intechopen.108563*

**Figure 26.** *Synthesis of sulfonyl coumarins.*

**Figure 27.** *Synthesis of 4-phenyl 3-sulfonylcoumarins.*

phenylpropiolates **56** and tosyl prolines **57** as starting material in the presence of AgNO3 (catalyst), and an oxidant like potassium persulphate in solvent MeCN/H2O (2:1) at a temperature of 50°C as showed in **Figure 26**. It is to be noticed that the yield is not good with alanine, phenylalanine, and glycine however, it is good with valine or 2-methylalanine sulfomide [74].

In the year 2018, Zhang et al. reported the synthesis of 3-phenyl sulfonylcoumarins. The reaction is carried out with starting material **54** and sodium sulfinate/ sulfinic acids, the reagents required for the reaction are silver nitrate, TBHP, and KI, in solvent (mixture of acetonitrile and water) at 80°C, in the presence of nitrogen atmosphere (**Figure 27**). Various substituted starting materials **54** can be used for synthesizing different derivatives of coumarin **59**. The yield of the product is better with sulfinates than sulfinic acid [75].

Recently in 2019, 3-monofluoromethylated coumarins **60a-c** have been synthesized by Fu and coworkers *via* monofluoromethylation in the presence of a silver catalyst. When used as a CH2F radical source, phenyl alkynoate **54** and monofluoromethyl benzo[*d*]thiazol-2-yl sulfone were combined with AgNO3(10 mol %) and potassium persulfate (4.0 equiv.) in DMSO (3.0 mL) and heated to 60°C in an environment of nitrogen for 24 h (**Figure 28**). The reaction is compatible with both electron-rich and deficient substituents at the para position of phenyl ring [76].

**Figure 28.** *Synthesis of 3-monofluoromethylated coumarins.*

#### **3.6 Metal catalyzed electrophilic cyclization**

It has been a challenge for chemists and is crucial in the disciplines of agrochemicals, medicines, and healthcare to activate the C-H bond by a metal-catalyst that results in the novel and advantageous chemically synthesized reaction that creates the C-C bond. A beneficial use relates to organic compounds such as annulated arenes, carbocycles, and heterocycles. Intramolecular hydroarylation is the methodical insertion of arene C-H bonds over numerous bonds in an intermolecular approach. In 2014, it was demonstrated that Au(III) catalyzed electrophilic hydroarylation of aryl alkynoate **61** yielded its respective coumarin analogues **62** through ortho cyclization route and de-aromative ipso-cyclized product in good yield by a modest adjustment in the reaction process. The specific production of coumarin derivatives **62** results from the utilization of an Au-catalyst and AgOTf as additives in an anhydrous DCE solvent, and the presence of a little amount of water results in spirocycles **63** as illustrated in **Figure 29** [77].

Anderson and colleagues demonstrated the electrophilic cyclization-catalyzed formation of 3-organoselenyl-2*H*-coumarins **64a-e** and 3-organoselenylquinolinones from related aryl alkynoates and arylpropiolamides **54**, respectively, in the ideal

**Figure 29.** *Au-catalyzed coumarin synthesis.*

*Recent Methods for Synthesis of Coumarin Derivatives and Their New Applications DOI: http://dx.doi.org/10.5772/intechopen.108563*

**Figure 30.** *Fe-catalyzed coumarin synthesis.*

**Figure 31.** *Pt-catalyzed coumarin synthesis.*

reaction conditions attained in a similar manner with organoselenium reagents in dichloromethane solvent as given in **Figure 30** [78].

In 2020, Zaitceva and colleagues showed that cyclometalated (ppy)Pt(II) compounds can catalyze the intramolecular cyclization of phenyl propynoates **54** to produce coumarins **17** and benzocoumarins. A considerable number of substituted coumarins and benzocoumarins were synthesized employing this catalytic approach, and a wide variety of variants were identified to be compatible with the cyclization mechanism (**Figure 31**) [79].

#### **3.7 Homogeneous catalytic reaction**

In 2014 Chang et al. proposed a gentle and metal-free approach to synthesize 3 sulfenylated coumarins **66a-c** through cyclization of aryl alkynoates **54** and corresponding *N*-sulfanylsuccinimides **65** promoted by BF3Et2O as a Lewis acid (**Figure 32**) [80].

Wu et al. published a practical and flexible approach for functionalizing 3 sulfenylcoumarin **67**a-c and derivatives of 3-sulfenylquinolinone *via* iodine-catalyzed electrophilic cyclization in 2017 (**Figure 33**). The reaction was carried out with phenyl

**Figure 32.**

*Preparation of 3-sulfenylated coumarin.*

**Figure 33.** *Iodine-mediated synthesis of 3-sulfenylcoumarin.*

**Figure 34.** *Formation of 3-organoselenyl-2H-coumarins by propargylic aryl ether.*

3-phenylpropiolate **56** and sodium benzenesulfinate, iodine and in DMSO and solvent mixture dioxane and [C2O2mim]BF4 were used as co-solvents [81].

Later in 2019, Fang and coworkers reported a methodology for the preparation of 3-organoselenyl-2*H*-coumarins **68** via oxidative radical cyclization of propargylic aryl ethers **49** and diaryl diselenides. The reaction of (3-phenoxyprop-1-yn-1-yl)benzene and diphenyl diselenide was carried in CH3CN with *tert*-butyl hydroperoxide(4.0 equiv.) at 80°C for 48 h yielded 85% of the expected product **68a-b** as shown in **Figure 34** [82].

#### **3.8 Heterogeneous catalytic reaction**

One of the foundational elements of the chemical and energy industries is heterogeneous catalysis will play a key role in facilitating the shift to these sectors' eventual transformation to carbon-neutral operations [83]. Nowadays, heterogenous catalysis is playing an important role in the organic synthesis, and still it is used for converting petroleum as well as natural gas into the cleaner, capable fuels [84, 85].

Researchers have long struggled with the activation of the C-H bond by metal catalysts, which results in the novel and advantageous synthetic organic reaction that creates the CdC bond and is crucial in the agrochemical, pharmaceutical, and medical fields. Intramolecular hydroarylation, which is the systematic introduction of arene CdH bonds over multiple bonds in the intermolecular path way, gives a useful organic products like annulated arene carbocycles as well as heterocycles. A novel method has been demonstrated by Yuzo Fujiwara et al. in the year 2000, for the preparation of coumarins and quinolinones *via* intermolecular hydroarylation substrate. Utilizing the procedure, different aryl alkynoates **54** and alkynanilides can be quickly converted to the required coumarin derivatives **69a-b** at a temperature between 25 and 27°C and with a catalytic quantity of Pd(OAc)2 in a mixture of solvents TFA and DCM as shown **Figure 35** [86].

Dalibor and coworkers in 2004 have also demonstrated PtCl4 catalyzed intramolecular electrophilic hydroarylation of various substrates having different structures which includes alkynoate esters **70**, propargylamines, and propargyl ethers, that results into a great yield of 6-endo cyclized compounds of coumarin derivatives **71** and **72** in DCM as well as in solvent like dioxane at 25°C. This reaction was studied with a variety of transition metals and their salts, and it was determined that PtCl2 and PtCl4 were both successful, however PtCl2 produced lower yields than PtCl4 when used with appropriate organic solvents such as DCM or dioxane (**Figure 36**) [87].

**Figure 35.**

*Synthesis of coumarins by pd-catalyzed intramolecular hydroarylation.*

**Figure 37.** *Method for preparation of coumarins catalyzed by AuCl3.*

Later in 2004 Chuan and coworkers have described gold(III)-mediated intermolecular hydroarylation reaction of aryl alkynoates **54** under neat conditions to give coumarin derivatives **69** in high yields (**Figure 37**). In this reaction higher temperature (70°C) was needed in some cases and the process of the reaction is distinct from the same reactions which were catalyzed by Pd(II), Pt(II), Pt(IV), and Ru(II) has been described [88].
