Synthesis of coumarins via Pechmann reaction catalyzed by 3-methyl-1-sulfonic acid imidazolium hydrogen sulfate as an efficient, halogen-free and reusable acidic ionic liquid

Abstract

3-Methyl-1-sulfonic acid imidazolium hydrogen sulfate has been used as an acidic task-specific ionic liquid for Pechmann condensation reaction. The coumarin products could simply be separated and the ionic liquid could be recycled and reused several times without noticeable decrease in the catalytic activity.

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Coumarin and its derivatives have attracted great interest because of their importance in the synthetic organic and medicinal chemistry. They are widely used as additives in food, perfumes, agrochemicals, cosmetics, pharmaceuticals¹ and in the preparation of insecticides, optical brightening agents, dispersed fluorescent and tunable laser dyes.² Coumarin and its derivatives have various bioactivities such as antimicrobial,³ antithrombotic,⁴ anticoagulant, antipsoriasis activity,⁵ anticancer,⁶ anti-HIV,⁷ antioxidant activity, antiproliferative activity,⁸ inhibitory activity on viral proteases,⁹ estrogen-like effects¹⁰ and central nervous system modulating activities.¹¹ Coumarins also act as intermediates in the synthesis of furocoumarins, chromenes, coumarones and 2-acylresorcinols.¹²

Coumarins have been synthesized by several routes including Pechmann,¹³ Perkin,¹⁴ Knoevenagel,¹⁵ Reformatsky,¹⁶ Wittig reactions¹⁷, and by flash vacuum pyrolysis.¹⁸ Among these, the Pechmann reaction is the most widely used method, as the reaction involves the use of simple starting materials, that is, phenols and β-ketoesters, in the presence of acidic condensing agents. The use of various reagents such as H₂SO₄, P₂O₅, FeCl₃, ZnCl₂, POCl₃, AlCl₃, PPA, HCl, phosphoric acid, trifluoroacetic acid, montmorillonite and other clays is well documented in the literature.¹⁹ Most of these methods suffer from severe drawbacks including the use of a large amount of catalysts, sometimes long reaction times, low yields and very often temperatures to the extent of 150 °C.

Nowadays acidic task-specific ionic liquids (TSILs), which possess the advantageous characteristics of solid acids and mineral acids, attract much interest as environmentally benign catalysts or excellent alternatives to organic solvents. TSILs are designed to replace traditional mineral liquid acids, such as sulfuric acid and hydrochloric acid, as catalysts in organic synthetic procedures. The introduction of Brönsted-acidic functional groups into the cation or anion of ionic liquids, especially the SO₃H and SO₄H functional groups, obviously enhanced their acidity and water solubility.^20–22 Moreover, their polar nature makes them useful for use under solvent-free conditions. An ever-increasing interest has been focused on TSILs for catalytic reactions where the catalyst is in one phase and the product in another, which makes product-isolation easy and catalyst-reuse convenient.

To date, reports on some ‘‘greener’’ halogen-free ionic liquids with phosphate or sulfate anions and the effects of the anion and toxicology have appeared in the literature.²³ Typical ionic liquids consist of halogen-containing anions (for example [Cl]⁻, [PF₆]⁻, [BF₄]⁻, [CF₃SO₃]⁻, or [(CF₃SO₂)2N]⁻) which to some extent limits their ‘‘greenness’’.^23,24 Therefore, it is necessary to synthesize novel efficient and halogen-free TSILs.

Based on the Zolfigol's report on the preparation of 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl),²⁵ in our previous work a novel SO₃H-functionalized halogen-free acidic ionic liquid that bears a sulfonic acid group in an imidazolium cation and hydrogen sulfate as a halogen-free anion was synthesized and its application in the promotion of the protection of hydroxyl groups was also investigated.²⁶ In continuation of our work in studying acid-catalyzed reactions in ionic liquids, we report here the synthesis of coumarin derivatives by the Pechmann condensation in the halogen-free acidic ionic liquid 3-methyl-1-sulfonic acid imidazolium hydrogen sulfate [Msim]HSO₄. To the best of our knowledge of the open literature, Pechmann-type reactions catalyzed by [Msim]Cl and [Msim]HSO₄ ionic liquids have not been reported.

For beginning this study and comparing the catalytic performance of [Msim]Cl and [Msim]HSO₄ ionic liquids (TSILs), resorcinol and ethyl acetoacetate (EEA) were employed as the model reactants. The Pechmann condensation of model reactants with equivalent ratio was carried out in the presence of various amounts of TSILs (2 and 5 mol%) at different temperatures ranging from 25 to 60 °C under solvent-free conditions (Table 1). As shown, after stirring for 1 h at 100 °C in the absence of ionic liquids, the reaction did not proceed as monitored by TLC (Table 1, entry 1). On the other hand, in the presence of a certain amount of ionic liquids and a specific temperature, the reaction was completed with 100% conversion. When the temperature of the reaction was raised from 25 to 40 °C, the reaction times and yields were improved considerably (Table 1, entries 2, 3, 5, 6, 8, 9, 11, and 12). However, with further increase in temperature, no significant improvement was observed in the yield and reaction time. So the temperature was not the only important factor for Pechmann reaction. According to the results in Table 1, it can be concluded that both ionic liquids were effective for Pechmann reaction at higher temperature, but [Msim]Cl is a halogen-containing ionic liquid, hence, [Msim]HSO₄ should be the best catalyst for the Pechmann condensation among the two TSILs. Under the optimized reaction conditions, the reaction gave 94% yield of 7-hydroxy-4-methylcoumarin after 25 min in the presence of 2 mol% [Msim]HSO₄ (Table 1, entry 9). The higher amount of [Msim]HSO₄ and increasing the reaction temperature did not improve the results to a greater extent.

Table 1 The Pechmann condensation between resorcinol and ethyl acetoacetate catalyzed by ionic liquids^a

Entry	TSIL	Amount of TSIL^b (mol%)	Temp (°C)	Time (min)	Yield^c (%)
a Reaction conditions: 5 mmol resorcinol, 5 mmol ethyl acetoacetate. b Molar ratio of TSILs to phenol. c Isolated yield.
1	—	—	100	180	—
2	[Msim]Cl	2	25	180	42
3	[Msim]Cl	2	40	60	82
4	[Msim]Cl	2	60	60	85
5	[Msim]Cl	5	25	180	44
6	[Msim]Cl	5	40	60	82
7	[Msim]Cl	5	60	60	86
8	[Msim]HSO4	2	25	180	48
9	[Msim]HSO4	2	40	25	94
10	[Msim]HSO4	2	60	25	96
11	[Msim]HSO4	5	25	180	52
12	[Msim]HSO4	5	40	25	96
13	[Msim]HSO4	5	60	25	96

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The Pechmann condensation reaction of other phenols and ethyl acetoacetate in the presence of [Msim]HSO₄ was accomplished under the optimized reaction conditions described above (Scheme 1) and the results are presented in Table 2. It can easily be seen that the Pechmann condensation proceeded smoothly under solvent-free conditions and gave good to high yields ranging from 75% to 98%. Many phenols, such as resorcinol, orcinol, pyrogallol, phloroglucinol, 4-chlorophenol and 3-methoxyphenol, could be converted to corresponding coumarins in high yields (Table 2, entries 1, 4, 5, 8, 10 and 13). The reactivities of 3-methylphenol and 1-naphthol seem to be inferior as compared with that of the former (Table 2, entries 15 and 16), only 82% and 78% yields were obtained, respectively.

Scheme 1 The synthesis of substituted coumarins in the presence of [Msim]HSO₄ at 40 °C under solvent-free conditions.

Table 2 Pechmann synthesis of various coumarins in the presence of [Msim]HSO₄ under solvent-free conditions^a

Entry	Substrate	β-Keto ester	Time (min)	Yield^b (%)	Ref.
a Reaction conditions: substrate, 5.0 mmol; EAA or MEAA, 5.0 mmol. b Isolated yield. c Obtained both a linear benzocoumarin (75%, mp: 267 °C) and an angular benzocoumarin (14%, mp: 276–277 °C).^38
1		EAA	25	94	28
		MEAA	30	92
2		EAA	40	88	29
3		EAA	40	92	30
4		EAA	38	98	28
		MEAA	42	96
5		EAA	22	96	31
		MEAA	26	92	32
6		EAA	30	92	29
7		EAA	32	88	29
8		EAA	28	98	33
		MEAA	34	96	32
9		EAA	42	88	29
10		EAA	40	90	34
11		EAA	46	85	31
12		EAA	34	92	33
13		EAA	40	94	35
14		EAA	42	93	36
15		EAA	38	82	37
16		EAA	44	78	28
17		EAA	42	88	2
18		EAA	45	75^c	38

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The reaction of resorcinol with EAA (Table 2, entry 1) occurred within 25 minutes. This could be due to the presence of only two hydroxyl groups, which were meta to each other. However, in the case of orcinol, the reaction (Table 2, entry 4) was somewhat slower, which could be due to the steric hindrance of the methyl group ortho to the position of hydroxylalkylation. Reaction of phloroglucinol with EAA (Table 2, entry 5) took place faster within 22 minutes. This was mainly due to the presence of three hydroxyl groups that cooperated in activating the aromatic ring. Similarly, reaction of pyrogallol with EAA (Table 2, entry 8) proceeded for 28 minutes, which was slower than the reactions of resorcinol and phloroglucinol presumably due to steric hindrance of hydroxyl groups.

To compare the activities of various β-keto esters with various phenols, two different types of β-keto esters were used, namely, ethyl acetoacetate [EAA] and α-methyl ethyl acetoacetate [MEAA] (Table 2, entries 1, 4, 5 and 8). Reactivity order for β-keto esters was found to be EAA > MEAA (Table 2, entries 1, 4, 5 and 8). In all instances except two, coumarins were obtained. As exceptions, 2,7-dihydroxynaphthalene and 2-naphthol gave a mixture of linear and angular coumarins and a chromone.

The possible mechanism of the synthesis of 7-hydroxy-4-methylcoumarin in the presence of [Msim]HSO₄ as a promoter under solvent-free conditions is shown in Scheme 2. On the basis of this mechanism, [Msim]HSO₄ catalyzes the reaction of hydroxyalkylation by the activation of the EAA, making the carbonyl group susceptible to nucleophilic attack by resorcinol. The transesterification and dehydration occur concomitantly condensing together the two reactants at two sites to form coumarin products and regenerating [Msim]HSO₄ in the reaction.

Scheme 2 Proposed mechanism of Pechmann reaction of resorcinol with EAA at 40 °C under solvent-free conditions.

As an air and moisture stable ionic liquid, [Msim]HSO₄ was superior than chloroaluminate ionic liquids in the aspect of recycle and reuse.²⁷ The recycling performance of [Msim]HSO₄ was then investigated in the reaction of resorcinol and EEA. The results listed in Fig. 1 showed that the [Msim]HSO₄ could be reused five times with only a slight decrease in the catalytic activity.

Fig. 1 Reuse of the catalyst in Pechmann reaction in the presence of [Msim]HSO₄ at 40 °C under solvent-free conditions.

In summary, to the best of our knowledge, the Pechmann coupling in the presence of [Msim]HSO₄ as an activator under solvent-free conditions is reported by us for the first time. The methodology has several advantages such as: green aspects by avoiding toxic catalysts and the traditional solvents, high reaction rates and excellent yields, no side reactions, ease of preparation and handling of the catalyst, effective recovery and reusability of the catalyst, use of a halogen-free catalyst with lower loading and a simple experimental procedure. Further work to explore this novel catalyst in other organic transformations is in progress.

General procedure for the preparation of coumarins

In a 25 mL batch reactor equipped with a distillation condenser the mixture of phenols (5 mmol), β-keto esters (5 mmol) and the [Msim]HSO₄ prepared according to the literature²⁶ (25 mg, 0.096 mmol) was stirred at 40 °C under solvent-free conditions for the time mentioned in Table 2. After completion of the reaction (monitored by TLC), the resulting solidified mixture was diluted with ethyl acetate (10 mL) and the catalyst was separated through decantation. The organic phase obtained was washed with water (2 × 5 mL) and the solvent was evaporated under reduced pressure, which yielded the crude product, which was purified by recrystallization in ethanol or an ethanol–water system to give the pure product as colorless prisms, pale yellow or white powder. The recovered ionic liquid, after drying, could be reused directly in the next run without further purification. All synthesized coumarin derivatives were characterized using analytical techniques like IR, ¹H NMR, ¹³C NMR and mass spectroscopy. Also the melting points were measured for all synthesized coumarin derivatives and were compared with the corresponding reported melting points.^28–38

The spectral data of selected compounds

5-Hydroxy-3,4,7-trimethylcoumarin (Table 2, entry 4)

White crystals, mp: 249–251 °C (ethanol) (lit. mp: 249 °C)²⁷; IR (KBr): ν = 3216, 3028, 2986, 1675, 1620, 1283, 1120, 1062 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ = 2.04 (s, 3H, CH₃), 2.27 (s, 3H, CH₃), 2.53 (s, 3H, CH₃), 6.57 (s, 2H, ArH), 10.32 (brs, 1H, OH). MS (EI, 70 eV): m/z = 204 [M⁺].

8-Hydroxy-4-methyl-2H-naphtho[2,3-b]pyran-2-one (Table 2, entry 18)

Yellow powder, mp: 275–277 °C (ethanol–water) (lit. mp: 267 °C)³⁷; IR (KBr) ν = 3360, 3031, 1705, 1564, 1238, 1062 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ = 2.46 (s, 3H, CH₃), 6.30 (s, 1H, ArH), 7.08 (dd, J = 8.8 and 1.8 Hz, 1H, ArH), 7.14 (d, J = 1.8 Hz, 1H, ArH), 7.54 (s, 1H, ArH), 7.88 (d, J = 8.8 Hz, 1H, ArH), 8.21 (s, 1H, ArH), 10.15 (brs, 1H, OH). MS (EI, 70 eV): m/z = 226 [M⁺].

Acknowledgements

The author is thankful to Guilan University Research Council for partial support of this work.

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