**2. Name reaction enabled coumarin synthesis**

In the present literature, several name reaction mediated methods are reported for the synthesis of coumarin derivatives used by following well-established reaction protocols such as Perkin reaction, Pechmann reaction, Claisen rearrangement, Knoevenagel reaction, Kostanecki-Robinson coupling reaction, Reformatsky Reaction, Wittig reaction, Michael addition, Heck-lactonization reaction, and Baylis–Hillman reaction in the presence of various metal-free or metal-based homogenous and heterogeneous catalyst systems. We have demonstrated suitable reaction and mechanisms for following name reactions mediated preparation of coumarin motifs (**Figure 2**).

**Figure 2.** *Name reactions mediated synthesis of coumarin.*

**Figure 3.** *Synthesis of coumarin via Perkin reaction.*

#### **2.1 Perkin reaction**

In 1968, the first time Pekin demonstrated the method for the construction of coumarin by the condensation reaction of simple salicylaldehyde in the presence of acetic anhydride [37].

The Perkin reaction of salicylaldehyde **1** and an acetic anhydride are mixed together in the basic reaction condition, a chemical process that furnished, α, β-unsaturated aromatic acid in the presence of sodium acetate followed by intramolecular cyclization produced the expected substituted coumarin **2**. The proposed mechanism of this reaction is described in **Figure 3** [2, 37, 38].

#### **2.2 Pechmann reaction**

The Pechmann achieved the initial discovery of the Pechmann condensation in 1883 [39]. Typically, carbolic acid **3** reacts with a carboxylic ester having α-carbonyl group **4** in an acidic environment to produce the desire coumarins **5** [40]. The most widely reported process for producing coumarins through Pechmann condensation, which scheme starts with two basic building blocks, phenol and β-ketoester, and produces good coumarin yields most of the cases. Several catalysts were tested for this reaction, including sulfuric acid, trifluoroacetic acid, phosphorous pentoxide, ZrCl4, TiCl4, and ionic liquids, etc. enabled by Pechmann condensation [41]. Various groups have reported for the preparation of coumarin scaffolds *via* Pechmann methods. In the mechanism of the reaction involved following paths initial step is esterification followed by the attack of activated carbonyl group, allows to forms the ring system. The last step of the reaction involves dehydration. The proposed plausible mechanism of this

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

**Figure 4.** *Coumarin synthesis via Pechmann reaction.*

reaction shown in **Figure 4**. By reacting substituted phenols and ethyl acetoacetate in the presence of a zinc-iodine mixture in refluxing toluene, a number of substituted coumarins have been produced in yields ranging from 25 to 77%. The proposed plausible mechanism of this reaction is shown in **Figure 4** [42].

#### **2.3 Claisen rearrangement**

The preparation of 3,4-substituted coumarin utilizing trifluoroacetic acid (TFA) as homogeneous promoter *via* Claisen rearrangement reaction. The reaction of phenol 3 reacts with protected allyl alcohol 6 in the presence of basic condition offers desired target compound followed by underwent 3,3 sigmatropic Claisen rearrangement in the presence TFA in moderate temperature followed by tautomerism or basic condition produced 3,4-substituted coumarin 7 in good yields. Several groups reported Claisen rearrangement mediated synthesis of coumarin analogs. The proposed plausible mechanism of this reaction is shown in **Figure 5** [43]**.**

**Figure 6.** *Synthesis of 3-substituted coumarin via Knoevenagel reaction.*

#### **2.4 Knoevenagel reaction**

Many coumarin derivatives have been derived from suitable starting materials *via* a Knoevenagel reaction. 3-substituted coumarin derivatives can be synthesized *via* base mediated process. The reaction needs to be carried out in the presence of 2-hydroxy benzaldehydes 8 and coupling partner 9 containing an active methylene group in the presence of the base under heating conditions. The yield obtained from coumarin product 10 is acceptable range [44]. The proposed plausible mechanism of this reaction is shown in **Figure 6**. There are various reports present in the literature regarding the synthesis of scaffolds of coumarin *via* Knoevenagel reaction in the presence of ultrasound solvent-free conditions [45, 46].

#### **2.5 Kostanecki-Robinson coupling reaction**

Kostanecki-Robinson coupling reaction could be utilized for the synthesis of derivatives of coumarin. The **Figure 7** shows the reaction between aliphatic anhydride **12** and aryl ketone **11** with a substitution of the hydroxyl group which gives the desired product as coumarin **13** with good to excellent yields. The proposed plausible mechanism of this reaction is described in **Figure 7** [14, 47].

In 2004 Song et al. synthesized 4-arylcoumarins **15** from phenyl ester **14** in the presence of 4-butyl-3-methylimidazolium bromide (phase transfer catalyst), Hf (OTf)4 (metallic catalyst), for 9 h at 80°C the yield of the expected product obtained was good (**Figure 8**) [48].

#### **2.6 Reformatsky reaction**

In the Reformatsky reaction of an activated acyl halide first reacts with a zinc metal to offer RZnBr followed 1,2 addition of organometallic zinc reagents to ketone **11** produced a zinc enolate after elimination of Zn [OH(Br)] to form ester. This process converts 3,4-disubstituted coumarins **13** from α, β-unsaturated ester. This synthesis protocol involving reaction steps are as shown in the **Figure 9** with the mechanism as well [49].

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

#### **Figure 7.**

*Synthesis of coumarin derivatives via Kostanecki-Robinson reaction.*

#### **Figure 8.**

*Synthesis of 4-arylcoumarins.*

#### **Figure 9.**

*Synthesis of coumarin via Reformatsky reaction.*

#### **2.7 Wittig reaction**

Wittig reaction of aldehyde or a ketone **11** is mixed with a Wittig phosphine reagent (a triphenyl phosphonium ylide) to offer the expected olefin 16 in good yields along with phosphine oxide as by-product (**Figure 10**). This Wittig name reaction is

**Figure 10.** *Preparation of coumarin via Wittig reaction.*

discovered by the German chemist Georg Wittig. He received Nobel Prize in Chemistry in 1979 his discovery of this significant olefin synthesis. This system allows the preparation of highly important natural products as well as drug molecules. The preparation of various substituted coumarin **19** derivatives obtained from corresponding phenols **17** having ortho-carbonyl group and triphenyl(αcarboxymethylene) phosphorane imidazole ylide **18** has been carried out by Kumar et al. by following applying the route of Wittig reaction, the yield of olefin reported was good. The mechanism of the reaction suggests that the reaction proceeds through the phosphorane intermediates as shown in **Figure 11** [50]. There are various reports present in the literature regarding the synthesis of coumarin scaffolds via Wittig reaction starting with an aldehyde or ketones with phosphonium ylide.

**Figure 11.** *Synthesis of coumarin via Wittig reaction.*

**Figure 12.** *Synthesis of 3-benzoyl coumarin through Michael addition approach.*

#### **2.8 Michael addition**

The synthesis of 3-aroylcoumarin **23** could be carried out *via* Michael addition reaction approach from the readily present 2-hydroxybenzaldehyde **20** and αaroylketene dithioacetals **21** in the presence of piperidine and refluxed condition in THF as a solvent. The mechanism of the reaction shows that the reaction proceeds *via* 2 steps, (i) initially *via* Michael addition (ii) aldol condensation (iii) elimination of water and -SCH3 as shown in **Figure 12** [51].

### **2.9 Heck-lactonization reaction**

The Heck-Lactonization reaction can be carried out for the synthesis of coumarin analogues **26** *via* Pd catalysis and were examined different reaction conditions tested using aqueous water and organic solvent conditions. Even with 10 mol% of the PdCl2 or Pd (OAc)2-catalysts showed, enoate **25** interacted with iodo compound **24** to produce coumarin **26** in good to moderate yields under conditions A and B with water. The organic solvent condition C was indicating low chemical yield and the proposed catalytic cycle as shown in **Figure 13** [52].

#### **2.10 Baylis-Hillman reaction**

As seen in **Figure 14**, the Baylis-Hillman approach was used to create substituted coumarins. In the presence of DABCO, 2-hydroxybenzaldehydes **8** reacts with methyl acrylate **27** to produce a combination of chromene **28** and coumarin **29**. Nevertheless, related interactions between 2-hydroxybenzaldehydes and *tert*-butyl acrylate in the presence of conventional or microwave heating led to respective

**Figure 13.** *Synthesis of coumarin via Heck-lactonization reaction.*

Baylis-Hillman adducts, that further undergoes cyclization *via* reflux in AcOH to produce a combination of both 3-substituted chromene and coumarin. Decent quantities of 3-(chloromethyl) coumarins **33** are obtained by treating the Baylis-Hillman adducts **30** and strong acid HCl when refluxed in AcOH. Additionally, 3-methyl coumarins **31** are produced by the reaction of compound **30** with HI under reflux in a solution of Ac2O and AcOH, and these 3-formyl coumarins **32** are produced by a subsequent reaction with SeO2. The plausible mechanism of the reaction has been shown in the **Figure 14** [53].
