**2. Methods to synthesize coumarin derivatives**

#### **2.1 Pechmann condensation reaction**

The general reaction sequence of Pechmann reaction and its mechanism, shown in **Figure 1**, involves an esterification/transesterification between the phenol **1** and β-keto ester **2** in the presence of protonic acid or Lewis acid (LA) catalyst to produce species **4** followed by an attack to the activated carbonyl carbon by the aromatic ring at ortho-position to yield the new ring in species **5**. Finally, dehydration of species **5** affords coumarin derivative **2**.

A series of substituted coumarins **8** have been synthesized in 25–77% yields by the reactions of substituted phenols **6** with ethyl acetoacetate **7** in the presence of zinc-iodine mixture in refluxing toluene (**Figure 2**) [36]. It is observed that phenols containing electron-donating substituent like ▬CH3 group result in higher yields compared to unsubstituted phenols and phenols having electron-withdrawing group such as NO2 group.

When 3-(*N,N*-dimethylamino)phenol **9** is subjected to react with ethyl 2-acetamide-3-oxobutyrate **10** in the presence of anhydrous ZnCl2 in absolute ethanol under reflux condition, the acetamido coumarin **11** is obtained only in 12.4% yield (**Figure 3**) [30].

Substituted coumarins **14** have been achieved in moderate to good yields from substituted phenols **12** and methyl acetoacetate **13** under conventional and microwave heating, respectively, catalyzed by concentrated H2SO4 (**Figure 4**) [37]. It is found that the reactions using the latter method are faster coupled with product in better yields compared to former one.

Synthesis of substituted coumarins **16** in 62–98% yields has also been described by Maheswara et al. [38] via reactions of substituted phenols **1** with β-keto esters **15** in the presence of a heterogeneous catalyst, HClO4.SiO2 under solvent-free conditions (**Figure 5**, Condition A). The aforementioned method involves recoverable cheap catalyst and shorter reaction time with high product yields. However, relatively lower yields (35–55%) of substituted coumarins **16** have been isolated from the similar starting precursors catalyzed by Amberlyst-15 acidic catalyst [39] in toluene under refluxing condition (**Figure 5**, Condition B).

Pechmann condensation reactions for the synthesis of substituted coumarins using various homogeneous and heterogeneous catalysts have been reported in literature and some important ones are summarized in **Table 1**.

**107**

From **Table 1**, it is quite evident that the reactions under microwave as well as ultrasound irradiation occur at a faster rate than those of the conventional methods (entries 10, 14, 15, 16, 25, 31, 32, and 39). Unsubstituted phenol produces lower yields of corresponding coumarin derivatives and/or requires longer reaction time (entries 2–4, 7, 10, 12, 13, 24, 28, 30, and 38), higher temperature (entries 2, 3, 7, and 12), and excess amount of catalysts (entries 7 and 12) than di- and trihydric phenols. This may presumably be due to the less reactivity of unsubstituted phenol toward Pechmann condensation reaction compared to di- and trihydric phenols. In

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

**Figure 2.**

**Figure 3.**

**Figure 4.**

**Figure 5.**

*Synthesis of substituted coumarins.*

*Synthesis of acetamido coumarin.*

*Synthesis of substituted coumarins.*

*Synthesis of substituted coumarins.*

**Figure 1.** *Mechanism for the acid-catalyzed Pechmann condensation.*

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

**Figure 2.**

*Phytochemicals in Human Health*

**2.1 Pechmann condensation reaction**

species **5** affords coumarin derivative **2**.

better yields compared to former one.

toluene under refluxing condition (**Figure 5**, Condition B).

*Mechanism for the acid-catalyzed Pechmann condensation.*

literature and some important ones are summarized in **Table 1**.

group such as NO2 group.

**2. Methods to synthesize coumarin derivatives**

The general reaction sequence of Pechmann reaction and its mechanism, shown in **Figure 1**, involves an esterification/transesterification between the phenol **1** and β-keto ester **2** in the presence of protonic acid or Lewis acid (LA) catalyst to produce species **4** followed by an attack to the activated carbonyl carbon by the aromatic ring at ortho-position to yield the new ring in species **5**. Finally, dehydration of

A series of substituted coumarins **8** have been synthesized in 25–77% yields by the reactions of substituted phenols **6** with ethyl acetoacetate **7** in the presence of zinc-iodine mixture in refluxing toluene (**Figure 2**) [36]. It is observed that phenols containing electron-donating substituent like ▬CH3 group result in higher yields compared to unsubstituted phenols and phenols having electron-withdrawing

When 3-(*N,N*-dimethylamino)phenol **9** is subjected to react with ethyl 2-acetamide-3-oxobutyrate **10** in the presence of anhydrous ZnCl2 in absolute ethanol under reflux condition, the acetamido coumarin **11** is obtained only in 12.4% yield (**Figure 3**) [30]. Substituted coumarins **14** have been achieved in moderate to good yields from substituted phenols **12** and methyl acetoacetate **13** under conventional and microwave heating, respectively, catalyzed by concentrated H2SO4 (**Figure 4**) [37]. It is found that the reactions using the latter method are faster coupled with product in

Synthesis of substituted coumarins **16** in 62–98% yields has also been described by Maheswara et al. [38] via reactions of substituted phenols **1** with β-keto esters **15** in the presence of a heterogeneous catalyst, HClO4.SiO2 under solvent-free conditions (**Figure 5**, Condition A). The aforementioned method involves recoverable cheap catalyst and shorter reaction time with high product yields. However, relatively lower yields (35–55%) of substituted coumarins **16** have been isolated from the similar starting precursors catalyzed by Amberlyst-15 acidic catalyst [39] in

Pechmann condensation reactions for the synthesis of substituted coumarins using various homogeneous and heterogeneous catalysts have been reported in

**106**

**Figure 1.**

*Synthesis of substituted coumarins.*

**Figure 3.** *Synthesis of acetamido coumarin.*

**Figure 4.** *Synthesis of substituted coumarins.*

**Figure 5.** *Synthesis of substituted coumarins.*

From **Table 1**, it is quite evident that the reactions under microwave as well as ultrasound irradiation occur at a faster rate than those of the conventional methods (entries 10, 14, 15, 16, 25, 31, 32, and 39). Unsubstituted phenol produces lower yields of corresponding coumarin derivatives and/or requires longer reaction time (entries 2–4, 7, 10, 12, 13, 24, 28, 30, and 38), higher temperature (entries 2, 3, 7, and 12), and excess amount of catalysts (entries 7 and 12) than di- and trihydric phenols. This may presumably be due to the less reactivity of unsubstituted phenol toward Pechmann condensation reaction compared to di- and trihydric phenols. In

addition, the substitution of an electron-donating group such as *m/p*-Me or *p*-OMe in the phenols leads to decrease of catalytic activity and, hence, requires longer reaction time and/or gives rise to lower yields of products (entry 13). The reactivity of monohydric phenols having electron-withdrawing groups such as *m*-NH2 and *m*-OMe is also lowered compared with simple di- and trihydric phenols (entries 19, 28, and 37). 1-Naphthol and 2-naphthol need longer reaction time (entries 13, 33, and 39) and/or furnish products with lower yields (entries 13, 37, and 40) compared to other phenols, due to the presence of another phenyl ring. However, better yield of benzocoumarin is obtained from the reaction between 1-naphthol and more reactive β-keto ester, ethyl 4-chloro-3-oxobutanoate (entry 37). It is interesting to note that β-keto ester having phenyl group at the β-position such as ethyl 3-oxo-3-phenylpropanoate is found to be less reactive in Pechmann condensation with resorcinol and 1,3-dihydroxy-5-methyl benzene due to the presence of conjugated keto center, which lengthens the reaction time than in the reactions of EAA and/or ethyl 4-chloro-3-oxobutanoate with resorcinol and 1,3-dihydroxy-5-methyl benzene (entries 21, 28, and 37). Besides, the reactivity of different types of phenols and β-keto esters, catalyst efficiency, and solvent effect of Pechmann condensation has also been studied. It is observed that TiCl4 (entry 5) is the most effective catalyst as far as reaction time is considered, whereas montmorillonite K-10 (entry 1) and sulfated zirconia (SZr) (entry 9) are found to be less effective. Ionic liquids (ILs) such as 1-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF6 and 1,3-disulfonic acid imidazolium hydrogen sulfate (DSIMHS) have been used as effective and reusable catalysts and reaction media as well (entries 6 and 18).

Lewis acid−surfactant-combined catalyst (LASC) such as nano-TiO2 on dodecyl-sulfated silica support (NTDSS) is used as a reusable and highly effective catalyst for Pechmann condensation of phenols containing different types of substituents in water led to excellent product yields (entry 20). Other recyclable solid acid catalysts have also been employed in Pechmann condensation reactions leading to coumarin derivatives in good to excellent yields under solvent-free (entries 22–24, 26–27, 29–30, and 42), microwave irradiation (entry 25) and/or ultrasound irradiation (entry 39) conditions.

More importantly, sulfonic acid-supported silica-coated magnetic nanoparticles (Fe3O4@SiO2@PrSO3H), CuFe2O4 nanoparticles, and zirconium(IV) complex grafted silica coated magnetic nanoparticles are found to be the most efficient catalysts toward Pechmann condensation, in which case the catalyst can be effortlessly separated by external magnet after completion of the reaction and reused for 22, 6, and 5 consecutive runs, without any significant loss in catalytic efficiency (entries 33–35).

Pechmann condensation of pyrogallol and resorcinol with ethyl acetoacetate over nanosponge MFI zeolite in comparison with conventional zeolites (MFI, BEA, and USY) and other layered MFI (lamellar, pillared, and self-pillared) have been investigated. It is important to note that the nanosponge catalysts exhibit the best catalytic performance with respect to the products' selectivity in the liquid-phase condensation reactions among all the investigated zeolites (entry 36).

On the other hand, the catalytic behavior of metal–organic frameworks such as Cu-benzene-1,3,5-tricarboxylate (CuBTC) and Fe-benzene-1,3,5-tricarboxylate (FeBTC) is investigated and compared with large-pore zeolites, beta (BEA), and ultrastable Y (USY) (entry 41). It is clear that zeolites BEA and USY are found to be more active catalysts in transformations of the most active substrates like resorcinol and pyrogallol but a low conversion of naphthol is observed. However, almost total transformation of naphthol (93–98% conversion) to the target product occurs within 23 h of the reaction time over metal–organic frameworks, CuBTC and FeBTC.

**109**

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

1 Montmorillonite K-10 K-10 (30 wt% of **12**),

3 InCl3 InCl3 (10 mol%),

5 TiCl4 TiCl4 (0.5 equiv. of

7 Bi(NO3).5H2O Bi(NO3).5H2O

<sup>2</sup><sup>−</sup>/CeO2-ZrO2 SO4

11 ClSO3H ClSO3H (0.2 ml),

12 LiBr LiBr (10–20 mol%),

14 Cu(ClO4)2 Cu(ClO4)2 (20 mol%),

15 Selectfluor Condition A: Selectfluor

2 1-Butyl-3-

6 1-Butyl-3-

8 SO4

methylimidazolium chloroaluminate [bmim]

methylimidazolium hexafluorophosphate [bmim]PF6

10 Ceric ammonium nitrate (CAN)

13 Nanocrystalline-cellulosesupported sulfonic acid

ionic liquid

Cl. 2AlCl3

**Entry Catalyst Reaction conditions Time Yields (%) Reference**

8–10 h 66–94 [40]

10–120 min 40–95 [41]

30–240 min 65–98 [42]

50–70 s 56–95 [32]

45 min 90–95 [43]

15–300 min 47–94 [44]

4–143 min 80–94 [45]

92–96 94–97

10 min 91–98 [48]

15–90 min 54–92 [1]

18 min-24 h 20–98 [49]

30–50 min 70–96 [50]

70–79 82–94 [47]

[51]

10–15 min 2–3 min

85–90 min 15–40 min

toluene, reflux

65–130°C

**12**), rt

[bmim]Cl.2AlCl3 (1.1 equiv. of **12**), 30–120°C

4 ZrCl4 ZrCl4 (2 mol%), 70°C 5–30 min 56–95 [31]

[bmim]PF6 (4 ml), solvent-free, 100°C

(5–10 mol%), 80–130°C

9 SZr (sulfated zirconia) SZr (1 wt% of **12**), 80°C 24 h 52–92 [46]

<sup>2</sup><sup>−</sup>/CeO2-ZrO2 (10 wt% of **12**), 120°C

Condition A: CAN (10 mol%), solventfree, 110°C Condition B: CAN (10 mol%), solventfree, MW (300 W)

solvent-free, 10°C

solvent-free, US (35 kHz), 45–50°C

(10 mol%), solvent-

Condition B: Selectfluor (10 mol%), solvent-free, US (30 kHz, 780 W)

free, rt.

NCC-supported sulfonic acid IL (10 wt% of **12**), solvent-free, 80°C

75–125°C

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

*Phytochemicals in Human Health*

media as well (entries 6 and 18).

irradiation (entry 39) conditions.

efficiency (entries 33–35).

addition, the substitution of an electron-donating group such as *m/p*-Me or *p*-OMe in the phenols leads to decrease of catalytic activity and, hence, requires longer reaction time and/or gives rise to lower yields of products (entry 13). The reactivity of monohydric phenols having electron-withdrawing groups such as *m*-NH2 and *m*-OMe is also lowered compared with simple di- and trihydric phenols (entries 19, 28, and 37). 1-Naphthol and 2-naphthol need longer reaction time (entries 13, 33, and 39) and/or furnish products with lower yields (entries 13, 37, and 40) compared to other phenols, due to the presence of another phenyl ring. However, better yield of benzocoumarin is obtained from the reaction between 1-naphthol and more reactive β-keto ester, ethyl 4-chloro-3-oxobutanoate (entry 37). It is interesting to note that β-keto ester having phenyl group at the β-position such as ethyl 3-oxo-3-phenylpropanoate is found to be less reactive in Pechmann condensation with resorcinol and 1,3-dihydroxy-5-methyl benzene due to the presence of conjugated keto center, which lengthens the reaction time than in the reactions of EAA and/or ethyl 4-chloro-3-oxobutanoate with resorcinol and 1,3-dihydroxy-5-methyl benzene (entries 21, 28, and 37). Besides, the reactivity of different types of phenols and β-keto esters, catalyst efficiency, and solvent effect of Pechmann condensation has also been studied. It is observed that TiCl4 (entry 5) is the most effective catalyst as far as reaction time is considered, whereas montmorillonite K-10 (entry 1) and sulfated zirconia (SZr) (entry 9) are found to be less effective. Ionic liquids (ILs) such as 1-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF6 and 1,3-disulfonic acid imidazolium hydrogen sulfate (DSIMHS) have been used as effective and reusable catalysts and reaction

Lewis acid−surfactant-combined catalyst (LASC) such as nano-TiO2 on dodecyl-sulfated silica support (NTDSS) is used as a reusable and highly effective catalyst for Pechmann condensation of phenols containing different types of substituents in water led to excellent product yields (entry 20). Other recyclable solid acid catalysts have also been employed in Pechmann condensation reactions leading to coumarin derivatives in good to excellent yields under solvent-free (entries 22–24, 26–27, 29–30, and 42), microwave irradiation (entry 25) and/or ultrasound

More importantly, sulfonic acid-supported silica-coated magnetic nanopar-

Pechmann condensation of pyrogallol and resorcinol with ethyl acetoacetate over nanosponge MFI zeolite in comparison with conventional zeolites (MFI, BEA, and USY) and other layered MFI (lamellar, pillared, and self-pillared) have been investigated. It is important to note that the nanosponge catalysts exhibit the best catalytic performance with respect to the products' selectivity in the liquid-phase

On the other hand, the catalytic behavior of metal–organic frameworks such as Cu-benzene-1,3,5-tricarboxylate (CuBTC) and Fe-benzene-1,3,5-tricarboxylate (FeBTC) is investigated and compared with large-pore zeolites, beta (BEA), and ultrastable Y (USY) (entry 41). It is clear that zeolites BEA and USY are found to be more active catalysts in transformations of the most active substrates like resorcinol and pyrogallol but a low conversion of naphthol is observed. However, almost total transformation of naphthol (93–98% conversion) to the target product occurs within 23 h of the reaction time over metal–organic frameworks, CuBTC and FeBTC.

ticles (Fe3O4@SiO2@PrSO3H), CuFe2O4 nanoparticles, and zirconium(IV) complex grafted silica coated magnetic nanoparticles are found to be the most efficient catalysts toward Pechmann condensation, in which case the catalyst can be effortlessly separated by external magnet after completion of the reaction and reused for 22, 6, and 5 consecutive runs, without any significant loss in catalytic

condensation reactions among all the investigated zeolites (entry 36).

**108**



**111**

**Table 1.**

Catalytic activity of many other catalysts under different reaction conditions is

An efficient green one-pot synthetic method for the synthesis of 3-substituted coumarin derivatives **21/22** has been observed by Knoevenagel condensation of various *o*-hydroxybenzaldehydes **18/19** with 1,3-dicarbonyl compounds **20** using

delineated in the recently published review [80].

*Synthesis of substituted coumarins via Pechmann condensation reactions.*

**2.2 Knoevenagel condensation reaction**

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

33 Sulfonic acid supported silica coated magnetic nanoparticles (Fe3O4@ SiO2@PrSO3H)

35 Zr(IV)-HMNQ@

36 MFI nanosponge zeolite (MFI-NSZ)

39 Poly(4-vinylpyridinium) hydrogen sulfate (PVPHS)

40 Polyvinylpolypyrrolidonebound boron trifluoride

(PVPP-BF3)

41 Zeolites e.g., beta (BEA) and ultrastable Y (USY) Metal–organic

> frameworks (MOFs) such as Cu-benzene-1,3,5 tricarboxylate (CuBTC) and Fe-benzene-1,3,5 tricarboxylate (FeBTC)

42 Zn0.925Ti0.075O NPs Zn0.925Ti0.075O

ASMPs [Zirconium(IV)- 3-hydroxy-2-methyl-1,4-naphthoquinone (HMNQ )@3 aminopropylated silica coated magnetic nanoparticles (ASMPs)]

32 FeCl3 FeCl3 (10 mol%),

34 CuFe2O4 nanoparticles CuFe2O4 (5 mol%),

37 In(OTf)3 In(OTf)3 (1 mol%),

38 Mg(NTf2)2 Mg(NTf2)2 (1 mol%),

solvent-free, US (20 kHz, 130 W)

H2O, rt

Zr(IV)-HMNQ@ ASMPs (20 mg), solvent-free, 110°C

MFI-NSZ (0.1 g), dodecane (0.5 g, internal standard), nitrobenzene, 120–150°C

solvent-free, 80°C

solvent-free, 80°C

PVPHS (2 mol%), solvent-free, US (35 kHz, 200 W)

PVPP-BF3 (33 mol%), ethanol, reflux

Condition A: Zeolite (0.2 g), nitrobenzene,

Condition B: MOF (0.2 g), nitrobenzene,

(10 mol%), solventfree, 110°C

130°C

130°C

Fe3O4@SiO2@PrSO3H (1.6 mol%), solventfree, 130°C

**Entry Catalyst Reaction conditions Time Yields (%) Reference**

1–20 min 55–99 [69]

3–50 min 87–98 [70]

15–34 min 82–98 [71]

(selectivity)

(selectivity)

10–87 min 68–98 [74]

25–60 min 85–98 [75]

3–18 min 62–96 [76]

2–3 h 76–96 [77]

23–91 (conversion) 2–98 (conversion)

3–5 h 51–89 [79]

23 h 23 h [72]

[73]

[78]

10 min 95–100

70 h 80–90

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

*Phytochemicals in Human Health*

18 1,3-Disulfonic acid

[HSO4])

(NTDSS)

20 Nano-TiO2 on dodecylsulfated silica support

22 Polydivinylbene-bound perfluoroalkylsulfonyl imide polymers (H-PDVB-*x*-SSFAI)

23 Polyaniline–fluoroboric acid–dodecyl hydrogen sulfate (PANI–HBF4–DHS)

25 ZrPW (Zirconium IV Phosphotungstate) 12-TPA/ZrO2 (12-Tungstophosphoric acid supported onto ZrO2)

26 12-Tungstophosphoric acid supported on SnO2 nanoparticles (12-TPA-SnO2)

27 Poly(4-vinylpyridine) supported copper iodide

28 Polystyrene-supported GaCl3 (PS–GaCl3)

30 CMK-5 supported sulfonic acid (CMK-5-SO3H)

19 *N,N*′-

imidazolium hydrogen sulfate (DSIMHS)

dimethylaminoethanol hydrosulfate ([N112OH]

16 I2 Condition A: I2

17 AgOTf AgOTf (10 mol%),

21 ZrOCl2.8H2O/SiO2 ZrOCl2.8H2O/SiO2

24 Silica sulfuric acid (SSA) SSA (15 mol%), solvent-

29 Silica tungstic acid (STA) STA (5 mol%), solvent-

31 FeF3 FeF3 (0.05 g), solvent-

(25 mol%), toluene,

**Entry Catalyst Reaction conditions Time Yields (%) Reference**

solvent-free, 60°C

[N112OH][HSO4] (5 mol%), solvent-free,

NTDSS (5 mol% TiO2),

(10 mol%), solventfree, 90°C

H-PDVB-*x*-SSFAI (10 mol%), solventfree, 140°C

PANI–HBF4–DHS (20 wt.% of **12**), solvent-free, 150°C

Condition A: ZrPW (0.2 g), solvent-free,

Condition B: ZrPW (0.2 g), solvent-free, MW (250 W), 130°C Condition C: 12-TPA/ ZrO2 (0.2 g), solventfree, 130°C Condition D: 12-TPA/ ZrO2 (0.2 g), solventfree, MW (250 W),

12-TPA-SnO2 (30 wt% of TPA), solvent-free,

P4VPy-CuI (0.1 g), solvent-free, 80°C

PS–GaCl3 (10 mol%), ethanol, reflux

CMK-5-SO3H (3 mol%), solvent-free, 130°C

free, MW (450 W),

free, 80°C

130°C

130°C

120°C

free, 80°C

110°C

DSIMHS (7 mol%), solvent-free, 70°C

18 h 1.5–5 min 42–89 80–96

3–12 h 60–95 [54]

2–27 min 80–96 [55]

3–24 h 20–99 [56]

3–8 h 89–98 [57]

5–80 min 75–99 [58]

2 h 78–94 [59]

6 h 94–98 [60]

0.5–2 h 70–97 [61]

42–65 47–66 38–63 41–65

2 h 78 [63]

10–90 min 84–92 [64]

45–300 min 45–96 [65]

20–90 min 75–97 [66]

15–120 min 60–97 [67]

6–9 min 61–98 [68]

[62]

8 h 30 min 8 h 30 min [52] [53]

90°C Condition B: I2 (1 mol%), MW

90°C

H2O, reflux

**110**


**Table 1.**

*Synthesis of substituted coumarins via Pechmann condensation reactions.*

Catalytic activity of many other catalysts under different reaction conditions is delineated in the recently published review [80].
