**Figure 6.**

*Synthesis of 3-substituted coumarins.*

**Figure 7.** *Synthesis of coumarin 3-carboxylic acid derivatives.*

#### *One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Phytochemicals in Human Health*

(**Figure 7**) [82].

nano-ZnO catalyst under microwave or thermal conditions, which affords moderate to good yield of the products (**Figure 6**) [81]. Reactions under microwave-irradia-

Various coumarin-3-carboxylic acid derivatives **25/26** have been synthesized in good yields using catalytic amounts of SnCl2.2H2O under solvent-free condition

Ultrasound irradiation technique is also useful to synthesize 3-aryl coumarin derivatives. Treatment of *o*-hydroxybenzaldehydes **18** with aryl substituted acetyl chloride **27** in the presence of K2CO3 as a catalyst in tetrahydrofuran (THF) using ultrasound irradiation leads to the formation of 3-aryl coumarin derivatives **28** in moderate to high yields (**Figure 8**) [83]. This green method appears to be a conve-

Coumarin-substituted benzimidazole or benzoxazole derivatives **32** that are known as coumarin dyes have been synthesized in good yields from 4-diethylamino-2-hydroxybenzaldehyde **29**, ethyl cyanoacetate **30**, and ortho-phenylenediamine/phenylenehydroxyamine derivatives **31** in the presence of reusable green solid acid like HZSM-5 zeolite, heteropoly acids, e.g., tungstophosphoric acid (H3PW12O40), and/or tungstosilicic acid (H4O40SiW12) in *n*-pentanol or water and

Cellulose sulfonic acid (CSA) is an efficient catalyst for the synthesis of 3 substituted coumarin via Knoevenagel condensation reaction. Thus, 3-acetyl coumarin **34** is obtained in 88% yield in the reaction between salicylaldehyde **33** and ethyl acetoacetate **7** in the presence of CSA under solvent-free conditions (**Figure 10**) [85].

tion conditions are found to be more convenient than thermal conditions.

nient and simple pathway than that of conventional heating.

even solvent-free conditions (**Figure 9**) [84].

**112**

**Figure 7.**

**Figure 6.**

*Synthesis of 3-substituted coumarins.*

*Synthesis of coumarin 3-carboxylic acid derivatives.*

Shaabani et al. [86] have described the synthesis of 3-substituted coumarins **21** in good yields via Knoevenagel condensation of 2-hydroxybenzaldehydes **18** with β-dicarbonyl compounds **35** in the presence of a recyclable ionic liquid 1,1,3,3-*N*,*N*,*N*′,*N*′-tetramethylguanidinium trifluoroacetate (TMGT) under thermal heating (**Figure 11**, Condition A) and/or microwave irradiation conditions (**Figure 11**, Condition B). 3-Substituted coumarins **21** are also synthesized from similar starting precursors using the 1,3-dimethylimidazolium methyl sulfate [MMIm][MSO4] ionic liquid in the presence of L-proline as an additional promoter under heating condition (**Figure 11**, Condition C) [87].

Imidazolium based phosphinite ionic liquid (IL-OPPh2) catalyzed synthesis of 3-substituted coumarin derivatives has been reported in literature; when *o*-hydroxy benzaldehydes **18** are treated with active methylene containing compounds **35** in the presence of IL-OPPh2 catalyst at 60°C, 3-substituted coumarin derivatives are obtained in moderate to good yields (**Figure 12**) [88]. TSIL plays both the reaction media and catalyst as well.

Reactions of *o*-hydroxybenzaldehydes **18** with activated methylene compounds **35** catalyzed by Bronsted acid ionic liquid (BAIL) and 1-(4-sulfonic acid)butyl-3-methylimidazolium hydrogen sulfate [(CH2)4SO3HMIM][HSO4] in water lead to 3-substituted coumarin derivatives in good yields (**Figure 13**) [89].

Synthesis of substituted coumarins via Knoevenagel condensation using various organic catalysts such as piperidine, ammonia, L-lysine, L-proline, benzoic acid, etc. has been reported in literature and some are summarized in **Table 2**.

**Figure 8.** *Synthesis of 3-aryl coumarin derivatives.*

**Figure 9.** *Synthesis of coumarin-substituted benzimidazoles/benzoxazoles.*

**Figure 10.** *Synthesis of 3-acetyl coumarin.*

#### *Phytochemicals in Human Health*

It is quite evident that in **Table 2** several methodologies for the synthesis of substituted coumarins using different organic catalysts are established. Among these, L-proline-catalyzed reactions offer high yields (entry 3), which explains synthesis of 3-substituted coumarins by the condensation of *o*-hydroxybenzaldehydes with a variety of active methylene compounds catalyzed by 1,3-dimethyl imidazolium methyl sulfate [MMIm][MSO4] and L-proline. Another L-prolinecatalyzed synthesis of coumarins is known, but in that case, the yield is very poor (entry 4). Similar result is also observed under L-lysine-catalyzed synthesis of coumarins (entry 5).

A series of 3-phenyl substituted coumarin analogues have been achieved via a two-step process involving esterification using 1,1-carbonyldiimidazole (CDI) followed by condensation reaction in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under mild conditions (entry 1).

Microwave-assisted synthesis of coumarins is also known, which not only reduces the reaction time but also increases the yields of the products (entries 2, 6, and 7).

Benzocoumarin derivatives have been synthesized from 1-hydroxy-4-methylnaphthalene-2-carbaldehyde and compounds containing active methylene group via piperidine-catalyzed Knoevenagel condensation reaction (entry 8). Moreover, benzothiazolyl coumarins with isothiocyanate functionality have been synthesized from commercially available 2-hydroxy-4-nitro benzoic acid in the presence of piperidine in ethanol (entry 9).

Application of sonochemistry for the synthesis of different coumarin derivatives is also useful due to better yield and shorter reaction time compared with the classical procedures (entry 10).

#### **Figure 11.** *Synthesis of 3-substituted coumarins.*

**115**

**Table 2.**

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

**Figure 13.**

*Synthesis of 3-substituted coumarins.*

**Entry Catalyst Reaction conditions Time Yield** 

(ii) DBU (1.0 equiv.), DCM, rt

Condition B: H2SO4, Benzoic acid,

sulfate, [MMIm][MSO4], L-proline

4 L-proline L-proline (20 mmol%), EtOH, rt 15–20 h 54–76 [92] 5 L-lysine L-lysine (20 mol%), H2O, rt. −80°C 6–24 h 50–90 [93] 6 Piperidine Piperidine (catalytic), rt. 20 min 84 [94]

9 Piperidine Piperidine (catalytic), EtOH, reflux 2 h 82 [97]

11 Piperidine Piperidine, EtOH, rt-reflux 1–2 h 82–92 [99] 12 Piperidine Piperidine (7.4 equiv.), EtOH, reflux 2 h 92 [100]

MW (900 W), 100°C

MW (900 W), 90°C Condition C: benzoic acid, *n*-pentanol, MW (900°C), 110°C

1 CDI-DBU (i) CDI (1.2 equiv.), DCM, rt.

2 PhCOOH Condition A: Polyphosphoric acid,

3 L-proline 1,3-dimethyl imidazolium methyl

7 Piperidine Piperidine (2.0 mol%), solvent-

8 Piperidine Piperidine (1.48 equiv.), EtOH, reflux

10 Piperidine Piperidine (1.0 equiv.), AcOH

(1 equiv.), 90°C

free, MW (400 W)

(2.5 mol%), EtOH, US, rt

*Synthesis of substituted coumarins via Knoevenagel condensation reactions.*

**(%)**

60–75 58–75 85–95

15–1440 min 87–99 [87]

1 min 50–97 [95]

30 min 85–92 [96]

5–30 min 49–90 [98]

42–59 [90]

30 min 1–2 h

4–6 min 3–4 min 3 min

**Reference**

[91]

**Figure 12.** *Synthesis of 3-substituted coumarins.* *One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

**Figure 13.**

*Phytochemicals in Human Health*

coumarins (entry 5).

7-ene (DBU) under mild conditions (entry 1).

piperidine in ethanol (entry 9).

cal procedures (entry 10).

*Synthesis of 3-substituted coumarins.*

*Synthesis of 3-substituted coumarins.*

It is quite evident that in **Table 2** several methodologies for the synthesis of substituted coumarins using different organic catalysts are established. Among these, L-proline-catalyzed reactions offer high yields (entry 3), which explains synthesis of 3-substituted coumarins by the condensation of *o*-hydroxybenzaldehydes with a variety of active methylene compounds catalyzed by 1,3-dimethyl imidazolium methyl sulfate [MMIm][MSO4] and L-proline. Another L-prolinecatalyzed synthesis of coumarins is known, but in that case, the yield is very poor (entry 4). Similar result is also observed under L-lysine-catalyzed synthesis of

A series of 3-phenyl substituted coumarin analogues have been achieved via a two-step process involving esterification using 1,1-carbonyldiimidazole (CDI) followed by condensation reaction in the presence of 1,8-diazabicyclo[5.4.0]undec-

Microwave-assisted synthesis of coumarins is also known, which not only reduces the reaction time but also increases the yields of the products (entries 2, 6, and 7). Benzocoumarin derivatives have been synthesized from 1-hydroxy-4-methylnaphthalene-2-carbaldehyde and compounds containing active methylene group via piperidine-catalyzed Knoevenagel condensation reaction (entry 8). Moreover, benzothiazolyl coumarins with isothiocyanate functionality have been synthesized from commercially available 2-hydroxy-4-nitro benzoic acid in the presence of

Application of sonochemistry for the synthesis of different coumarin derivatives is also useful due to better yield and shorter reaction time compared with the classi-

**114**

**Figure 12.**

**Figure 11.**

*Synthesis of 3-substituted coumarins.*




**Table 2.**

*Synthesis of substituted coumarins via Knoevenagel condensation reactions.*

6,8-Diiodocoumarin derivatives have also been synthesized in good yields by Knoevenagel condensation using piperidine as catalyst (entry 11). The reaction of 3-ethoxysalicylaldehyde with ethyl acetoacetate in the presence of piperidine leads to 3-acetyl-8-ethoxycoumarin (entry 12).

## **2.3 Baylis-Hillman reaction**

Baylis-Hillman strategy has been employed to the synthesis of substituted coumarins as shown in **Figure 14**. When 2-hydroxybenzaldehydes **18** are subjected to react with methyl acrylate **39a** (R2 = Me) in the presence of DABCO (1,4-Diazabicyclo[2.2.2] octane), a mixture of chromenes **40** and coumarins **41** are formed [101, 102]. However, similar reactions of 2-hydroxybenzaldehydes **18** with tert-butyl acrylate **39b** (R2 = t Bu) under classical method [103] and/or microwave irradiation [104] afford corresponding Baylis-Hillman adducts **42**, which undergo cyclization under reflux in AcOH yielding a mixture of 3-substituted chromene **43** and coumarin **44**. Treatment of the Baylis-Hillman adducts **42** with concentrated HCl in refluxing AcOH produces 3-(chloromethyl) coumarins **45** in excellent yields. Moreover, the reaction of **42** with HI under reflux in a mixture of Ac2O and AcOH furnishes 3-methyl coumarins **46**, which upon further reaction with SeO2 affords the corresponding 3-formyl coumarins **47**.

The suggested mechanism for the formation of the coumarin derivatives **44/45/46** is shown in **Figure 15**.

Kaye et al. have also demonstrated the synthesis of substituted coumarins employing Baylis-Hillman strategy in different ways as shown in **Figure 16** [105, 106].

#### **2.4 Kostanecki reaction**

4-Arylcoumarins **59** have been synthesized in good yields employing Kostanecki reaction between 2-hydroxybenzophenones **57** and acetic anhydride **58** in the presence of DBU under mild condition (**Figure 17**) [107].

The mechanism of the Kostanecki reaction is outlined in **Figure 18**.

Similarly, 3,4-disubstituted coumarins **65** are isolated from readily available 2-acyloxybenzophenones **64** under Kostanecki reaction conditions (**Figure 19**) [107].

#### **2.5 Michael addition reaction**

Michael addition could be applied [108] to the synthesis of 3-aroylcoumarins **68** in good yields from easily available 2-hydroxybenzaldehydes **66** and α-aroylketene dithioacetals (AKDTAs) **67** in the presence of a catalytic amount of piperidine in refluxing THF (**Figure 20**).

The reaction proceeds via initial Michael addition followed by intramolecular aldol condensation reaction as depicted in **Figure 21**.

### **2.6 Wittig reaction**

Kumar and coworkers [109] have reported the synthesis of substituted coumarins **3** from phenolic compounds **23** containing ortho-carbonyl group and triphenyl (α-carboxymethylene)phosphorane imidazole ylide **73** via intramolecular Wittig cyclization in good yields (**Figure 22**). All the reactions proceed via formation of the phosphorane intermediates **74** as established by spectroscopic results.

**117**

**Figure 14.**

**Figure 15.**

*Synthesis of 3-substituted coumarins.*

acetylene-dicarboxylate **75** in the presence of phosphinite ionic liquid (IL-OPPh2) under solvent-free microwave irradiation conditions (**Figure 23**) [110]. It is noticed

The proposed mechanism for the formation of coumarins **76** via vinyl phospho-

4-Carboxymethyl coumarins **82** have been synthesized by Yavari et al. [111] in moderate to excellent yields from the reactions of substituted phenols **1** and dimethyl acetylenedicarboxylate (DMAD) **81** in the presence of triphenylphosphine (**Figure 25**) via vinyl triphenylphosphonium salt-mediated aromatic electrophilic

that the diphenylphosphine group in ionic liquid accelerates the reaction.

nium salt-mediated electrophilic substitution is shown in **Figure 24**.

*Possible mechanism for the formation of 3-substituted coumarins.*

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

#### **2.7 Vinyl phosphonium salt-mediated electrophilic substitution reaction**

A series of 4-carboxy(ethyl/methyl) coumarins **76** have been synthesized in good yields from substituted phenols **1** and di(ethyl/methyl) *One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Phytochemicals in Human Health*

**2.3 Baylis-Hillman reaction**

with methyl acrylate **39a** (R2

**44/45/46** is shown in **Figure 15**.

**2.5 Michael addition reaction**

refluxing THF (**Figure 20**).

**2.6 Wittig reaction**

ence of DBU under mild condition (**Figure 17**) [107].

aldol condensation reaction as depicted in **Figure 21**.

**2.4 Kostanecki reaction**

to 3-acetyl-8-ethoxycoumarin (entry 12).

6,8-Diiodocoumarin derivatives have also been synthesized in good yields by Knoevenagel condensation using piperidine as catalyst (entry 11). The reaction of 3-ethoxysalicylaldehyde with ethyl acetoacetate in the presence of piperidine leads

Baylis-Hillman strategy has been employed to the synthesis of substituted coumarins as shown in **Figure 14**. When 2-hydroxybenzaldehydes **18** are subjected to react

octane), a mixture of chromenes **40** and coumarins **41** are formed [101, 102]. However, similar reactions of 2-hydroxybenzaldehydes **18** with tert-butyl acrylate **39b** (R2

under classical method [103] and/or microwave irradiation [104] afford corresponding Baylis-Hillman adducts **42**, which undergo cyclization under reflux in AcOH yielding a mixture of 3-substituted chromene **43** and coumarin **44**. Treatment of the Baylis-Hillman adducts **42** with concentrated HCl in refluxing AcOH produces 3-(chloromethyl) coumarins **45** in excellent yields. Moreover, the reaction of **42** with HI under reflux in a mixture of Ac2O and AcOH furnishes 3-methyl coumarins **46**, which upon

Kaye et al. have also demonstrated the synthesis of substituted coumarins employ-

4-Arylcoumarins **59** have been synthesized in good yields employing Kostanecki reaction between 2-hydroxybenzophenones **57** and acetic anhydride **58** in the pres-

Michael addition could be applied [108] to the synthesis of 3-aroylcoumarins **68** in good yields from easily available 2-hydroxybenzaldehydes **66** and α-aroylketene dithioacetals (AKDTAs) **67** in the presence of a catalytic amount of piperidine in

The reaction proceeds via initial Michael addition followed by intramolecular

Kumar and coworkers [109] have reported the synthesis of substituted coumarins **3** from phenolic compounds **23** containing ortho-carbonyl group and triphenyl (α-carboxymethylene)phosphorane imidazole ylide **73** via intramolecular Wittig cyclization in good yields (**Figure 22**). All the reactions proceed via formation of

the phosphorane intermediates **74** as established by spectroscopic results.

A series of 4-carboxy(ethyl/methyl) coumarins **76** have been synthesized in good yields from substituted phenols **1** and di(ethyl/methyl)

**2.7 Vinyl phosphonium salt-mediated electrophilic substitution reaction**

further reaction with SeO2 affords the corresponding 3-formyl coumarins **47**. The suggested mechanism for the formation of the coumarin derivatives

ing Baylis-Hillman strategy in different ways as shown in **Figure 16** [105, 106].

The mechanism of the Kostanecki reaction is outlined in **Figure 18**. Similarly, 3,4-disubstituted coumarins **65** are isolated from readily available 2-acyloxybenzophenones **64** under Kostanecki reaction conditions (**Figure 19**) [107].

= Me) in the presence of DABCO (1,4-Diazabicyclo[2.2.2]

 = t Bu)

**116**

**Figure 14.** *Synthesis of 3-substituted coumarins.*

**Figure 15.** *Possible mechanism for the formation of 3-substituted coumarins.*

acetylene-dicarboxylate **75** in the presence of phosphinite ionic liquid (IL-OPPh2) under solvent-free microwave irradiation conditions (**Figure 23**) [110]. It is noticed that the diphenylphosphine group in ionic liquid accelerates the reaction.

The proposed mechanism for the formation of coumarins **76** via vinyl phosphonium salt-mediated electrophilic substitution is shown in **Figure 24**.

4-Carboxymethyl coumarins **82** have been synthesized by Yavari et al. [111] in moderate to excellent yields from the reactions of substituted phenols **1** and dimethyl acetylenedicarboxylate (DMAD) **81** in the presence of triphenylphosphine (**Figure 25**) via vinyl triphenylphosphonium salt-mediated aromatic electrophilic

**Figure 16.** *Synthesis of 3-substituted coumarins.*

**Figure 17.** *Synthesis of 4-arylcoumarins.*

**Figure 18.** *Mechanism for Kostanecki reaction.*

substitution reaction as mentioned in **Figure 24**. Similar results are found from the given starting materials under microwave irradiation in shorter reaction time [112].

However, reactions of di- and trihydric phenols with dimethyl acetylenedicarboxylate (DMAD) in the presence of triphenylphosphine in toluene under reflux afford polyfunctionalized coumarin analogues along with unwanted by-products in appreciable amount (**Figure 26**) [113].

**119**

**Figure 21.**

Similar reactions of 2-hydroxybenzaldehydes **18** with di(ethyl/methyl)acetylenedicarboxylates **75** leads to the corresponding 4-carboxy(ethyl/methyl)-8-formyl

The methodology has also been employed to the synthesis of angular pyridocoumarins **97**/**98** and benzo-fused 6-azacoumarin **100** as shown in **Figure 28** [115].

coumarins **93** in moderate to good yields (**Figure 27**) [114].

*Probable mechanism for the formation of 3-aroylcoumarins.*

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Synthesis of 3,4-disubstituted coumarins.*

**Figure 19.**

**Figure 20.**

*Synthesis of 3-aroylcoumarins.*

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

#### **Figure 19.**

*Phytochemicals in Human Health*

**118**

**Figure 18.**

**Figure 16.**

**Figure 17.**

*Synthesis of 4-arylcoumarins.*

*Synthesis of 3-substituted coumarins.*

*Mechanism for Kostanecki reaction.*

appreciable amount (**Figure 26**) [113].

substitution reaction as mentioned in **Figure 24**. Similar results are found from the given starting materials under microwave irradiation in shorter reaction time [112]. However, reactions of di- and trihydric phenols with dimethyl acetylenedicarboxylate (DMAD) in the presence of triphenylphosphine in toluene under reflux afford polyfunctionalized coumarin analogues along with unwanted by-products in *Synthesis of 3,4-disubstituted coumarins.*

#### **Figure 20.** *Synthesis of 3-aroylcoumarins.*

#### **Figure 21.**

*Probable mechanism for the formation of 3-aroylcoumarins.*

Similar reactions of 2-hydroxybenzaldehydes **18** with di(ethyl/methyl)acetylenedicarboxylates **75** leads to the corresponding 4-carboxy(ethyl/methyl)-8-formyl coumarins **93** in moderate to good yields (**Figure 27**) [114].

The methodology has also been employed to the synthesis of angular pyridocoumarins **97**/**98** and benzo-fused 6-azacoumarin **100** as shown in **Figure 28** [115].

#### **Figure 22.**

*Synthesis of substituted coumarins.*

**Figure 23.** *Synthesis of 4-carboxy(ethyl/methyl) coumarins.*

#### **Figure 24.**

*Proposed mechanism for the synthesis of substituted coumarins via vinyl phosphonium salt-mediated electrophilic substitution.*

#### **2.8 Palladium-catalyzed reactions**

Palladium-catalyzed reactions between substituted phenols **101** and ethyl propiolates **102** lead to substituted coumarins **103/104** (**Figure 29**) [116, 117].

Unsymmetrical monohydric phenols having *m*-OMe or *m*-Me substituent as respectively in 3-methoxyphenol and *m*-cresol show regioselectivity toward the

**121**

**Figure 26.**

**Figure 27.**

*Synthesis of polyfunctionalized coumarin analogues.*

*Synthesis of 4-carboxy(ethyl/methyl)-8-formyl coumarins.*

formation of a new bond in coumarins, which occurs at the *para* position to the methoxy group, and therefore, the regioisomers **103** are found to be formed predominantly over **104**. However, symmetrical dihydric phenol with OMe substituent like that in 5-methoxybenzene-1,3-diol affords the regioisomer **104** predominantly over **103** under the reaction condition applied. This may be due to the steric effects

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Synthesis of 4-carboxymethyl coumarins.*

**Figure 25.**

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Phytochemicals in Human Health*

**Figure 22.**

**Figure 23.**

*Synthesis of substituted coumarins.*

**120**

**Figure 24.**

*electrophilic substitution.*

**2.8 Palladium-catalyzed reactions**

*Synthesis of 4-carboxy(ethyl/methyl) coumarins.*

Palladium-catalyzed reactions between substituted phenols **101** and ethyl propiolates **102** lead to substituted coumarins **103/104** (**Figure 29**) [116, 117]. Unsymmetrical monohydric phenols having *m*-OMe or *m*-Me substituent as respectively in 3-methoxyphenol and *m*-cresol show regioselectivity toward the

*Proposed mechanism for the synthesis of substituted coumarins via vinyl phosphonium salt-mediated* 

**Figure 25.** *Synthesis of 4-carboxymethyl coumarins.*

**Figure 26.** *Synthesis of polyfunctionalized coumarin analogues.*

#### **Figure 27.**

*Synthesis of 4-carboxy(ethyl/methyl)-8-formyl coumarins.*

formation of a new bond in coumarins, which occurs at the *para* position to the methoxy group, and therefore, the regioisomers **103** are found to be formed predominantly over **104**. However, symmetrical dihydric phenol with OMe substituent like that in 5-methoxybenzene-1,3-diol affords the regioisomer **104** predominantly over **103** under the reaction condition applied. This may be due to the steric effects

#### **Figure 28.** *Synthesis of pyridocoumarins and benzo-fused azacoumarin.*

**Figure 29.** *Synthesis of substituted coumarins.*

of the R4 group of ethyl propiolate **102**, which dominates over the electronic effect of the methoxy group of the phenol.

A proposed mechanism for the formation of coumarins **103/104** is shown in **Figure 30**.

Substituted coumarins **3** have been synthesized in moderate yields (42–69%) via Pd(OAc)2-catalyzed reaction of substituted phenols **1** with substituted propiolic acid **110** (R3 = CO2H) in TFA under mild conditions (**Figure 31**, Condition A) [118]. However, a mixture of catalysts FeCl3 and AgOTf showed better catalytic efficiency toward yields (60–93%) of coumarin derivatives **3** (**Figure 31**, Condition B). Propiolic acid ester **110** (R3 = CO2Et) also furnishes the desired products **3** upon

**123**

bulky t

**Figure 31.**

*Synthesis of substituted coumarins.*

**Figure 30.**

reactions with substituted phenols **1** under specified conditions as provided in

4,6-Disubstituted coumarins **113** have been achieved employing palladiumcatalyzed tandem Heck-lactonization of the *Z*- or *E*-enoates **112** with *o*-iodophenols

For Heck-lactonization, the enoate *Z*-**112a** is found to be more reactive than its *E*-isomer, leading to the corresponding coumarin **113** in good yields (68–84%) under all reaction conditions studied. The enoate *Z*-**112b** leads to coumarin derivative **113** in relatively lower yields (42–56%), which may be due to the presence of the

Bu ester group that hampers the lactonization step. Moreover, the reactiv-

= CH2CHMe2,

**Figure 31** (Conditions C and D) [119–121].

*Possible mechanism for Pd-catalyzed synthesis of coumarins.*

**111** (**Figure 32**, Conditions A, B, and C) [122, 123].

ity of *E*-enoates depends on the β-substituent. *E*-enoates **112c** (R2

*One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013* *One-Pot Synthesis of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89013*

*Phytochemicals in Human Health*

**122**

of the R4

**Figure 29.**

**Figure 28.**

**Figure 30**.

acid **110** (R3

of the methoxy group of the phenol.

*Synthesis of pyridocoumarins and benzo-fused azacoumarin.*

Propiolic acid ester **110** (R3

*Synthesis of substituted coumarins.*

group of ethyl propiolate **102**, which dominates over the electronic effect

= CO2H) in TFA under mild conditions (**Figure 31**, Condition A) [118].

= CO2Et) also furnishes the desired products **3** upon

A proposed mechanism for the formation of coumarins **103/104** is shown in

Substituted coumarins **3** have been synthesized in moderate yields (42–69%) via Pd(OAc)2-catalyzed reaction of substituted phenols **1** with substituted propiolic

However, a mixture of catalysts FeCl3 and AgOTf showed better catalytic efficiency toward yields (60–93%) of coumarin derivatives **3** (**Figure 31**, Condition B).

**Figure 30.** *Possible mechanism for Pd-catalyzed synthesis of coumarins.*

**Figure 31.** *Synthesis of substituted coumarins.*

reactions with substituted phenols **1** under specified conditions as provided in **Figure 31** (Conditions C and D) [119–121].

4,6-Disubstituted coumarins **113** have been achieved employing palladiumcatalyzed tandem Heck-lactonization of the *Z*- or *E*-enoates **112** with *o*-iodophenols **111** (**Figure 32**, Conditions A, B, and C) [122, 123].

For Heck-lactonization, the enoate *Z*-**112a** is found to be more reactive than its *E*-isomer, leading to the corresponding coumarin **113** in good yields (68–84%) under all reaction conditions studied. The enoate *Z*-**112b** leads to coumarin derivative **113** in relatively lower yields (42–56%), which may be due to the presence of the bulky t Bu ester group that hampers the lactonization step. Moreover, the reactivity of *E*-enoates depends on the β-substituent. *E*-enoates **112c** (R2 = CH2CHMe2,
