Current Organic Chemistry, 2020, 24, 4-43

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REVIEW ARTICLE

ISSN: 1385-2728 eISSN: 1875-5348

Impact Factor: Green Chemistry Approaches to the Synthesis of Coumarin Derivatives 2.029

BENTHAM SCIENCE

Maja Molnar1,*, Melita Lončarić1 and Marija Kovač2

1Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology Osijek, F. Kuhača 20, HR-31000 Osijek, Croatia; 2Inspecto d.o.o., Industrijska zona Nemetin, Vukovarska cesta 239b, HR-31000 Osijek, Croatia

Abstract: This review is a compilation of the green synthetic methods used in the synthesis of coumarin derivatives. Coumarins are a class of compounds with a pronounced wide range of biological activities, which have found their application in medicine, pharmacology, cosmetics and food industry. Their biological activity and potential application are highly dependent on their structure. Therefore, many researchers have been performing the synthesis of coumarin derivatives on a daily basis. High demands for their synthesis often result in an increased generation of different waste chemicals. In order to minimize the utilization and generation of toxic organic substances, green synthetic methods are applied in this manner. These methods are getting more attention in the last few decades. A R T I C L E H I S T O R Y Green chemistry methods cover a wide range of methods, including the application of ultrasound and microwaves, ionic liquids and deep eutectic solvents, solvent-free synthesis, mechanosynthesis Received: October 26, 2019 Revised: November 27, 2019 and multicomponent reactions. All typical condensation reactions for coumarin synthesis like Knoevenagel, Accepted: December 02, 2019 Perkin, Kostanecki-Robinson, Pechmann and Reformansky reactions, have been successfully performed using

DOI: these green synthetic methods. According to the authors mentioned in this review, not only these methods re- 10.2174/1385272824666200120144305 duce the utilization and generation of toxic chemicals, but they can also enhance the reaction performance in terms of product yields, purity, energy consumption and post-synthetic procedures when compared to the conventional methods. Due to the significance of coumarins as biologically active systems and the recent demands of reducing toxic solvents, catalysts and energy consumption, this review provides a first full literature overview on the application of green synthetic methods in the coumarin synthesis. It covers a literature search over the period from 1995-2019. The importance of this work is its comprehensive literature survey on a specific class of heterocyclic compounds, and those researchers working on the coumarin synthesis can find very useful information on the green synthetic approaches to their synthesis. There are some reviews on the coumarin synthesis, but most of them cover only specific reactions on coumarin synthesis and none of them the whole range of green chemistry methods.

Keywords: Coumarin derivatives, green methods, deep eutectis solvents, ionic liquids, solvent-free, mechanosynthesis.

1. INTRODUCTION and coumarins, eculin, esculetin, fraxin and fraxetin [6]. Many Coumarin is a heterocyclic compound, with a characteristic other examples of the bioactivity of different plant extracts due to benzopyrone structure, where the benzene ring is condensed with a the coumarin presence are described, emphasizing their great poten- pyrone ring. It was first discovered when it was isolated from the tial in pharmacology and medicine. Its structure allows a substitu- plant Coumarouna odorata Aube (Dipteryx odorata) in 1820 [1]. tion at six different positions, thus providing numerous possibilities Afterwards, coumarin and its derivatives were found in many other of synthetic modifications on the core structure, with a wide range plants, in a free form or in a form of heterosides, like Apiaceae, of possible novel derivatives with novel biological activities. Asteraceae, Fabiaceae, Rosaceae, Rubiacae and Solanaceae [2], Coumarins can be synthesized via Perkin, Pechmann or predominantly in Rutaceae and Umbelliferae [3]. Plant coumarins Knoevenagel reaction, as well as Wittig, Kostanecki-Robinson and are characterized as phytoalexins, compounds that are synthesized Reformatsky reaction. when the plant is subjected to adverse conditions, wilting, various Perkin reaction also referred to as Perkin condensation or diseases or pathogen attacks [2, 4, 5]. They possess a wide variety Perkin synthesis, often includes condensation of aromatic aldehydes of different pharmacological and biological effects and can be and carboxylic acid anhydrides or carboxylic derivatives, in a base found in different extracts, like Cortex Fraxini, whose anti- catalysed reaction, where cinnamic acid derivatives are formed [7]. inflammatory activity correlates to the presence of phenolic acids Coumarin synthesis by Perkin reaction proceeds by heating salicylaldehyde sodium salt with acetic anhydride (Scheme 1) [8].

*Address correspondence to this author at the Josip Juraj Strossmayer University of Pechmann condensation (Scheme 2) into coumarins proceeds Osijek, Faculty of Food Technology Osijek, F. Kuhača 20, HR-31000 Osijek, Croatia; from phenols and β-keto esters or α,β-unsaturated carboxylic acids, Current Organic Chemistry Tel: +385 31 224 342; Fax: 0385 31 207 115; E-mail: [email protected] and is often acid catalysed [7, 9].

CHO O O Synthesis of substituted coumarins via Wittig reaction proceeds from the substituted salicylaldehydes, methyl or ethyl chloroacetate + O and triphenylphosphine (Scheme 4), using different catalysts [13]. ONa O O Kostanecki-Robinson synthesis of coumarins proceeds from o- Scheme 1. Perkin synthesis of coumarin [8]. hydroxyarylalkyl ketones, acid anhydride and the sodium salt of an Knoevenagel condensation includes a nucleophilic addition of acid, by the formation of the 3,4 carbon-carbon bond via the ester an active methylene compound with aldehydes or ketones, in a enolate (Scheme 5). When the reaction proceeds via keton enloate, weak base, catalysed reaction, usually followed by the elimination chromones (4H-1-benzopyran-4-ones) 1 can be the major products of water [7]. Knoevenagel condensation into coumarins proceeds in [7, 14]. the reaction from salicylic aldehydes and malonic acid or esters, Reformatsky reaction includes a reaction between an activated and is usually catalyzed by weak bases or Lewis acids (Scheme 3) alkyl halide with a carbonyl compound in the presence of zinc, to [10, 11]. Activation of the methylene group can be achieved with form a hydroxy compound, which is converted to β-hydroxy esters. the presence of at least one electron-withdrawing group (nitro, O-Hydroxy aryl/alkyl ketones can be transformed to 3,4-disub- cyano, carbonyl, sulfonyl) [7]. stituted coumarins via this reaction (Scheme 6). Wittig reaction proceeds from carbonyl compounds, which re- In the past few decades, conventional synthetic methods in act with phosphorus compounds called ylides, to yield alkenes [12]. coumarin synthesis are being modified or even replaced with the

OH O O H2SO4 or HF + R3 R2 O or Lewis acid R1 O O R 1 Scheme 2. Pechmann synthesis of 7,4-disubstituted coumarins [7].

CHO O O COR catalyst 2 + R2 R3 OH O O R1 R1 Scheme 3. Knoevenagel synthesis of 3-substituted coumarins [10, 11]. O

H O PPh3 + Cl catalyst OH O R O O R Scheme 4. Wittig synthesis of coumarins [13]. R O O R' R OH O O R' + ONa + R' R' R' O R O O O 1 O Scheme 5. Kostanecki-Robinson synthesis of coumarins [7, 14].

COCH2R

OH HO OCH OCH3 3 HO SOCl COOC2H5 R'CHBrCOOC2H5 2 CHR'COOC2H5 pyridine OH R' OCH3 RH2C OH RH2C

CH2R

HI or H2SO4 R'

HO O O Scheme 6. Reformatsky synthesis of coumarin derivatives [7].

6 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

CHO GWE R R EDDA 20 mol% + COOEt [bmim]BF , r.t. OH 4 O O O NH

1 2 3 4 Scheme 7. Synthesis of coumarin derivatives in ionic liquids performed by Su et al. (2003) [19]. green ones, such as microwave or ultrasound synthesis, solvent-free phosphate ([bmim]PF6). The reaction was catalyzed with 20 mol% and mechanosynthesis or synthesis using so-called designer sol- EDDA (ethylenediammonium diacetate), stirred for 1 h at r.t. Cou- vents, like ionic liquids or deep eutectic solvents. marin derivatives 3 were successfully synthesized in high yields All these “green” methods are being developed and applied in (82-95%), while in the case of ethyl cyanoacetate, an imino deriva- order to reduce or eliminate the generation or use of toxic volatile tive 4 was formed [19]. organic solvents, catalysts or other toxic chemicals, to perform Knoevenagel condensation into coumarins was also performed reactions under milder conditions, with higher yields and purity of using ionic liquid 1,1,3,3-N,N,N',N'-tetramethylguanidinium tri- the final products. fluoroacetate (TMGT), with stirring and heating (69-78% yields in This review paper gives an overview of the application of green 30 min to 8 h) and under microwave heating (yields of 70-83% in synthetic methods in the synthesis of coumarin derivatives and 1-4 minutes) [20]. A reaction without TMGT yielded no products. provides the literature survey encompassing the data of the last two Coumarin derivatives were synthesized starting from salicylalde- decades (1995-2019), concerning various reaction paths. Typical hyde or 2-hydroxy-1-naphthaldehyde, to obtain desired derivatives synthetic routes performed by different authors are compared, con- 5a-d (Scheme 8) [20]. The authors obtained ethyl 2-oxo-2H- sidering the yields of some most frequently synthesized coumarin chromene-3-carboxylate in 74-75% yield with this method, while derivatives. Supplementary material contains a tabulated review of Su et al. [19] obtained a yield of 93% using the previously de- the green synthetic methods in the synthesis of coumarin deriva- scribed method. tives with a full comparison of reaction conditions and yields for each coumarin derivative, with the complete reference list. R1 R1 2. IONIC LIQUIDS IN COUMARIN SYNTHESIS

Ionic liquids (ILs) are salts that contain anions and cations, and X O O O O most of them are liquids at room temperature [15]. Different anions and cations can be combined to form an ionic liquid, and their 5a 5b properties are highly dependent on their structure. Therefore, varying their composition, one can tune their physical and chemical COOH COOH properties in order to use them for different purposes [16]. ILs, designated as so called designer solvents, have a wide range of X O O O O applications such as catalysts, reaction media, extraction media and solubilizing agents. Ionic liquids possess many advantages, such as 5c 5d high ionic conductivity, high thermal stability, low viscosity, chemical stability and high solubilization capacity for many solutes. Scheme 8. Coumarin derivatives synthesized in IL TMGT [20]. Negligible vapor pressure and low flammability are the desirable Ethyl 2-oxo-2H-chromene-3-carboxylate was also synthesized characteristics that classify them as green solvents [17]. The major in a method applied by Harjani et al. [21]. They obtained the prod- concerns about ILs are their cost and the fact that some of them are uct in 86% yield. In general, they reacted 2-hydroxyarylaldehydes toxic, raising a question about their reuse. There are some recycling with diethylmalonate to yield different 3-ethoxycarbonyl coumarins methods proposed for the ILs, but their application depends on the 6, in two ionic liquids [bmim]Cl·AlCl3 and [bpy]Cl·AlCl3, and the type of the solute which is to be separated from IL [18]. reaction took only a few minutes (Scheme 9) [21]. They also, just like Shaabani et al. [20], employed 2-hydroxy-1-naphthaldehyde in 2.1. Knoevenagel Condensation this reaction to obtain ethyl 3-oxo-3H-benzo[f]chromene-2- In the Knoevenagel synthesis of coumarin derivatives (Scheme carboxylate, which was obtained in 78% yield, while Shaabani et 7), salicylaldehyde 1 and active methylene compounds 2 were dis- al. [20] obtained 69% and 70%. solved in ionic liquid, 1-butyl-3-methylimidazonium tetrafluorobo- In the other research performed by Verdía et al. [22], the un- rate ([Bmim]BF4), and 1-butyl-3-methylimidazonium hexafluoro- dried ionic liquid 1,3-dimethylimidazolium methyl sulphate,

CHO COOEt COOEt [BMIM]Cl.AlCl3 + R COOEt OH R O O

6 Scheme 9. Synthesis of 3-ethoxycarbonyl coumarins performed by Harjani et al. [21].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 7

H3C COOH COOH Br COOH

O O O O O O OCH CH3 3

SO2Me SO2Me SO2Me

Br O O O O HO O O Scheme 10. Some coumarin derivatives synthesized by Verdia et al. [22].

R2 CHO R2 Z1 Z1 [(CH2)4SO3HMIM][HSO4] + Z OH 2 water O X

R1 R1 Z , Z = CN, COOEt X = O, NH 1 2 Scheme 11. Synthesis of 3-substituted coumarins by Heravi et al. [24]. R R

O OH O O R2 CHO R2 [(CH2)4SO3HMIM][HSO4] + R OH R water O O R R R1 R 1 7 Scheme 12. Synthesis of benzopyran coumarin derivatives by Heravi et al. [24].

O O + - [bmim] PF6 O O H NaOMe + + Cl O PPh3, 200-210°C R O O OH 8 R OH

Scheme 13. Wittig synthesis of coumarin performed in [bmim]PF6 [13].

[MMIm][MSO4] was applied as the solvent in coumarin synthesis, was the most suitable solvent, when compared to other butylmeth- starting from different salicylaldehydes, using L-proline as a pro- ylimidazolium salts, with the highest yields of the products (66- motor (Scheme 10). Coumarins were obtained in high yields in time 85%) [13]. This reaction path demanded a temperature of 95 °C. from 15 min to 19 hrs. When L-proline was not used as the promo- They obtained methyl 7-methoxy-2-oxo-2H-chromene-3-carboxy- tor, coumarins were not formed [22]. In this research, ethyl 2-oxo- late in 71% yield, while Verdia et al. [22] obtained the same prod- 2H-chromene-3-carboxylate was obtained in 98% yield and ethyl 6- uct in 90% yield. In addition, ethyl 7-hydroxy-2-oxo-2H-chromene- methyl-2-oxo-2H-chromene-3-carboxylate was synthesized in 88% 3-carboxylate was obtained in 76% yield, while Harjani et al. [21] yield, while Harjani et al. [21] obtained the same product in 82% obtained the same product in 80% yield. 3-Substitued coumarins yield. were also synthesized in 1-(4-sulfonic acid)butyl-3-methyl- The same reaction was performed in piperidine/HOAc/ imidazolium hydrogen sulfate catalyzed reaction, in water at 85 °C, - [Emim]BF4 system at r.t. and 50 °C [23]. The addition of from salicylaldehide and malononitrile or diethyl malonate (Scheme piperidine and acetic acid was crucial, since the use of the ionic 11). In this reaction, ethyl 2-oxo-2H-chromene-3-carboxylate was liquid only, yielded no coumarins. When ethyl acetoacetate was obtained in 89% yield. The same conditions were applied for the used as an active methylene compound, the reaction proceeded at synthesis of benzopyran coumarin derivatives 7 from substituted r.t. only; when ethyl cyanoacetate was used, no coumarin was salicylaldehydes and 1,3-cyclohexanediones (Scheme 12) [24]. IL formed [23]. The authors also performed a recycling of the IL, by was recycled by filtration of the product, further washing with di- extraction of the synthesized compound with ethyl ether and further ethyl ether and drying. concentration of IL under vacuum. 2-Oxo-2H-chromene-3- carboxylate was obtained in 80% (r.t.) and 87% (50 °C) yield, while 2.2. Wittig Condensation 6-chloro-2-oxo-2H-chromene-3-carboxylate was obtained in 86% 3-Carbo(ethoxy or methoxy)coumarin derivatives were ob- yield [23], lower than 92% obtained by Harjani et al. [21]. Vali- tained via Wittig reaction, in the reaction of chlorodiethyl- or di- zadeh and Vaghefi [13] compared a Knoevenagel synthesis and methyl malonates, salicylaldehide derivatives, NaOMe and PPh3 Wittig synthesis of coumarins in the same ILs. For Knoevenagel (triphenylphosphine) in [bmim]PF6 at 210 °C (Scheme 13). The condensation, NaOMe was used as a catalyst and [bmim]PF6 IL reaction greatly depended on the applied temperature. When it was

8 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

OH R1 OH R1 = Me, Ph R = Me, Et O O IL (cat) 2 + R OR solvent-free, r.t. HO O O HO OH 1 2

9 Scheme 14. Pechmann synthesis of coumarins performed by Shaterian and Aghakhanizadeh [25]. O

OH R1 Ar O O IL (cat) NC R1 + CH2(CN)2 + Ar H HO O O solvent-free, 80°C H2N O OH

10 Scheme 15a. Synthesis of pyrano[2,3-h]coumarin derivatives by Shaterian and Aghakhanizadeh [25].

OH R1 Ar N N

O N N HO O O Ar H

H O N H O H O N H O

OH R1

O O O HN H C O Ar CN Ar O NC R1

H2N O OH Scheme 15b. A proposed mechanism for the synthesis of pyrano[2,3-h]coumarin derivatives catalyzed by IL [25]. performed at room temperature, no product was formed, at medium nesulfonate) as catalysts (Scheme 14). All reactions were performed temperatures, the E-cinamic ester 8 was the major product. In order at r.t. to yield 5,7-dihydroxy-4-methylcoumarin of 91% and 5,7- to obtain isomerization into Z-isomer and further cyclization into dihydroxy-4-phenyllcoumarin in 91% yield. Afterwards, those coumarin, temperatures of 200-215 °C should be applied [13]. coumarins were used in the synthesis of pyrano[2,3-h]coumarin derivatives 10, in reaction with malononitrile and aromatic alde- 2.3. Pechmann Condensation hydes, in basic ILs (Scheme 15a) [25]. The authors point out that Pechmann condensation of phloroglucinol and β-keto esters this method is a good alternative to the conventional ones due to its into 5,7-dihidroxy-4-substituted coumarins was performed in dif- fast and clean performance, giving high yields of the products with ferent Brønsted acidic ILs (2-pyrrolidonium hydrogen sulfate- a simple work-up procedure. [Hnmp][HSO4], N-methyl-2-pyrrolidonium hydrogen sulfate- A proposed mechanism for the synthesis of pyrano[2,3- [NMP][HSO4], N-methyl-2-pyrrolidonium dihydrogen fosfate- h]coumarin derivatives 10 is shown in Scheme 15b. The authors [NMP][H2PO4], (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hyd- explain that Knoevenagel products are formed from aryl aldehyde rogen sulfate and triphenyl(propyl-3-sulfonyl)phosphonium tolue- and malononitrile carboanion in a reaction catalyzed by IL. The

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 9

R1 N N SO H O O Ts- 3 + R OR 85 °C OH 1 2 R O O

AcO O O TsO O O O O

11 12 13 Scheme 16. Pechmann synthesis of coumarin using IL 1-butanesulfonic acid-3-methylimidazolium tosylate [26].

O O IL/anhyd. FeCl3 O O EtO 70 °C

14 Scheme 17. Pechmann reaction in synthesis of coumarins derivatives performed by Kumar et al. [27]. addition of 4-substituted-5,7-dihydroxy-coumarin to Knoevenagel ionic liquid, such as N,N,N-trimethyl-N-propanesulfonic acid am- product then occurs, followed by further cyclization to the final monium hydrogen sulfate [TMPSA][HSO4], N,N,N-triethyl-N- product [25]. propanesulfonic acid ammonium hydrogen sulfate [TEPSA] Among other derivatives, 5,7-dihydroxy-4-methylcoumarin and [HSO4], N,N,N-tributhyl-N-propanesulfonic acid ammonium hy- 5,7-dihydroxy-4-phenylcoumarin were synthesized by Das et al., as drogen sulfate [TBPSA][HSO4], N,N,N-trimethyl-N-butanesulfonic well [26]. They obtained those products in 70% and 80% yield, acid ammonium hydrogen sulfate [TMBSA][HSO4] and N,N,N- lower than Shaterian and Aghakhanizadeh [25] and it took more triethyl-N-butanesulfonic acid ammonium hydrogen sulfate time (few hours compared to 12 and 24 min obtained by Shaterian [TEBSA][HSO4] [28]. The best catalyst among all ILs was shown and Aghakhanizadeh [25]). Das et al. [26] performed a Pechmann to be [TMPSA][HSO4] at 80 °C. In this work, 7-hydroxy-4- synthesis of coumarins in a solvent-free reaction at 85 °C, with methylcoumarin was obtained in 93% yield, higher than Kumar et acidic ionic liquid 1-butanesulfonic acid-3-methylimidazolium al. [27] and Das et al. [26]. 5,7-Dihydroxy-4-methylcoumarin was tosylate (10 mol%) as a catalyst (Scheme 16). This method was also obtained in 91% yield, while 75% yield was obtained for 4-methyl- applicable for tosyl and acetyl substituted phenols, which is very 2H-benzo[h]chromen-2-one, similar as the previous researchers important since those groups are often used as –OH protective [28]. Cholinium based ILs were also very efficient in the Pechmann groups (compounds 11 and 12). Condensation of ethyl 2- condensation of resorcinol and ethyl acetoacetate into 7-hydroxy-4- oxocyclopentanecarboxylate with α-naphthol was also successful, methylcoumarin [29]. No significant activity was observed for ILs yielding compound 13. They describe their procedure as simple, with cholinium cation and weak acidic anions, [choline][Ac], [cho- mild with the possibility of recycling and reuse of the catalyst [26]. line]Cl, [choline][H2PO4]. Moderate catalytic activity was observed Pechmann reaction of resorcinol and ethyl acetoacetate was per- for ILs of cholinium cation and strong acidic anion, [choline][HSO4]. The best yield was obtained with N,N-dimethyl- formed in few ionic liquids using anhydrous FeCl3 (20 mol%) as a catalyst at 70 °C (Scheme 17). Considering the product yields, ionic aminoethanolic ILs, [N112OH][HSO4], in 2 hrs, with the molar ratio liquids’ efficiency was as follows: 1-methoxyethyl-3-methylimida- of IL:resorcinol 0.05:1, while ILs [N112OH][H2PO4] and [N112OH]Cl showed no activity. This method yielded 7-hydroxy-4- zolium hexafluorophosphate [Moe-MIm][PF6] > 1-butyl-3-methyli- methylcoumarin in 99% yield, 5,7-dihidroxy-4-methylcoumarin in midazolium bis(triflic)-imide [BMIm][Tf2N] > 1-methoxyethyl-3- 98%. All reactions were performed in 3-24 h [29]. The same reac- methylimidazolium tetrafluoroborate [MoeMIm][BF4]; 1-methoxy- tion was performed from phenols and ethyl acetoacetate at ambient ethyl-3-methylimidazolium bis(triflic)-imide [MoeMIm][Tf2N]. 1- Methoxyethyl-3-methylimidazolium trifluoroacetate [MoeMIm] temperature using neutral ionic liquids, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) and 1-butyl-3-methyli- [CF3COO] was not effective for this kind of reaction. The authors midazolium hexafluorophosphate ([bmim]PF6) in a combination also found that [MoeMIm][BF4] and [MoeMIm][PF6] could not be recycled [27]. They obtained 5,7-dihydroxy-4-methylcoumarin in with POCl3 [30]. IL [bmim]PF6 was not used in combination with 75% and 77% yield, also lower than by Shaterian and Aghakhani- POCl3, since it liberates HF at higher temperatures. Reactions were zadeh [25]. Furthermore, Das et al. [26] obtained 7-hydroxy-4- performed for 45-60 min and similar results were also obtained methylcoumarin in 75% yield and 4-methyl-2H-benzo[h]chromen- when the reaction was performed in the same IL, but without POCl3 2-one (14) in 80% yield, while Kumar et al. [27] obtained 80% and at 100 °C. In this method, 7-hydroxy-4-methylcoumarin was ob- 85% for 7-hydroxy-4-methylcoumarin, and 7% and 71% for 4- tained in 95% (91%) yield, 5,7-dihydroxy-4-methylcoumarin in methyl-2H-benzo[h]chromen-2-one 14. 94% (95%) yield [30]. When nanocrystalline-cellulose-supported sulfonic acid ionic liquid was employed in this kind of reaction, 7-Hydroxy-4-methylcoumarins were synthesized via Pechmann substituted 4-methylcoumarins were also obtained in high yields condensation in water using SO H-functional halogen-free acidic 3 [31]. The solvent-free reaction gave almost the same results as the

10 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

O O O O O catalyst, H2O NC CN Ar H sonication, Ar 20 min, r.t. O OH 15 CN NH2 Scheme 18a. Synthesis of coumarine derivatives performed by Mayank et al. [32].

IL CNTs IL CNTs O IL CNTs NC NC NH N CN H Ar Ar H -H2O O Ar O Ar + IL CNTs

O N O N N OH O O

O O

NC NH2

Ar O

O O

Scheme 18b. A proposed mechanism for the synthesis of chromene compounds 15 [32]. conventional organic solvents, THF, acetonitrile, dichloromethane tone. The intramolecular cyclization of that intermediate yields the and n-hexane, with a temperature of 80 °C. Here, 7-hydroxy-4- other intermediate which loses water and forms a final compound, a methylcoumarin was obtained in 95% yield, and 4-methyl-2H- pyranocoumarin. The authors claim that the acidic IL activates the benzo[h]chromen-2-one in 94% yield. Reactions were performed in protonation of the carbonyl ketone group and increases the electro- 20 min to 24 h, depending on the phenol [31]. philic character at the β-carbon, thus promoting the Michael adduct formation. Furthermore, the acidic IL causes the intramolecular 2.4. Other cyclization of the first step intermediate (Scheme 19b). This reaction is performed under the solvent-free conditions, Mayank et al. [32] produced a carbon nanotubes coated with where the applied IL can be recycled and reused for several times. imidazolium and benzimidazolium based ionic liquid, in order to The only by-product of this reaction is water, while the final com- apply them in the synthesis of chromene compounds 15 (Scheme pounds were easily isolated with minimal demands for further puri- 18a). Thus, synthesized catalyst was utilized in the reaction of 4- fication [33]. hydroxycoumarin, malononitrile and aromatic aldehydes, under sonication, using water as a solvent. Both catalysts were proven to be very efficient in this reaction, and high yields 88-64% were ob- 3. DEEP EUTECTIC SOLVENTS IN COUMARIN SYNTHE- tained [32]. SIS Mayank et al. proposed a mechanism for this reaction (Scheme Deep eutectic solvents (DESs) are mixtures of two or more 18b). Carbonyl and nitrile functional groups of the reactants are components, which are bonded by hydrogen bonds and have melt- activated by the positively charged surface of the nanotubes and ing point much lower than each component individually [29, 34]. their hydrogen bonding ability, causing a formation of ben- Synthesis in DESs is considered as a green approach, since those zylidenemalononitrile intermediate. Then the addition and cycliza- solvents are easily synthesized from biodegradable and environ- tion of 4-hydroxycoumarin to this intermediate compound occur mentally benign components, with 100% atom economy. In addi- and the final product is formed [32]. tion, DESs have low toxicity, high availability, low inflammability, Pyrano coumarin derivatives 16 were synthesized from 4- high recyclability, low volatility and low price [35]. hydroxy coumarin derivatives and different chalcones in a solvent- free reaction, using 1-butane sulfonic acid-3-methylimidazolium 3.1. Knoevenagel Condensation tosylate ([BSMIM]OTs) as a catalyst (Scheme 19a). When different Coumarin synthesis by Knoevenagel condensation (Scheme solvents were applied, DMF, DMSO, EtOH, MeOH, water, toluene, 20), using choline chloride: urea deep eutectic solvent as a catalyst, PEG, dioxane, DCE and low yields were obtained [33]. from salicylaldehyde and active methylene groups, was performed Mahato et al. described that the first intermediate is formed by Harishkumar et al. [36]. This reaction yielded coumarin deriva- from the reaction of 4-hydroxycoumarin and α,β-unsaturated ke- tives 17 and 18 in high yields (95%), in 1-4 hours, with no addi-

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 11

OH O O BAIL-1 (5 mol%)

R1 O O 100 °C, 3h R1 R2 O O

16 Scheme 19a. Synthesis of pyrano coumarin derivatives performed by Mahato et al. [33].

O R2 OH

OH OH R2 O O R + R R H+ H R1 R1 + R1 R2 O O O O O O

O + H R R1

H O O O 2 Scheme 19b. Proposed mechanism for the synthesis of pyrano coumarins by Mahato et al. [33].

R3 R3 O R1 CHO O O R1 100 °C OH + O R2 OH choline chloride:urea R2 O O R4 O R4 17

R CHO 1 O R1 R3 100 °C R3 + R O R OH 4 choline chloride:urea 2 R2 O O

18 Scheme 20. Synthesis of coumarin-3-carboxylic acid derivatives and 3-substituted coumarins [36]. tional need for other solvents or catalysts [36]. The authors point Choline chloride could act as a Lewis base and eliminate the proton out several advantages of DES compared to the conventional meth- from diethylmalonate, while zinc chloride acts as a Lewis acid ods, such as the environmentally friendly character of the solvent, (Scheme 21b). reaction time is shorter and the workup is simple and not expensive Phadtare et al. [38] synthesized a series of 7-diethylamino cou- [36]. marins 19 in choline chloride: urea deep eutectic solvent (Scheme When choline chloride-based DESs are compared for the reac- 22). First 4-diethylamino salicylaldehyde was cyclized into 7- tion of salicylaldehyde and dimethyl malonate, varying HBD such diethylamino-3-acetylcoumarin, which in reaction with malononi- as ZnCl2, 2ZnCl2, 2ZnCl2 and SnCl2, the most suitable DES was trile gave compound 20. A reaction of 20 with aryl aldehydes ChCl:ZnCl2 1:2, yielding 61-96% of the products at 80 °C in 20 hrs yielded compounds 21. All compounds were obtained in excellent (Scheme 21a). Methyl 2-oxo-2H-chromene-3-carboxylate was ob- yields, while DES was successfully recycled and the whole reaction tained by this method [37] in 96% yield, the same as Harishkumar was scaled up [38]. et al. [36] obtained. 3-Cyanocoumarin was obtained in 92% yield Phadtare et al. explain the reaction mechanism based on the [37], while Harishkumar et al. [36] obtained it in a 98% yield. weak acidic nature of the DES. The catalytic activity of the DES is The reaction mechanism includes the involvement of acidic attributed to the co-existence of chlorine ion and hydrogen bond

DES in this reaction in the form of choline cation and ZnCl3 anion. donors [38].

12 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

OH O R O ChCl. 2ZnCl2 2 H R2 OR 80 °C, 20h 3 O O R1 R1

R1 = H, OH, Br R2 = CO2Me, CN, COPh, R = Me, Et 3 Scheme 21a. Synthesis of coumarin derivatives catalysed by deep eutectic solvents [37].

Cl Zn 2 H+Cl- O ZnCl2 + - Ch ZnCl3 OH H OH SiH O Ch+ H -ZnCl2 H3CO OCH3 H3CO OCH3 -HCl H CO O O O O O 3

Ch+ Cl2Zn Cl- ChCl + H2O ChOH + HCl

OH OH O O OH O H -ZnCl2 esterification O

O O O H CO O H3CO 3

Scheme 21b. A proposed mechanism for the synthesis of coumarin derivatives in ChCl:ZnCl2 DES [37].

R3 O O O CHO 70-75 °C NC CN + EtO DES N OH N O O 70-75 °C, DES 19 Ar

CN Ar-CHO CN

CN N O O 30-40 °C, CN DES N O O

20 21 Scheme 22. Synthesis of 7-diethylamino coumarin derivatives in DES by Phadtare et al. [38].

HO OH O O DES + O HO O O Scheme 23a. Synthesis of 7-hydroxy-4-methylcoumarin in DESs by Zhang et al. [29].

3.2. Pechmann Condensation acid/malonic acid and succunic acid DES, at 90 °C and found it to Zhang et al. [29] performed a Pechmann condensation of resor- give moderate yields of 7-hydroxy-4-mathylcoumarin 22 (10-43%) cinol and ethyl acetoacetate, in choline chloride: oxalic (Scheme 23a) [29].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 13

- HSO4

NH O

HO OH H - HO OH HSO4 + O O H H O

HO O O HO O O HO OH - HSO4 O -H2O H OH OH O - HSO4

H NH O Scheme 23b. A plausible mechanism for the synthesis of 7-hydroxy-4-methylcoumarin [29].

40 °C S H N N N O O O H H NCS O 24

H N H2N O O O O 22 80 °C N N O O O O O O N HN N N

HS 25 S

O N N NH2 SH N H N R/Ar-NCS R/Ar

HO O O HO O O 23 26 Scheme 24. Synthesis of coumarinyl thiosemicarbazides and triazoles in DESs by Molnar et al. [39].

The reaction mechanism is explained in terms of the polariza- The selectivity of the reaction was affected by the temperature as tion of EAA carbonyl group, by the cation hydroxyl group. This well. This reaction path was successfully applied in the synthesis of cation hydroxyl group acts as a hydrogen bond donor in this polari- triazoles, both from 7-substituted coumarins 22 and 4-substituted zation process, causing higher susceptibility of the carbonyl group coumarins 23 (Scheme 24) [39]. to the resorcinol nucleophilic attack (Scheme 23b) [29]. Coumarinyl Schiff bases (27-29) were synthesized in choline chloride: malonic acid deep eutectic solvent, at 70 °C without any 3.3. Other catalyst added (Scheme 25) [40]. Coumarinyl thiosemicarbazides 24 or triazoles 25 and 26 were 4. MICROWAVE-ASSISTED SYNTHESIS OF COUMARINS synthesized using deep eutectic solvents. Depending on the solvent used, either thiosemicarbazides or triazoles were formed, both in Microwave synthesis is considered as eco-friendly and green the reaction of coumarinyl hydrazide and different isothiocyanates. technique, due to many advantages it provides compared to the

14 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

H N N O O O R O

27 ChCl:MA

70 °C

Cl H N ChCl:MA N O O O H N O H2N O O O 70 °C O O O 28 70 °C R1

ChCl:MA

H N N O O O N N O 29

R2 Scheme 25. Synthesis of coumarinyl Schiff bases in choline chloride: malonic acid deep eutectic solvent [40]. O R O R1 R4 1 ZnO (10% mol) R4 EtO MW R2 O O R2 OH R R3 3 31 Scheme 26. Solvent-free microwave synthesis of coumarin derivatives via Knoevenagel condensation [42].

CHO R R3 piperidine 3

R1 OH CO Et MW 2 R1 O O R2 R2 30 Scheme 27. Knoevenagel synthesis of various coumarin derivatives under microwave irradiation by Kumar et al. [44]. conventional heating. During microwave irradiation, only the sol- Balalaie and Nemati [43] performed a Knoevenagel condensa- vent and solute are heated and not the entire apparatus, so signifi- tion in the reaction of different salicylaldehydes or 2-hydroxy-1- cant energy saving is achieved. The reduction in energy naphthaldehyde and ethyl or methyl malonate. It was a solvent-free consumption is also supported by the reduced duration of reactions. reaction, performed under microwave irradiation, with ammonium Compounds obtained in microwave synthesis are of high purity and acetate as a catalyst, on basic alumina or silica gel. Ethyl 2-oxo-2H- give better yields. An important factor in a microwave synthesis is chromene-3-carboxylate was obtained in 76% and 78% yield [43], the reduced utilization of solvents, both for the reactions and while Bogdal [42] obtained it in 89%. Ethyl 3-oxo-3H- purification, which significantly contributes to the reduction of benzo[f]chromene-2-carboxylate was also successfully obtained in environmental pollution [41]. this research, 77(81)%, while the same compound was obtained in 80% by Bogdal [42]. Kumar et al. [44] obtained ethyl 2-oxo-2H- 4.1. Knoevenagel Condensation chromene-3-carboxylate in 92% (MW) and 85% (heating) yield. Solvent-free microwave synthesis via Knoevenagel condensa- They applied zinc oxide nanoparticles (10 mol%) as a catalyst to tion was performed with piperidine as a catalyst, in 1-10 min (87- obtain various coumarin derivatives 31 under microwave irradiation 220 °C) and excellent yields of the coumarin derivatives 30 were (300 W), at 120 °C in solvent-free conditions (Scheme 27). In addi- obtained (Scheme 26) [42]. tion, they compared a microwave-induced synthesis to the thermal

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 15

O K2CO3, O [bmim]+Br- R1 H R R R1 OEt MW OH O O Scheme 28. Synthesis of coumarin derivatives via Knoevenagel condensation by Valizadeh et al. [46].

R3 R3

R2 CHO O O R2 COOH

O O OH O O R1 R1 R R 32

Scheme 29. Knoevenagel synthesis of coumarins according to [47].

H2N OHC

O O O O O O O O

NH2 CHO 33 34 35 36

O2N

O O O O O O O O

NO2 37 40 38 39 Scheme 30. Some coumarin derivatives synthesized by Cahudhary and Datta [48]. conditions, and microwaves gave better yields in all cases. The solvent-free conditions. The solvent-free reaction gave lower yields authors also compared different solvents (DMF, ethanol, methanol, than the one in ethanol, while both being performed without the acetonitrile and dioxane) and a solvent-free reaction. The highest catalyst. When these synthetic methods are compared, the best product yield was as follows: solvent-free > ethanol > methanol > yields were accomplished with near-infrared and microwave irra- acetonitrile > dioxane > DMF [44]. diation in the shortest times [47]. Moghaddam et al. [45] performed a Knoevenagel condensation in a solvent-free reaction under microwaves, using 10 mol% of 4.2. Pechmann Condensation ZrOCl2·8H2O as a catalyst. When compared to other catalysts, such Phosphotungstic intercalated Bentonite (PTA–Ben) catalyst was as CuSO4, SiO2/KOH and piperidine (in EtOH), ZrOCl2x8H2O was prepared from phosphomolybdic acid and bentonite and used as a found to be the most efficient for a solvent-free reaction, where catalyst in the Pechmann synthesis of different coumarin deriva- ethyl 2-oxo-2H-chromene-3-carboxylate was obtained in 6 min in tives 33-40. Desired compounds were obtained under microwave 86% yield. Ethyl 3-oxo-3H-benzo[f]chromene-2-carboxylate was irradiation (Scheme 30), in 1-7 min [48]. 7-Hydroxy-4-methyl- obtained in 69% yield [45], lower than the previously described coumarin was obtained in 98% yield in 1.5 min, while 6,7-benzo-4- research. Knoevenagel condensation can also be performed using + - methylcoumarin 75% in 7 min and 7,8-benzo-4-methylcoumarin K2CO3 in 1-n-butyl-3-methylimidazolium bromide (bmim Br ) 72% in 7 min. The same compounds were obtained by Vahabi and ionic liquid, using microwaves (Scheme 28). The reaction mixture Hatamjafari [49] as follows: 7-hydroxy-4-methylcoumarin was was microwave irradiated for 1-1.7 min in a domestic oven to ob- obtained in 95% yield in 7 min, while 6,7-benzo-4-methylcoumarin tain product yields 70-91%. This method yielded 85% of ethyl 2- 87% in 7 min and 7,8-benzo-4-methylcoumarin 85% in 8 min. In oxo-2H-chromene-3-carboxylate in 1.5 min and ethyl 3-oxo-3H- this research, a Pechmann condensation was performed under benzo[f]chromene-2-carboxylate 89% in 1.2 min [46]. solvent-free conditions with FeF3 as a catalyst at 110 °C [49]. Martinez et al. [47] compared different methods for the synthe- WO –ZrO nanocomposite oxide (10 wt%) was applied as a sis of coumarin-3-carboxylic acids 32, starting from salicylalde- 3 2 catalyst in a solvent-free Pechmann synthesis of different coumar- hydes and Meldrum’s acid (Scheme 29). Compared methods were as follows: microwave synthesis (5 min, 70 °C/10 min, 80 °C), ins via microwave irradiation (Scheme 31). This method yielded near-infrared synthesis (20 min, 70 °C/25 min, 80 °C), ultrasound 90% of 7-hydroxy-4-methylcoumarin in 2 min, 6,7-benzo-4- synthesis (30 min, 70 °C), mechanical milling (25 min/40 min), methylcoumarin 76% in 2.5 min and 7,8-benzo-4-methylcoumarin mantle heating (350 min, 78 °C), all performed in ethanol and in 82% in 2.5 min [50].

16 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

OH O O O O WO3-ZrO2 R R

EtO R1 solvent-free MW, 1-2 min R1 Scheme 31. Pechmann synthesis of different coumarins via microwave irradiation by Naik et al. [50].

COOCH3 O O 130 °C H3CO OCH 3 MW H2N OH H N O O O 2

41 Scheme 32. Synthesis of 7-aminocoumarins by Frere et al. [56]. O O Ph P CO2CH3 3 OCH 3 + OH MW (300W), O O OH toluene 42 43 Scheme 33. Synthesis of coumarin derivatives by Konradova et al. [57]. O HO HO Ph3P CO2Me OH O O O DIAD, PPh3, THF OH MW, toluene 220 °C, 60 min 0 °C to r.t. O O 44 Scheme 34. Synthesis of O-prenylated coumarin by Konradova et al. [57].

A solvent-free microwave irradiated Pechmann reaction was the best performance. When microwave heating was compared to successfully performed to yield a wide variety of coumarin deriva- the conventional heating, microwaves yielded 87.6% of the product tives in excellent yields (80-96 %), using p-TSA as a catalyst. The in 12 min, while the conventional method yielded 66.4% of the reaction was performed in only a few minutes in a microwave oven product in 1.5 h [54]. Rajitha et al. [55] used a microwave heating at 400 W. The yields of the obtained products are comparable to of 450 W and solvent-free conditions, using dipyridine copper chlo- those described before, with the yield of 7-hydroxy-4-methyl- ride to obtain 93% of 7-hydroxy-4-methylcoumarin in 10 min [55]. coumarin 94% [51]. The same reaction can be performed under 7-Amino coumarins 41 were synthesized via Pechmann con- microwave irradiation (140 W) using [bmim][HSO4] (1-butyl-3- densation using a solid support graphite/montmorillonite K10 under methyl-imidazolium hydrogen sulphate) as a catalyst, in 2-10 min- microwave irradiation (130 °C) in 8 minutes, obtaining the yields of utes, while the conventional heating in 1,2-dichloroethane as a sol- 61-75% (Scheme 32). Utilization of the solid support was not effec- vent took 5-20 hrs of heating. For example, 7-hydroxy-4- tive in case of liquid/solid reactants due to the occurrence of some methylcoumarin was obtained in 81% and 2 min by microwaves, uncontrolled reactions followed by the decrease in the final yields while thermal heating yielded 62% of the same product in 12 h. [56]. Also, 7,8-benzo-4-methylcoumarin was obtained in 96% yield in 6 min by microwaves, and in 75% yield and 6 h by thermal heating 4.3. Wittig Condensation [52]. A microwave Wittig reaction between salicylaldehyde and cor- 4-Methylcoumarins were also synthesized in a Pechmann reac- responding ylide was performed under microwaves at 300 W by tion of substituted phenols and ethyl or benzoyl acetoacetate, in a Konradova et al. (Scheme 33) [57]. Lower temperatures and shorter sulfuric acid adsorbed on silica gel catalyzed reaction. Reactions reaction times of 30 min yielded both coumarin 42 and cinnamic were performed in 3-12 minutes in high yields (55-93%). A reac- acid 43 derivatives, while higher temperatures (220 °C) and longer tion of only 3 min yielded 91% of 7-hydroxy-4-methylcoumarin reaction times 45-75 min yielded only coumarin derivatives 42 and 6 min 92% of 7,8-benzo-4-methylcoumarin [53]. 7-Hydroxy-4- [57]. methyl coumarin can be synthesized via Pechmann condensation under microwaves using zirconium sulfate tetrahydrate as a cata- The same authors also prepared two biologically active cou- lyst, in 12 min at 500 W using cyclohexane as a dehydration agent marin derivatives, O-prenylated coumarin 44 and osthole. O- [54]. In this reaction, 7-hydroxy-4-methylcoumarin was obtained in prenylated coumarin was prepared in a two-step reaction, where an 87.5% yield. The authors compared benzene, toluene and cyclo- only the first step was performed under microwaves, following the hexane as dehydrating agents, and cyclohexane was found to have above-described procedure (Scheme 34) [57].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 17

S O Br O R O S

S 49 O O Br R = CH , C H Br O O R 3 2 5 KS O , EtOH/MeOH 45 S K CO , DMF 2 3 Conventional or MW O O O R r.t., 10 h S O O O O OH Br 50

R = CH3, C2H5

46 O O S O Br O R O S S O O OH R 51 KS O , EtOH/MeOH O O O O R = CH3, C2H5 47 Conventional or MW S O O O R O O O Br S O Br Br 52 K2CO3, DMF r.t., 12 h R = CH3, C2H5 48 Scheme 35. Synthesis of various coumarin derivatives by Mangasuli et al. [58].

O O O KI, KIO3, H Piperidine OEt HCl, HAc OEt r.t., 2h HO O O HO OH r.t., 4h HO O O I 53 O O OEt

OEt R1 B(OH)2 Pd(OAc)2, KF HO O O HO O O R2 PEG-400:EtOH I MW, 110 °C, 30 min 54

R1 R2 Scheme 36. Synthesis of coumarin derivatives via Suzuki coupling by Vieira et al. [59].

4.4. Other 37). Desired compounds were obtained in piperidine catalyzed reac- Mangasuli et al. [58] synthesized various coumarin derivatives tion in excellent yields, in 4-6 minutes under microwave irradiation, 45-52 (Scheme 35) and compared a microwave and conventional much shorter time compared to the KOH catalyzed conventional synthesis, where microwaves were predominant considering method (6-9 h) [60]. Further cyclization of synthesized chalcones reaction selectivity, time, rate and yields [58]. with guanidine hydrochloride yielded the corresponding pyrimidine derivatives 57 and 58, where microwave synthesis once again was Different coumarin derivatives 54 were synthesized via Suzuki much more efficient considering product yields and reaction time coupling, using PEG-400 as a solvent, 10 mol% of Pd(OAc) as a 2 [61]. catalyst, KF as a base, under microwave irradiation, from 8- iodocoumarin with different phenylboronic acids (Scheme 36). 8- Coumarin derivatives with cyanopyridine and furan groups 60 Iodocoumarin 53 was synthesized in Knoevenagel condensation were synthesized under microwave irradiation. First, coumarinyl between 2-hydroxybenzaldehyde and diethyl malonate, followed by nicotinonitriles 59 were synthesized in the reaction of 3- the iodination [59]. acetylcoumarin, aromatic aldehydes, malononitrile and ammonium acetate at 130 °C for 6-10 min under microwaves. Then, nicotinoni- Helmy et al. [60, 61] compared microwave and conventional triles in reaction with 2-furfuraldehyde, in the presence of acetic methods in the synthesis of some coumarinyl chalcones 55 and 56, acid and ZnCl as a catalyst, yielded the desired compounds 60, in starting from 3-acetylcoumarin and different aldehydes (Scheme 2 8-10 min at 300 W (Scheme 38) [62].

18 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

O O

COCH3

Pip-acetate/EtOH/Reflux or KOH/EtOH/MWI R X

O O O O X COCH=CH COCH=CH R 55 X = O, S 56

NH·HCl EtOH/MWI NH·HCl EtOH/MWI or H2NC H2NC or NAOAc/EtOH/Reflux NAOAc/EtOH/Reflux NH2 NH2

O O O O X R

NN NN

57 NH2 NH2 58 Scheme 37. Synthesis of coumarinyl chalcones and pyrimidine derivatives by Helmy et al. [61]. CHO O O O O R CH2(CN)2 + NH4OAc

R EtOH, 350W, 130 °C, 6-10 min O N CN R = -H; -4-Cl; -4-F; -4-OCH3; -4-NO2; 59 NH -4-CH3; -3-Cl; -3-F; -3-NO2; -4-OH; 2 -3-OCH3; -3-OH; -3-CH

O O OHC O R

AcOH + ZnCl2 300W, 100 °C N 8-10 min CN N HC

O 60

Scheme 38. Synthesis of coumarin derivatives performed under microwave irradiation by Desai et al. [62].

Coumarinyl benzoimidalozes 61 were efficiently synthesized which took 4-6 hrs, the microwave method greatly reduced the under microwave irradiation by condensation of o-arylenediamines reaction time [63]. and coumarinyl aldehydes in 5-8 minutes, yielding up to 94% of the Excellent yields were obtained using a microwave (100 W) syn- products (Scheme 39). Compared to the conventional method, thesis of coumarin-purine derivatives 62 (Scheme 40). They were

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 19

O O NH2 R X O O Y CHO N Y NH2 R NH N Reflux or MW N N Ph N

Ph 61 Scheme 39. Synthesis of coumarinyl benzoimidalozes under microwave irradiation by Kumbar et al. [63]. O

N N Br O O N N N N Activated K2CO3, Acetone R O O O N N Conventional (r.t. 6-8h) H or MW (100W, 50 °C, 5-9 min) R O O

62 Scheme 40. Synthesis of coumarin-purine derivatives under microwave irradiation [58]. O O O OH H H EtOAc, r.t. H

MeO OH TFFA, Cu(acac) MeO O H2 (1 atm), MeO O DBU, CH CN 3 Pd/CaCO3 -5 °C to 0 °C, 5 h

Ph3P CO2Me MeO O O MW (300 °C), toluene 185 °C, 60 min 63

Scheme 41. Synthesis of osthole in three-step reaction performed by Konrádová et al. [57]. synthesized from 4-bromomethyl coumarin and purine in acetone, than the conventional synthesis (4-6 hrs) (Scheme 43). Product and using anhydrous potassium carbonate, in 5-9 minutes. Conven- yields obtained by this method (82-95%) were much higher when tional heating took 6-8 hrs to yield the same compounds [58]. compared to the conventional synthesis 45-68% [65]. The synthesis of osthole 63 was performed in a three-step reac- A formylation of different coumarins was performed under mi- tion, where only the third step was performed under microwave crowave irradiation at 800 W, in a reaction of coumarins 67 with irradiation at 185 °C for 60 min (Scheme 41) [57]. hexamethylenetetramine, in the presence of trifluoroacetic acid, for A solvent-free microwave synthesis of 7-substituted coumarin 3 minutes (Scheme 44). A formylation yielded formylated coumar- derivatives was performed and compared to the conventional heat- ins 68 and 69. Other solvents such as acetic acid, PEG-400, acetic ing using different catalysts (Scheme 42). Ester 64 was synthesized acid:PEG-400 and TFAA:PEG-400, were less efficient than TFAA. in a solvent-free reaction using potassium carbonate as a catalyst. PEG-400 and acetic acid:PEG-400 yielded no product under these Schiff bases 65 were synthesized in a microwave oven at 80 W for conditions [66]. 2-3 min. A reaction that was performed conventionally took 1-2.5 Coumarinyl-triazoles 72 were synthesized under microwave ir- hrs, while in a microwave oven took only 2-3 minutes [64]. radiation in a catalyst-free reaction, from coumarinyl-benzotriazoles Coumarin-pyrazole derivatives 66 were synthesized in 8-12 70 and 1,2,4-triazole derivatives 71. Reactions were performed minutes at 35 °C using K2CO3 as a catalyst, in much shorter times in ethanol, at 130-140 °C, for 20-35 min (Scheme 45). Microwave

20 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

O C2H5 HO O O Conv. (K2CO3) O O O O Conv. (NaBiO ) 3 C2H5O C O Solvent-free, MW H2C CH 64 3 Cl CH3

H2N NH2

O O

R N O O O R-CHO H2N O O O N N H H H+, Reflux

CH CH3 65 3 Scheme 42. Solvent-free microwave synthesis of 7-substituted coumarin performed by Satyanarayana et al. [64].

N N N

K CO , OH 2 3 O N O acetone R Br MW (200 W), 8-12 min, 35 °C N O N Conventional, 4-6 h O 66 R O O Scheme 43. Synthesis of coumarin-pyrazole derivatives by Chavan and Hosamani [65]. R R R O O O

HMTA, TFAA O R1 R1 AND R1 MW O O O O O O

67 68 O 69 Scheme 44. Synthesis of different coumarin derivatives under microwave irradiation [66]. O H2NHN O R N H N R N N N O N N MW N N H R1 O O O O R N N 1 O O O NH2 NH2 70 71 72 Scheme 45. Synthesis of coumarinyl-triazoles under microwave irradiation in a catalyst free reaction [67]. synthesis was found to be more efficient in terms of reaction times The same authors performed a reaction of 3-hydrazino-2- (25-35 min) and yields (58-72 %) than the conventional method (6- quinoxalinone 76 with 3-acetyl coumarin derivatives 75, to obtain 8 h; 38-51%) [67]. different hydrazones 77, in only 1 min under microwave irradiation The reaction of 3-acetylcoumarin 73 with different amines (Scheme 47) [68]. yielded Schiff bases 74 under microwave heating (300 W) in 1-2 A novel coumarin-thiazoline hybrids 79 were synthesized in the minutes (Scheme 46). The same reaction performed conventionally reaction of 3-bromoacetyl coumarin and 2-arylidenehydrazino- gave much lower yields (14-91%) in longer times (15-210 min) carbothioamides 78 under microwave irradiation (60 W), using [68]. NaOH as a catalyst in 10 min at 100 °C (Scheme 48) [69].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 21

Ar/R O N

CH3 amine CH3

O O EtOH, MW O O 74 73 Scheme 46. Reaction of 3-acetylcoumarin with different amines under microwave heating [68].

HN N O NH O N H O N DMF/EtOH (1:1) CH CH3 3 + H2N O O N N O O R H R 75 76 77 Scheme 47. Synthesis of different hydrazones under microwave irradiation performed by Ajani et al. [68]. O S S Br NH Ar N N N NH + EtOH/MW, 10 min N H 2 O O Ar O O 78 79 Scheme 48. Synthesis of coumarin-thiazoline hybrids under microwave irradiation [69]. O O H R O MW, 135 °C, N 1 R1 N R N 15 min N N R H HN O R EtOH, 4h, reflux O O 2 R2 O O NH2 R3 R3 82 80 81

Scheme 49. Synthesis of coumarinyl hydrazides under microwave irradiation performed by Yilmaz [70].

Coumarinyl hydrazides 82 were synthesized from correspond- (Scheme 51). Acetic acid as a solvent gave better results in this ing benzotriazoles 80 and hydrazides 81 (Scheme 49). Microwave reaction, when compared to THF and dioxane. Iodine as a catalyst heating was applied and the reaction times were 15 minutes, with was predominant when compared to BF3·OEt2, SnCl2, Bi(NO2)3, excellent yields 65-82%, while conventional heating took 4 hours AlCl3, CuI, AuCl3, Ag(OTf) [72]. [70]. In a Claisen-Schmidt microwave supported condensation of 5. SOLVENT-FREE REACTIONS IN COUMARIN SYNTHE- coumarinyl-ketone 83 and pyrazolyl-aldehydes 84, chalcones 85 SIS were formed. Further condensation of chalcones with hydrazine Solvent-free reactions are widely used due to the reduction in hydrate, yielded desired pyrazolyl-coumarin hybrids 86 (Scheme economical cost and reduced environmental pollution. In compari- 50). The reactions were completed in only a few minutes for each son with conventional methods, solvent-free reactions are cleaner, step, with much higher yields than the ones obtained by the conven- faster, safer, cheaper and easier to perform [73]. tional method. All reactions were performed in a Milestone multi- SYNTH microwave system [71]. 5.1. Knoevenagel Condensation Microwave induced multicomponent reaction of aromatic Scott and Raston (2000) described the solvent-free synthesis of amine, aromatic aldehyde and 4-hydroxycoumarin, catalyzed by 3-carboxycoumarins 89 from different salicylaldehydes and Mel- iodine, yielded different fused coumarinyl quinazolinine derivatives drum’s acid, with a catalytic amount of ammounium acetate, per- 87. A reaction was performed at 165 °C for 30 min in acetic acid

22 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

R2 N O R2 Ph N Ph N HO O O N EtOH, MW R O + 1 Piperidine HO O O CHO 83 84 85

O 2 · H 2

R1 N-NH H 2 Ph N N XH R2 NaOH, NaOAc, MW NH N HA HB HO O O

86 Scheme 50. Pyrazolyl-coumarin hybrids synthesis in Claisen-Schmidt microwave supported condensation [71].

O NH CHO O 2 CHO O R1 I2/CH3COOH O OH S 165 °C, MW, 30 min N R3

R1 R2 87 R2 Scheme 51. Synthesis of coumarinyl quinazolinine derivatives in multicomponent reaction described by Sashidhara et al. [72]. R O O O O O O + - O -H2O NH4 CH3CO2 + O OH OH O R R O OH O O 89 88 Scheme 52. Synthesis of 3-carboxycoumarins performed by grinding according to Scott and Raston [74]. formed by grinding. Their reaction includes a formation of a A solvent-free Knoevenagel condensation of 2-hydroxyben- Knoevenagel product 88, which is converted to the final coumarin zaldehyde derivatives and malonic acid was performed with ammo- product 89 upon the addition of ammonium acetate (Scheme 52) nium bicarbonate as the catalyst, in the synthesis of 3,4- [74]. unsubstituted coumarins 92 (Scheme 54). In this reaction, an inter- A condensation of salicylaldehydes and active methylene com- mediate 3-carboxycoumarin 91 is formed at 90 °C, followed by pounds into coumarins 90 can be performed in a solvent-free condi- decarboxylation at 140 °C to form 3,4-unsubstituted coumarin 92 tion, when L-proline is used as a catalyst, in 30 min (Scheme 53). [76]. Ethyl 2-oxo-2H-chromene-3-carboxylate in this method was obtained in 96% yield, while coumarin-3-carboxylic acid was ob- 5.2. Pechmann Condensation tained in a reaction with malonic acid, in 91% yield and in a reac- Silver supported on hydroxyapatite-core–shell magnetic γ- tion with Meldrum’s acid in 84% yield [75]. Fe2O3 nanoparticles were synthesized and applied as a catalyst in

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 23

CH OH R R 2 1 L-proline 1 R + R solvent-free OH COOEt 80-90 °C O O 90 R1 = COMe, COOEt, CN, COOH

Scheme 53. L-proline catalyzed reaction of coumarin derivatives performed by Karade et al. [75]. H H NH HCO 4 3 R O 140 °C O O O O H 92 R + HO OH OH

H O NH4HCO3 OH 90 °C R O O

91 Scheme 54. Synthesis of coumarin derivatives in solvent-free Knoevenagel condensation [76].

OH O O O O g-Fe2O3@HAp-Ag NPs R1, R2 R1, R2 R3 OEt solvent-free, 80 °C

R1 = OH, Me, OMe, NH2, Ar R3 R2 = OH, Me R = Me, CH Cl, Ph, cyclic 1,3-ketoester 3 2 Scheme 55a. Solvent-free reaction of coumarin derivatives according to Abbasi et al. [77]. the coumarin synthesis (Scheme 55a). The reaction conditions were to 1 h [80]. The same reaction was performed solvent-free and in 80 °C and 20 min. Other catalysts, like polyvinylpolypyrrolidone- toluene, where the solvent-free conditions gave better yields in less bound boron trifluoride, sulfated zirconia, hydrophobic sulfonated time. Therefore, 7-hydoxy-4-methylcoumarin was obtained in 87% nanocatalyst CMK-5-SO3H, iodine, H6P2W18O62·24H2O, and in 0.7 h solvent-free and 82% in 4.5 h in toluene. 7,8-Benzo-4- mesoporous zirconium phosphate, were also used in this reaction, methylcoumarin was obtained in 75% yield in 0.8 h [80]. Chavan et but above-mentioned catalyst was the most efficient, considering al. (2015) performed a Pechmann reaction with phosphomolybdic reaction conditions, solvents, reaction time, product yield. The cata- acid (PMA):silica-supported BF3:OEt2 as a catalyst under, solvent- lyst was efficiently separated using an external magnetic field. The free conditions, using a grinding method. This method yielded 96% catalytic activity of this catalyst is assumed to exist due to its role as 7-hydroxy-4-methylcoumarin, 69% 7,8-benzo-4-methylcoumarin a Lewis acid (Scheme 55b). In this research, 7-hydroxy-4- and 55% 6,7-benzo-4-methylcoumarin [81]. Zirconyl(IV) chloride methylcoumarin was obtained in 95% yield in 20 min [77], while (ZrOCl2) was found to be very efficient in a solvent-free Pechmann Maheswara et al. [78] obtained it in 95% yield in 35 min. They synthesis of coumarins, yielding 75-95% of the products at 120 °C. synthesized coumarins from substituted phenols and ethyl or methyl The yield of 7-hydroxy-4-methylcoumarin thus obtained was 95%, acetoacetate, in the presence of HClO4·SiO2 catalyst, under the while for 7,8-benzo-4-methylcoumarin was 82% [82]. The same solvent-free conditions at 130 °C. 7,8-Benzo-4-methylcoumarin was investigated for ZrCl4 as a catalyst. A reaction was performed was obtained in 89% yield in 65 min, while other coumarins were at 70 °C with the 2 mol% of the catalyst, obtaining 95% 7-hydoxy- obtained in 30-90 min [78]. Keri et al. [79] performed a Pechmann 4-methylcoumarin in 8 min and 78% 7,8-benzo-4-methylcoumarin condensation in the solvent-free conditions under reflux, using in 15 min [83]. phosphotungstic acid, H3PW12O40 (2 mol%) as a catalyst. A reac- Pechmann condensation was also performed by Reddy et al. tion was performed at 90 °C yielding 94% 7-hydroxy-4- [84] under the solvent-free conditions, with H2SO4/silica gel as a methylcoumarin in 30 min and 60% 7,8-benzo-4-methylcoumarin catalyst at 120 °C (Scheme 56a). They compared the reactivity of in 90 min [79]. Solvent-free conditions showed higher product different β-keto esters to obtain coumarin derivatives and found that yields than the conventional organic solvents, toluene, THF, diethyl acetoacetate ≈ methyl acetoacetoacetate > methyl cyclohex- oxane and acetonitrile. Another heteropolyacid catalyst, the Wells– anone-2-carboxylate > α-methyl ethyl acetoacetate > ethyl trifluoro Dawson (WD) catalyst (H6P2W18O62·24H2O) was efficiently ap- acetoacetate. This reaction yielded 80% of 7-hydroxy-4- plied for the Pechmann synthesis of coumarins, at 130 °C in 30 min methylcoumarin in 5 min [84]. Narwal et al. [85] applied a grinding

24 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

H H O O O O O O O O O + H O O HO HO

O O O -H O O -EtOH 2

HO O HO O O HO O O H Scheme 55b. A proposed mechanism for the synthesis of coumarin derivatives by Abbasi et al. [77].

CH3 CH3 CF3 O O H2SO4/silica gel + F3C OEt HO OH HO O O Scheme 56a. Synthesis of coumarins under solvent-free conditions performed by Reddy et al. [84].

HO OH HO OH

H H

R1 R1

HO OH O OH SO H HO OH 3 R' + R' R'' O R O H R'' R OH R1 R1 O

HO O HO O HO OH -H O R' R' 2 R'' R'' O O R'' -R'OH R OH R R OH2 O R1 R R1 2 O 1

Scheme 56b. A reaction mechanism for the synthesis of coumarins by Reddy et al. [84]. method with anhydrous P2O5, at room temperature to perform a methylcoumarin in 20 min (r.t.) and 86% of 7,8-benzo-4- Pechmann condensation. Coumarin derivatives were obtained in methylcoumarin in 60 min (65 °C). Furthermore, this catalyst was high yields, 80-90%, with the yield of 7-hydroxy-4-methylcoumarin also used in the reaction of phenols and propionic acid to yield of 89% and 6,7-benzo-4-methylcoumarin 82% [85]. different coumarins 93, like 6-methylcoumarin, 7-hydroxy- The reaction mechanism includes transeseterification, in- coumarin, 7-methoxycoumarin, 7,8-dihidroxycoumarin and 5,7- tramolecular hydroxyalkylation and finally dehydration (Scheme dihidroxycoumarin [86]. 7-Hydroxy-4-methylcoumarin was synthe- 56b) [84]. sized in a solvent-free Pechmann reaction, catalyzed by trifluoro- A synthesis of 4-methylcoumarins 92 via Pechmann condensa- methanesulfonic acid (triflic acid) functionalized Zr-TMS (Zr-TMS, zirconia-based transition metal oxide mesoporous molecular sieves) tion was performed using ZrCl4 in a catalytic amount at room temperature (Scheme 57). This reaction yielded 98% of 7-hydroxy-4- with 100% selectivity at 373 K [87].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 25

CH3

O O ZrCl4

OEt solvent-free R HO OH r.t. - 65 °C O O 92

ZrCl4 solvent-free HO OH HOOC 100 °C R O O 93

Scheme 57. Synthesis of coumarin derivatives catalyzed by ZrCl4 [86].

H3CO O O H3CO OH O O AlSBA-1

H3C OC2H5 CH3 Scheme 58. Synthesis of 7-methoxy-4-methylcoumarin in solvent-free Pechmann condensation by Peng et al. [88]. O

R1 O R1 H Ph3P/Et3N + Br O CH3 R2 OH R2 O O

R1 = H, MeO, OH R = H, OH 2 Scheme 59. Wittig coumarin synthesis in solvent-free triethylamine catalyzed reaction [94].

7-Methoxy-4-methylcoumarin was obtained with 74% selectiv- phenol, 2-nitrophenol and p-chlorophenol were not obtained by this ity in a solvent-free Pechmann condensation using AlSBA-1 mo- method. 7-Hydroxy-4-methylcoumarin was obtained in 68% yield lecular sieves (Scheme 58), which were synthesized by Peng et al. at 110-140 °C in 7 min, while 7,8-benzo-4-methylcoumarin yielded [88]. They explain the reaction mechanism in terms of its catalytic 39% and 6,7-benzo-4-methylcoumarin 57%, all yields lower than activity due to the Bronsted acid sites of the catalyst. For compari- previously reported solvent-free reactions [93]. son, Keri et al. [79] obtained the same product in 94% yield, Cha- van et al. [66] 90%, Narwal et al. [85] 90%, Maheswara et al. [78] 5.3. Wittig Condensation 82%, Abbasi et al. [77] 87%, all in the solvent-free reactions. Wittig coumarin synthesis (Scheme 59) was performed from o- A solvent-free Pechmann reaction in the synthesis of coumarins hydroxybenzaldehydes or o-hydroxyacetophenones with ethoxyl- was performed over three heterogeneous catalysts under microwave carbonyl triphenylphosphine in a solvent-free, triethylamine cata- irradiation. Amberlyst-15, zeolite β and sulfonic acid functionalized lyzed reaction [94]. hybrid silica were used as the catalysts in this reaction. Amberlyst- 5.4. Other 15 was found to be the most efficient one with a reaction temperature of 130 °C. 7-Hydroxy-4-methylcoumarin was obtained in 97% Coumarinyl thiazolidinones 94 were synthesized in a solvent- yield [89]. Hussien et al. [90] also performed a solvent-free Pech- free, one-pot reaction by grinding method, in the reaction of cou- mann reaction with Amberlyst-15 (10 mol%) as a heterogeneous marinyl carbothioamide, chloroacetyl chloride and aldehydes, with catalyst at 110 °C, starting from resorcinol and ethyl acetoacetate, alum [KAl(SO4)2 ·12H2O] (Scheme 60) [95]. to obtain 7-hydroxy-4-methylcoumarin. Different solvents were Dihydropyrano[2,3-c]chromenes 95 were synthesized in a also examined in this research for their efficiency, where only tolu- three-component, visible light promoted reaction from aromatic ene gave a high 7-hydroxy-4-methylcoumarin yield of 92%, but aldehydes, different nitriles and 4-hydroxycoumarin in a solvent still lower than the solvent-free reaction, 95% [90]. and catalyst-free reaction (Scheme 61). Different intensities of the Glutamic acid can also be used as a catalyst in a solvent-free light were used, 8, 15, 20, 22 and 32 W, with 20 W giving the best Pechmann synthesis of coumarin derivatives [91], as well as other results. An amount of malononitrile was found to have an important acids. Therefore, a Pechmann solvent-free synthesis of coumarins impact on the product yield, therefore the ratio of the optimum was performed under microwave irradiation with L-ascorbic acid as reactants was proven to be 1:1.2:1 (aldehyde:malononitrile:cou- a catalyst, obtaining the desired coumarins in 88-97% yield [92]. marin). All reactions were performed for 1.5-2.5 hrs, at room tem- Oxalic acid could also be used as a catalyst in this kind of reaction. perature and under air [96]. An oxalic acid-catalyzed solvent-free Pechmann condensation was A solvent-free cycloaddition of 3-nitrocoumarins with trimeth- performed from phenols and β-ketoesters under microwave irradia- ylsilyl azide was performed (Scheme 62). This reaction was tion by Monga et al. [93]. All reactions were conducted at tetrabutylammonium fluoride catalyzed and performed at 50 °C for 110-140 °C, for 5-10 minutes, in 39-70% yields. Derivatives with 0.75-31 h [97].

26 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

R H N NH2 N O N S [KAl(SO4)2 · 12H2O] S N O O Cl Cl HN grind (8-15 min), r.t. OEt O O H O O OEt 94

Scheme 60. Synthesis of coumarinyl thiazolidinones in a solvent-free one-pot reaction by [95].

NH2

R2 O OH

CHO CN visible light R1 R1 + + solvent-free O O R2 O O no-catalyst 95 R1 = aryl, heteroaryl R = CN, COOEt 2 Scheme 61. Synthesis of dihydropyrano[2,3-c]chromenes in catalyst-free three-component reaction [96].

N N N N N N H NO2 TMS N3-TMS R R R NO2 TBAF O O O O O O

Scheme 62. Synthesis of coumarin derivatives in solvent-free reaction catalyzed by tetrabutylammonium fluoride [97].

OH OH

SH solvent-free, 80 °C S R R I /DMSO O O 2 O O 96 Scheme 63. Synthesis of coumarin derivatives in solvent-free reaction performed by Parumala and Peddinti [98].

CHO R2 OEt MgFe2O4 nano R1 + R2 R1 OH O Ultrasound O O 45 °C, solvent-free R1 = OH, OCH3, N(CH3)2 97 R = COCH , CO Et 2 3 2

Scheme 64a. Synthesis of 3-substituted coumarins under ultrasonic irradiation catalyzed by MgFe2O4 [100].

Different aryl thioles were reacted with 4-hydroxycoumarin sound-assisted processes are based on the cavitation phenomena. yielding different coumarinyl aryl sulfides 96. Reactions were per- Within the reaction media, cavitation bubbles are collapsed, gener- formed in solvent-free conditions at 80 °C, using I2/DMSO as an ating a certain amount of energy [99]. oxidant (Scheme 63) [98]. 6.1. Knoevenagel Condensation 6. ULTRASOUND-ASSISTED SYNTHESIS OF COUMARINS Knoevenagel synthesis of 3-substituted coumarins 97 was per- Ultrasound irradiation is different from other conventional formed in MgFe2O4 nanoparticles (4 mol%) catalyzed reaction, of methods with energy sources like heat, light or ionizing radiation. salicylaldehydes and 1,3-dicarbonyl compounds, under ultrasonic Pressure and energy per molecule in an ultrasound-assisted synthe- irradiation (20 kHz, 35W, 45 °C) (Scheme 64a). MgFe2O4 nanopar- sis affects faster chemical reaction and therefore lower costs. Usu- ticles can be easily separated from the reaction mixture using a ally, milder reaction conditions and shorter reaction times are ap- magnet. Nano CuO, nano MgO and nano ZnO were also examined, plied, with high efficiency and low energy requirements. Ultra- but MgFe2O4 nanoparticles showed the best efficiency. Ethyl 2-

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 27

O OEt R2 O OEt OH R2 CHO R2 H O HO -H2O

)))) )))) )))) R OH R1 OH R1 O O 1 R1 Scheme 64b. A proposed mechanism for the synthesis of 3-substituted coumarins by Ghomi et al. (2018) [100].

O R2

R2 FeCl3 R1 R1 MW or ultrasound OH OEt O O O 98 R1 = OH, OMe R = Me, Propyl, CH Cl 2 2

Scheme 65. Ultrasonic assisted coumarin synthesis via Pechmann condensation catalyzed by FeCl3 [101].

R1 R2 CH2COCl R CH OH 2 R1 R THF, K2CO3 + OH O O

R2 R = H, NO2, Br 99 R = R = H, NO 1 2 2

Scheme 66. Synthesis of 3-aryl coumarins under ultrasound irradiation [104]. oxo-2H-chromene-3-carboxylate was obtained in 93% yield in 10 ZSM-5 zeolites purchased from different companies, and the effi- minutes, which was better than the conventional synthesis (70%, cacy order was: mordenite>Y>beta>ZSM-5 [102]. Poly(4- 240 min) [100]. vinylpyridinium) hydrogen sulfate (PVPHS) was also used as a This mechanism includes a formation of the complex between catalyst in an ultrasound-assisted Pechmann reaction of phenols and carbonyl group oxygen in salicylaldehyde and nanocatalyst Mg. methyl/ethyl acetoacetate. Solvent-free conditions were much more Then it reacts with the active methylene group from ethyl acetoace- efficient than the conventional solvents like toluene, methanol, tate, followed by transesterification and dehydration. The reaction ethanol and dichloromethane under reflux. 7-Hydroxy-4- is promoted by both the nanoparticles and cavitation caused by the methylcoumarin was obtained in 96% yield in 5 min [103]. ultrasound irradiation (Scheme 64b) [100]. 6.3. Wittig Condensation 6.2. Pechmann condensation 3-Aryl coumarins 99 were synthesized in one-pot reaction from Ultrasonic assisted (20 kHz, 130 W) coumarin synthesis via different salicylaldehydes and phenyl acetyl chlorides, in the pres- Pechmann condensation was compared to the microwave synthesis ence of K2CO3, under ultrasound irradiation (Scheme 66) [104].

(100 °C, 150W), when FeCl3 was used as a catalyst, and was found 3-Phenylcoumarins 100 were synthesized in the reaction of to give better yields of the products 98 (Scheme 65). Both methods salicylaldehyde and phenyl acetyl chloride, in the presence of N- gave much higher yields than the conventional one. Therefore, 7- methyl imidazole (Scheme 67). The reaction took 3 hrs under soni- hydroxy-4-methylcoumarin was obtained as follows: ultrasound cation at 50 °C with 12-98% yields. 4-Nitrophenyl acetyl chloride 97%, 20 min; microwave 76%, 10 min, conventional heating 99%, gave the lowest yields (12 and 15%). N-Methyl imidazole was used 12 h. 7,8-Benzo-4-methylcoumarin was obtained by ultrasound to absorb a liberated HCl, forming N-methylimidazole hydrochloride, which can be deprotonated using NaOH, and further dehy- 87%, 20 min, microwave 40% 10 min, conventional heating 54%, drated back to N-methyl imidazole [105]. Katkar et al. [105] ob- 12h [101]. tained 3-phenylcoumarin in 98% yield in 180 min, 6-nitro-3- An ultrasound was applied in the synthesis of 7-hydroxy-4- phenylcoumarin in 75% yield in 180 min, 6-bromo-3- methylcoumarin by Pechmann condensation, where the obtained phenylcoumarin 25% yield, 3-(4-nitro-phenyl)coumarin 12% and 6- yield was 70% and the selectivity almost 100%. Different types of bromo-3-(4-nitrophenyl)coumarin 15%, while Sripathi et al. [104] zeolite were applied as catalysts and their efficacy was channel size obtained the yields of 69% (30 min), 55% (20 min), 20% (30 min), and acidity dependent. The authors used mordenite, Y, beta and 7% (25 min) and 10% (30 min).

28 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

OH Cl N + + N H O H O + HCl+ 2 N O O N O 100 Scheme 67. Ultrasound assisted synthesis of 3-phenylcoumarins [105]. O

CH3 CH3 H N N N R O O S O O N N 3N /Et 101 Ar NH2NHCSNH2 xan nd dio ethanol/HCl, ultrasound ultrasou X

RCOC ArN Cl/ NNHAr 2 CH3COONa ·3H2O CH3 H N NH2 N

S CH O O 3 H RCOCH2X N N 103 N R dioxan S ultrasound O O

ClCH2COOH 104 AcOH, AcONa ))) CH3 H N N N O S ArCHO O O 105

ClCH2COOH AcOH, AcONa AcOH, AcONa ))) ))) ArCHO

CH3 H N N N O S O O

102 Ar Scheme 68. Synthesis of coumarin thiazole or thiazolidinone derivatives in ultrasound assisted reactions [106].

6.4. Other and thiosemicarbazide yielded compound 103, which is one-step Various coumarin thiazole 101 or thiazolidinone 102 deriva- reaction with hydrazonoyl halides yielded desired thiazole derivatives were synthesized from 3-acetylcoumarin in an ultrasound tives 101. The same could be obtained in a two-step reaction, first assisted reactions (Scheme 68). The reaction of 3-acetylcoumarin thiazole derivatives 104 are synthesized from compound 103 and

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 29

O CH3 H CH N CH2CN 3 NH2NHCOCH2CN N

O O EtOH, HCl, ))) O 106 O O

ArCHO, EtOH EtOH, piperidine, salicylaldehyde ))) piperidine ))) CN CH3 H HN O N C Ar CH3 N H N O N O O 107 O O O 108 Scheme 69. Synthesis of different coumarin derivatives performed by [106].

R O OH OH OH

H ultrasound R + H O, ambient O O 2 O O O O

109 Scheme 70. Synthesis of bis-coumarin derivatives in ultrasound-assisted reaction [107]. O O O O gly-SH R2 ylg S H2C ultrasound

110 R1 111 R1

R1 = H, CH3 R = 6 or 7-CH Br 2 2 Scheme 71. Synthesis of coumarin thioglycopyranoside derivatives performed by Yu et al. [108]. further reaction with diazotized aniline produces the desire thiazole 7. MECHANOSYNTHESIS OF COUMARIN DERIVATIVES derivatives 101 [106]. Thiazolidinones 102 were synthesized in the Mechanosynthesis is a process where mechanical energy is used one-step reaction of 103, chloroacetic acid, anhydrous sodium ace- to carry out a chemical reaction. Most often, these reactions are tate, acetic acid and corresponding aldehyde. The same can be performed in a two-step process, where compound 103 is first reacted performed by grinding of two or more components in a mortar or with chloroacetic acid, anhydrous sodium acetate and acetic acid to using a ball mill. One of the biggest benefits of mechanosynthesis is form compound 105, and further addition of aldehyde yields tha- a reduction of side reactions, which contributes to the increase in izolidinone 102 [106]. yield, and higher purity of the final product. It is one of the eco- friendly techniques due to reduced usage of solvents that contribute When 3-acetyl coumarin is reacted with 2-cyanoaceto- hydrazide, compound 106 is formed. Compounds 106 in reaction to environmental pollution [109]. with different aromatic aldehydes yield Schiff bases 107, while in 7.1. Knoevenagel Condensation the reaction with salicyladehyde, compound 108 is formed (Scheme 69) [106]. Sugino and Tanaka [110] performed a solvent-free Knoeve- Bis-coumarin derivatives 109 were synthesized from different nagel and Pechmann synthesis of coumarins (Scheme 72). Pech- aromatic aldehydes and 4-hydroxycoumarin in ultrasound-assisted mann synthesis was performed using p-toluenesulfonic acid as a reaction (36 kHz, 100 W), in the water at ambient temperature catalyst, in a mortar at 60 °C to obtain coumarins 112. They also (Scheme 70) [107]. performed a Knoevenagel condensation by grinding method, using When bromomethyl-coumarins 110 are reacted with peracetyl piperidine as a catalyst, to obtain coumarins 113 in good yields. sulfhydryl glycose, coumarin thioglycopyranoside derivatives 111 When ethyl cyanoacetate is used in Knoevenagel condensation, two are synthesized (Scheme 71). When the reaction is performed under derivatives were formed, ethyl 8-methoxycoumarin-3-carboxylate ultrasound conditions, higher yields (51-77%) and shorter times and 3-cyano-8-methoxycoumarin (Scheme 73). The obtained yields (15-20 min) are achieved, compared to the conventional conditions were 73-99%, with the yield of ethyl coumarin-3-carboxylate of (yields 25-69%, 90-140 min) [108]. 95%.

30 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

R3 R R1 R OH 2 O O p-TsOH

R OC H solvent-free R2 O O 2 5 60 °C, 10 min R1 112 R3

CHO COR O O piperidine

OH R OEt solvent-free r.t., 50 min O O R 1 R1 113 Scheme 72. Synthesis of coumarin derivatives via Knoevenagel and Pechmann reaction [110].

CO2Et piperidine solvent-free O O CHO O r.t., 5 min OMe 114 + NC OC H OH 2 5 CN OMe piperidine

reflux in EtOH O O

OMe 115 H H CO Et CN 2 CO2Et

CO Et CN OH 2 OH O NH OMe OMe OMe 116 117 118 Scheme 73. Knoevenagel condensation in synthesis of coumarin derivatives performed by Sugino and Tanaka [110]. O CHO O O WEP OH R OO grinding OH O O 119 Scheme 74. Synthesis of 3-carboxycoumarin performed by grinding method [111].

The authors describe that compound 115 is formed when in- Therefore, considering this compound, the yield was lower and it tramolecular cyclization of 116 occurs, and 114 is formed when 117 took more time for the reaction than what Kantharaju and Khatavi is cyclized. Furthermore, compound 115 can be obtained by hy- [111] described. drolysis of 118 (Scheme 73) [110]. A synthesis of 3-carboxycoumarin 119 was performed by a 7.2. Pechmann Condensation grinding method, in the presence of water extract of papaya (WEP), Chavan and Baseer [113] compared different methods in Pech- at room temperature (Scheme 74). The obtained yields varied from mann synthesis of 7-hydroxy-4-methylcoumarin (Scheme 75). They 81% to 92% and the desired compounds were obtained in 8-12 min. applied MW irradiation, ultrasound irradiation, neat reaction, dif- Coumarin-3-carboxylic acid was obtained in 92% yield in 8 min ferent catalysts (BTSA-SiO2, IL, PVS acid, PTC) and simple grind- [111]. ing method in a mortar, with TsOH as a catalyst. The grinding Sharma, Kumar and Makrandi [112] applied the same reaction method was the most successful, yielding the desired product in path to synthesize 3-carboxycoumarins, also with a grinding tech- 98% yield in 10 min at 60 °C [113]. nique. They used a few drops of water, no catalyst and the reaction 7-Hydroxy-4-methylcoumarin and other derivatives were also was performed at r.t. for 20 min. The obtained yields varied from synthesized, with p-toluenesulfoni c acid as a catalyst, by Jain et al. 85-92%, and for 3-carboxycoumarin 90%. The reaction mixtures [114]. Reactants were grounded for 15 min at room temperature and were grinded for 20 min and left at r.t. for an additional 40 min. an exothermic reaction yielded desired products, 7-hydroxy-4-

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 31

CH3 O O

H3C OC2H5 HO OH HO O O

Scheme 75. Pechmann synthesis of 7-hydroxy-4-methylcoumarin performed by Chavan and Basser [113].

R2 R2 R I , r.t. O 3 N 2 O O N O + R3 grinding R N CH 1 3 HS N N R1 H N O S 120

Scheme 76. Synthesis of coumarin pyrazole derivatives described by Jakhar and Makrandi [115].

R O N N R R N 1 N N O O N N 121 R2 124 122 Ar

N R N

123

Scheme 77. Synthesis of different pyrazoles, pyrazolopyridazines and pyrimidines from coumarin derivative [116]. methylcoumarin derivatives in 81-90 % yield. For comparison, this 8. MULTICOMPONENT REACTIONS method yielded 90% of 7-hydroxy-4-mehylcoumarin in 45 min 8.1. Knoevenagel Condensation [114]. Sharma et al. [112] also used p-TSA as a catalyst, in the synthesis of different 4-substituted coumarins. The reaction mix- In the reaction of salicylaldehydes and ethyl acetoacetate, using tures were grinded for 10 min and then left at r.t for 20-80 min. The L-proline as a green catalyst and triethanolamine as a reaction me- products were obtained in excellent yields (82-95% by grinding), dia, 3-acetylcoumarins 125 was formed (Scheme 78). When they with 7-hydroxy-4-methyl coumarin in 95% yield in 30 min, 7,8- were reacted with malononitrile in the presence of L-proline in benzo-4-methylcoumarin 92% (90 min) and 6,7-benzo-4- EtOH (r.t., 3-4 h), a 2-[1-(2-oxo-2H-chromen-3-yl)ethylidene]malo- emethylcoumarin 90% (90 min) [112]. nonitriles 126 were formed, which in heating with elemental sulfur using L-proline (as a catalyst and polyethylene glycol 600 (PEG- 7.3. Other 600) as a solvent), at 100 °C, gave thiophene derivatives 127. The same reaction was performed as a one-pot reaction from 3- Coumarin pyrazole derivatives 120 were obtained by grinding acetylcoumarins, malononitrile, and elemental sulfur in the pres- 3-acetyl coumarin with 5-mercapto-3-(4-methoxyphenyl)-1,2,4- ence of L-proline in PEG-600 (100 °C, 1–2 h). In general, better triazole and iodine moist, at r.t (Scheme 76). Reaction with yields were obtained in a multi-step reaction [117]. substituted reactants yielded 71-88% of the products in 10 minutes [115]. Benzylpyrazolyl coumarin derivatives 127 were synthesized in MCR from ethyl acetoacetate, aromatic aldehydes, aromatic Abdel-Aziem et al. [116] examined an application of a grinding hydrazine hydrates and 4-hydoxycoumarin, in excellent yields method in the formation of different pyrazoles 121, pyrazolopyri- (Scheme 79). This reaction was catalysed by ZrO nanoparticles 10 dazines 122 and pyrimidines 123, from coumarin derivative 124. 2 mol%. When different solvents were compared, EtOH, H O, DCM, Compound 122 was successfully synthesized in a reaction of 124 2 DMF, acetonitrile, and solvent-free reaction, the best was proven to with hydrazonoyl halides and further grinding with hydrazine hy- be EtOH:H O 1:1, yielding 92% of the product [118]. drate. When 124 was grinded with hydrazine hydrate and thiocar- 2 bohydrazide, pyrazoles represented with the structure 121 were 8.2. Other formed. Grinding 124 with 3-amino-4-cyanopyrazole, 3-amino-4- phenylpyrazole, 3-aminotriazole, 2-aminobenzimidazole or 4,6- Benzylamine coumarin derivatives 128 were successfully dimethyl-1H-pyrazolo[3,4-b]pyridin-3-amine yielded compounds formed in a multicomponent reaction of 4-hydroxy coumarin, alde- 123 (Scheme 77) [116]. hydes and secondary amines, using 3 mol% PEG400 as a catalyst at

32 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

R2 R2 R2 H3C NC CN O O O O CN OH O L-proline L-proline + R1 CH3 PEG-600 NH2 O N(CH2CH2OH)3 R R CHO 1 100 °C, 1-2 h 127 1 C H O r.t., 30-40 min 125 S 2 5 O

NC CN EtOH L-proline r.t., 3-4 h , L-Proline S 8 PEG-600 R2 O O 100 °C, 30-45 min CN

R1 CN CH3 Scheme 78. Synthesis of 3-acetylcoumarins catalyzed by using L-proline [117].

OH OH Ar O O O Ar-CHO ZrO NPs 2 R + N H C OC H 3 2 5 EtOH:H2O (1:1), r.t. O NH R-NHNH2 O O O

127 126

Scheme 79. Synthesis of benzylpyrazolyl coumarin derivatives catalysed by ZrO2 [118].

R OH OH CHO

PEG-400 N R r.t. N O O O O H 128 Scheme 80. Synthesis of benzylamine coumarin derivatives in multicomponent reaction [119].

R1 O O N N morpholinium glycolate H R R N H2N R1 90 °C, solvent-free O O O O 129 Scheme 81. Synthesis of coumarin derivatives in a multicomponent reaction catalysed by morpholinium glycolate [121]. r.t. (Scheme 80). PEG400 showed better efficiency than PEG200, MCR reaction, Ghosh and Das [120] used water as a solvent, at r.t. PEG600 and PEG800, while higher temperatures gave lower prod- using nanocrystalline ZnO as a catalyst. Nanocrystalyne ZnO was uct yields. The obtained product yields using this procedure were the most efficient (93%) among other catalysts, like Alum (29%), 65-80% [119]. The same coumarin derivatives were synthesized by nano aluminium oxide, zeolites, L-proline, commercial ZnO and Chavan and Hosamani [65], using a grinding technique in alum as a tetrabutylammonium bromide, while water gave the highest yield catalyst (20 mol %), at room temperature. They compared different when compared to the solvents like methanol, ethanol, DMSO, catalysts for the synthesis of 4-hydroxy-3-(phenyl-piperidin-1-yl- acetonitrile, tetrahydrofuran and toluene. This method yielded 92% methyl)-chromen-2-one, including PEG400 (for this catalyst the 4-hydroxy-3-(phenyl-piperidin-1-yl-methyl)-chromen-2-one in 15 yield was 17%), in the reaction performed for 20 min, and alum min [120]. showed the best product yield (55%). Different solvents, like Shaikh et al. [121] performed a multicomponent reaction start- DMSO, DMF, MeOH, EtOH, water, dichloromethane and THF ing from 3-acetylcoumarin, aldehyde and hydrazine hydrate or gave lower product yield than the solvent-free reaction. Therefore, phenyl hydrazine hydrochloride, in a morpholinium glycolate cata- at optimized conditions, the yield of 4-hydroxy-3-(phenyl- lyzed reaction, to obtain derivatives 129 in 70-110 min (Scheme piperidin-1-yl-methyl)-chromen-2-one was 87% in 20 min Chavan 81). 3-Acetylcoumarin was also synthesized in morpholinium gly- [65], while Viradiya et al. [119] obtained 4-hydroxy-3-(phenyl- colate Knoevenagel condensation [121]. piperidin-1-yl-methyl)-chromen-2-one in 80% yield. For the same

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 33

H Het OH + - O N NH2 Cl O H Het H2N NH2 N H HetNH2 CH(OEt)3 H O O solvent-free, O O O O 90 °C 130 131 Scheme 82. Synthesis of coumarin derivatives in guanidinium chloride catalysed solvent-free reaction [122].

OH OH Ar O O O ArCH3OH H2O, reflux N R + H3C OC2H5 gl. AcOH NH O O O O 132 RNH NH 2 2 Scheme 83. Synthesis of benzylpyrazolyl coumarin derivatives in one-pot four-component reaction [123].

NH2 CN O H H NC CN Ar OH EtOH:H2O (1:1) O O 133 O GO

Ar H nanosheets OH Ar OH O O H2O

O O O O 134 Scheme 84. Synthesis of pyranocoumarins and bis-4-hydroxycoumarins in a multicomponent reaction performed by Khodabakhshi et al. [124].

H2N O CHO OH O catalyst, H2O R1 + NC R1 + R 75 °C, 2h O O O O O R O O 135 Scheme 85. Synthesis of bis-coumarin derivatives in a multicomponent reaction performed by Chougala et al. [125].

A multicomponent reaction of 4-hydroxycoumarin, different tion of aryl aldehydes and 4-hydroxycoumarin yielded bis-4- amines and triethyl orthoformate was performed in guanidinium hydroxycoumarins in excellent yields [124]. chloride catalysed solvent-free reaction to produce coumarin Some bis-coumarin derivatives 135 were synthesized in L- enamines 130 and 131 (Scheme 82) [122]. proline catalysed MCR using 4-formyl coumarin, 4-hydroxy cou- A series of benzylpyrazolyl coumarin derivatives 132 was syn- marin and malononitrile in water (Scheme 85). Other catalysts were thesized in a reaction of 4-hydroxycoumarin, different hydrazines, also investigated, sodium carbonate, potassium carbonate, sodium ethyl acetoacetate and aromatic aldehydes (Scheme 83). The syn- bromide, sodium chloride, L-cysteine, sodium benzoate, sodium thesis was performed in one-pot four-component reaction, in water bisulfite and iodine, but L-proline was the most efficient [125]. and glacial acetic acid was used as the catalyst [123]. The further synthetic route led the same authors to the forma- Khodabakhshi et al. [124] developed a multicomponent reaction of the unexpected compounds 136a and 136b (Scheme 86). tion for the synthesis of pyranocoumarins 133 and bis-4- The formation of either compound 136a or 136b was temperature hydroxycoumarins 134. They used graphene oxide nanosheets, and time-dependent. Therefore, compound 136a was formed at prepared by a modified Hummers method, as a catalyst (Scheme 80 °C and 90 °C, while an increase in temperature caused a forma- 84). Pyranocoumarins were successfully synthesized from 4- tion of compound 136b [125]. hydrohycoumarin, aryl aldehydes and malononitrile, while the reac-

34 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

O HOOC

HCOOH O R 90 °C O O 136a H2N O

O R1 O R O O O O O HCOOH

130 °C O R O O 136b Scheme 86. Synthesis of coumarin derivatives in multicomponent reaction performed by Chougala et al. [125].

HN O R5 O R3 O O R4 R3 RO CN R2 R OR HN 5 CN catalyst-free R2 O NH + + 2 EtOH:H2O (1:1) R1 O O O R4 CN R1 O O O 137 Scheme 87. Synthesis of coumarin-spiro[indoline-3,4’-pyran] conjugates performed by Omar et al. [126]. O O

O O H2N R2 PEG-600 N R2 + + TBATB R1 H N 100 °C, 1-2 h R1 2 N O 138 Scheme 88. Synthesis of coumarinyl quinoxalines in one-pot reaction [127].

X CN O O O O CHO + boronic acid

O stirr, r.t., 4 h O HN X O 139 Cl CH3 O Scheme 89. Synthesis of 3-acetyl coumarin derivatives performed by Soumya et al. [128].

A series of coumarin-spiro[indoline-3,4’-pyran] conjugates 137 mine and TBATB (tetrabutylammonium tribromide), in a PEG-600 was synthesized in MCR of different coumarin β-ketoesters, isatins as a solvent (Scheme 88). PEG-600 was found to be the most effec- and malononitrile, in aqueous ethanol in a catalyst-free reaction tive in this reaction when compared to other conventional solvents, (Scheme 87) [126]. like isopropyl alcohol, ethylene glycol, glycerol, ethanol, acetoni- A one-pot protocol was developed for the synthesis of cou- trile, methanol, THF, 1,4-dioxane and acetone. The reaction in marinyl quinoxalines 138, from 3-acetyl coumarin, o-phenylenedia- PEG-600 was completed in 45 min (89% yield), while in other

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 35

O O O O Cl NH2 O OH O H DCM N O Cl N r.t., 3 days H CuSO4·5H2O CN O sod. ascorbate

DMSO/t-BuOH/H2O

O O O N N H N O N N

O O 140

Scheme 90. Synthesis of coumarin–triazole–carboxamide conjugates in a multicomponent reaction [128].

Br R1 CHO CN

CN H2O:CH3CN (9:1) R2 R R1 NEt3, r.t., stirring O O R2 R

O O

141 Scheme 91. Synthesis of coumarin linked cyclopropane derivatives in a one-pot reaction [129]. solvents it took more time, 1.5-4.5 hrs with lower yields (58-79%) same reaction was performed by Chavan and Bandgar [131] using [127]. aqueous extract of Acacia concinna pods as a natural catalyst at r.t. Condensation of 3-acetyl coumarin with different aldehydes, Products were obtained in 94-98% yield in 55-75 min [131]. 3- acetyl chloride and acetonitrile, catalyzed by 20 mol% of phenyl Carboxycoumarin was obtained in 98% yield [131], while Fiorito et boronic acid, at room temperature, yielded different coumarin alkyl al. [130] obtained it in 92-99% depending on the solvent. Another amides 139 (Scheme 89) [128]. water extract used in the synthesis of coumarin-3-carboxylic is a A click chemistry approach was used for the synthesis of cou- water extract of rice straw ash, which was used as a catalyst. When marin–triazole–carboxamide conjugates 140, from the correspond- the suitability of different solvents was compared, the authors ob- ing azides and propargyl coumarin esters (Scheme 90) [128]. tained the yields as follows: ethanol>acetonitrile>methanol> solvent-free. In this work, 3-carboxycoumarin was obtained in 92% Coumarin linked cyclopropane derivatives 141 were synthe- yield in 260 min at r.t. [132]. Furthermore, the uncatalyzed reaction sized in the one-pot reaction of 4-bromomethyl-2H-chromen-2-one, of different salicylaldehydes and Meldrum’s acid was performed in aromatic aldehydes and different nitriles (Scheme 91). Wa- water by refluxing the mixture for 10 hrs, yielding 3-carboxy- ter:acetonitrile 9:1 as a solvent and triethylamine as a base was coumarins in excellent yields. When this reaction is performed in found to be the most suitable for this reaction, which was per- solvent-free conditions, lower yields are obtained, but the excellent formed at room temperature for 2 hrs [129]. selectivity remained. 3-Carboxycoumarin was obtained in 93% yield [133]. 9. OTHER GREEN APPROACHES TO COUMARIN SYN- Coumarin-3-carboxylic acids can be synthesized at room tem- THESIS perature in one-pot reaction of salicylaldehydes and Meldrum’s 9.1. Knoevenagel Condensation acid, using water as a solvent, catalysed by potassium carbonate (10 Different coumarin-3-carboxylic acids were synthesized in the mol%) or sodium azide (50 mol%). A reaction mixture was stirred Knoevenagel condensation from salicylaldehydes or 2-hydroxy- at r.t. for 20 h, to yield 92% of 3-carboxycoumarin with K2CO3 as acetophenones and Meldrum’s acid, in the natural juices (lemon, a catalyst, and 99% with NaN3 as a catalyst [134]. grapefruit, carrot, pomegranate, kiwi, vinegar, tomato), or wastewa- Knoevenagel synthesis of coumarin derivatives is usually per- ter derived from different industry processes (buttermilk wastewater formed in a piperidine catalyzed reaction, but it can also be per- and oil mill waste water). A reaction was performed at r.t. under formed with potassium dihydrogen phosphate as a catalyst, which is stirring for 24 h. All applied reaction solvents were very efficient in less toxic than piperidine [135]. The same reaction can also be per- this transformation, yielding 92-99% of the products [130]. The formed in the presence of Mg-Al 3.0 CHT (Mg–Al hydrotalcites

36 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

OH O O

COOH OH O O 142

OH OH O O O O

143 Scheme 92. Synthesis of coumarin derivatives catalysed by Zeolite H-Beta [137].

O O Br aqueous O PPh3 O Ph NaHCO3 R Ph R R solvent, 60 °C 20-30 min, r.t. Br P O O O O Ph 144 Scheme 93. One-pot Wittig synthesis of coumarin derivatives performed by Belavagi et al. [138].

O O OH CHO O O

MnCl2 · 4H2O + R 100 °C OH O O OH 145 R

Scheme 94. Synthesis of bis-(4-hydroxycoumarin) methanes catalysed by manganous chloride [139].

R O NH2 O O

O lactic acid O

H R ethyl-L-lactate, 100 °C N O O H O 146

O R O NH2 O O lactic acid O

H R ethyl-L-lactate, 100 °C N O O H O 147 Scheme 95. Synthesis of indenodihydropyridine and dihydropyridine coumarin derivatives one-pot reaction using (±)lactic acid as a catalyst [140]. with Mg:Al atomic ratio of 3) (10% w/w) as a catalyst. Reactivity 9.3. Wittig Condensation of the active methylene compounds was as followed: cyanoethyl Aqueous sodium bicarbonate can be employed for the one-pot acetate > diethyl malonate > ethyl acetoacetate > ethyl acetate- Wittig synthesis of coumarins 144 at r.t. in 20-30 minutes (Scheme Ethyl coumarin-3-carboxylate was obtained in 87% yield [136]. 93) [138].

9.2. Pechmann Condensation 9.4. Other Coumarin synthesis catalyzed by Zeolite H-Beta (Si/Al= 12) Manganous chloride was efficiently applied as a catalyst in the was described by Gunnewegh et al. [137]. They reacted resorcinol synthesis of bis-(4-hydroxycoumarin)methanes 145, which were and different α,β-unsaturated carboxylic acids [137]. When the synthesized from 4-hydroxycoumarin and different aldehydes in reactants were added in an equimolar ratio, compound 142 was water (Scheme 94) [139]. predominantly formed, but when the ratio of resorcinol and prope- Paul and Das [140] synthesized indenodihydropyridine 146 and noic acid was 1:2, compounds 143 was formed (Scheme 92). They dihydropyridine coumarin derivatives 147 in one-pot reaction, us- also found that resorcinol and 3-methoxy phenol are suitable for ing ethyl-L-lactate as a solvent and (±)lactic acid as a catalyst this kind of reaction, while m-cresol and phenol were not yielding (Scheme 95). This reaction did not proceed without catalyst, and the desired products in satisfying yields [137].

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 37

O OH

R5 OH O N

R1 R3 CHO R1 L-proline R4 + NH OAc 4 + solvent-free R3 R2 O O R4 O R2 O O 148 R5 Scheme 96. Synthesis of chromenopyridinones in one-pot three-component reaction [141].

R1 OH O CO2R2 OH R3 NH2 ethanol, 80 °C N + + + OH OH R3 catalyst-free CO2R2 O O R1 CO2R2

CO2R2 O O 149 Scheme 97. Synthesis of 3-pyrrolyl coumarin derivatives in a four-component reaction by Wang et al. [142]. R OTf DABSO R white LED O O I (10 W, 9000-15000 K) S Ph + MeOH, N , r.t., 8h O X 2 O X 150 Scheme 98. Synthesis of sulfonylated coumarin derivatives irradiated with white LED [143].

OH OH HN CHO 80 °C, 24h R2 R2 NH3·H2O R R1 1 O O COOH O O 151 Scheme 99. Synthesis of coumarinyl isoindolinones according to Shen et al. [144]. conventional solvents like water, acetonitrile, DMF, ethanol and bis(sulfur dioxide)) and diaryliodonium salt was performed in ethylene glycol gave much lower yields than ethyl-L-lactate. Also, methanol, under nitrogen atmosphere. A reaction mixture was other catalysts like alumina, FeCl3, InCl3, SiO2, L-proline, citric and irradiated with a white LED (10 W, 9000-15000 K) for 8 hrs oxalic acid gave much lower yields than lactic acid [140]. (Scheme 98) [143]. Different chromenopyridinones 148 were synthesized in one- Coumarinyl isoindolinones 151 were successfully synthesized pot three-component reaction of 4-hydrocoumarins, ammonium from substituted 4-hydroxycoumarins, 2-formyl benzoic acid de- acetate and 3-formyl chromone derivatives, in a reaction catalyzed rivatives (1.5 eq) in ammonium hydroxide (Scheme 99). The reac- by L-proline (Scheme 96). Different catalysts, Cu(OTf)2, FeCl3, tion was performed at 80 °C for 24 hrs [144]. In(OTf)3, TsOH and AcOH were also investigated, but L-proline Different coumarin derivatives 152 were synthesized from 2 eq. gave the best yields in a solvent-free reaction [141]. of (Z)-azalactones and 4-hydroxycoumarin in propylene carbonate A series of 3-pyrrolyl coumarin derivatives 149 was synthe- as a solvent, using diisopropylethylamine (DIPEA) at 80 °C sized in ethanol at 80 °C in a four-component reaction of 4- (Scheme 100). Other bases were also employed, DMAP, DBU, hydroxycoumarin, amines, alkynoates and arylglyoxal monohy- Et3N, but DIPEA was the most efficient. Other solvents like drates, without any catalyst (Scheme 97). When different solvents DMSO, DMF, toluene, PEG-200, 1,4-dichlorobenzene and acetoni- were compared, ethanol was shown to give the best yields com- trile were used, but the yield was lower compared to DIPEA [145]. pared to acetone, water, DMF, THF, acetic acid and ethylene gly- 3-Iodocoumaron derivatives 153 were successfully synthesized col. The best temperature was shown to be 80 °C, while 40 °C and from different aryl alkynoates and Niodosuccinimide, by exposing 60 °C gave lower yields. Reactions were finished in 0.5-4.5 hrs the reaction mixture to the sunlight at room temperature for 6 hrs [142]. (Scheme 101). Among solvents like methanol, DCM, THF, DMF, Synthesis of sulfonylated coumarin derivatives 150 from acetone and acetonitrile, the latter one gave the highest yield for different propynoates, DABSO (1,4-diazabicyclo[2.2.2]octane this kind of reaction. Led and fluorescent lamp did not give better

38 Current Organic Chemistry, 2020, Vol. 24, No. 1 Molnar et al.

O R Ar O 1 2 OH R2 HN O Ar2 N R1 DIPEA Ar Ar1 1 Ar1 N R O O PC, 80 °C O N 2 Ar2 Ar2 Ar O O 1 O O 152 O Scheme 100. Synthesis of coumarin derivatives performed by Shafiee et al. [145].

R2 O R2 I H sunlight, r.t. N I R R1 1 O O O O O 153 Scheme 101. Synthesis of 3-iodocoumaron derivatives according to Ni et al. [146] O

S SH H Ph H2O, 8-10 h R R O O OH Me O O 154 Scheme 102a. Synthesis of 3-mercaptocoumarins in catalyst-free reaction [147].

H H O O O H H OH H H S S -H O O O HO 2 S Δ S H2O O Ph O Ph O OH R O O 8-10h R O O Ph Ph H H O HSCH2COOH H

LiBr SH

PhCOMe + R O O Scheme 102b. A proposed mechanism for the synthesis of 3-mercaptocoumarins [147]. yields when compared to the sunlight, when the reaction was con- used as a catalyst, coumarin dimers 156 were formed. Catalyst-free ducted for 6 hrs [146]. conditions in water as a solvent gave the best results in order to 3-Mercaptocoumarins 154 were synthesized in a catalyst-free form 3-substituted coumarins 155. Room temperature afforded 3- reaction of different salicyladehydes and 2-methyl-2-phenyl-1,3- substituted coumarins, while reflux conditions afforded coumarin oxathiolan-5-ones, using water as a solvent (Scheme 102a) [147]. dimers 156. Prohydrophobic additives such as LiCl, glucose, NaCl The authors claim that water acts both as a solvent and a cata- increased the yield of the product [148]. lyst for this reaction. A formation of hydrogen bonds between water CONCLUSION and carbonyl oxygen in salicylaldehyde increases the electrophilic- This review summarizes an application of green methodologies ity of the carbonyl atom, while the formation of the hydrogen bonds in coumarin derivatives synthesis during the past two decades. between water and OH increases the nucleophilicity of the methyl- Since coumarins have significant biological activities, their large ene carbon of oxathiolanone (Scheme 102b) [147]. production contributes to the pollution of the environment. These 4-Hydroxycoumarin derivatives were reacted with different ter- green chemistry methods have been explored in order to reduce tiary aryl amines and formaldehyde to form 3-substituted coumarins environmental pollution and reaction time and to improve purity, 155 (Scheme 103). When different Brønsted and Lewis acids were selectivity and product yields.

Green Chemistry Approaches to the Synthesis of Coumarin Derivatives Current Organic Chemistry, 2020, Vol. 24, No. 1 39

R R OH 1 1 R N 3 N R3 O O R2 aq. solution LiCl, r.t. R2 + CH2O + R4 R4 H catalyst-free O O OH OH OH 155

R R O O O O 156

Scheme 103. Synthesis of 4-Hydroxycoumarin derivatives in catalyst-free reaction performed by Kumar et al. [148].

In this paper, we have explored the application of solvent-free [2] O’Kennedy, R.; Thornes, R.D. Coumarins: Biology, Applications and Mode of Action, 1st ed.; Wiley & Sons: New York, 1997. reactions, IL or DES catalyzed reactions, microwave or ultrasound- [3] Lacy, A.; O’Kennedy, R. Studies on coumarins and coumarin-related com- induced reactions and multicomponent reactions. Each of these pounds to determine their therapeutic role in the treatment of cancer. Curr. approaches shows some advantages compared to the conventional Pharm. Des., 2004, 10(30), 3797-3811. http://dx.doi.org/10.2174/1381612043382693 PMID: 15579072 ones. Theoretical approaches to this subject explain the phenomena [4] Razavi, S. Plant coumarins as allelopathic agents. Int. J. Biol. Chem., 2011, that could influence the higher reaction rates, higher yields, de- 5, 86-90. creased reaction times, etc. when green methods are applied in the http://dx.doi.org/10.3923/ijbc.2011.86.90 [5] Kai, K.; Shimizu, B.; Mizutani, M.; Watanabe, K.; Sakata, K. Accumulation synthesis of desired compounds. A detailed review of the applica- of coumarins in Arabidopsis thaliana. Phytochemistry, 2006, 67(4), 379-386. tion of such methods in the synthesis of coumarin derivatives con- http://dx.doi.org/10.1016/j.phytochem.2005.11.006 PMID: 16405932 firms these entire hypotheses. Authors mentioned in this paper have [6] Wu, C-R.; Huang, M-Y.; Lin, Y-T.; Ju, H-Y.; Ching, H. Antioxidant properties of cortex Fraxini and its simple coumarins. Food Chem., 2007, 104(4), successfully proven that coumarins can be synthesized in higher 1464-1471. yields, shorter reaction times and with less toxic volatile organic http://dx.doi.org/10.1016/j.foodchem.2007.02.023 solvents, when compared to the conventional organic synthetic [7] Wang, Z. Comprehensive Organic Name Reactions and Reagents, 1st ed.; Wiley & Sons: New York, 2009. routes. Some of them have even performed a scale-up of the proc- [8] Rosen, T. The Perkin reaction. Comprehensive organic synthesis; Winter- esses to prove those that can be successfully applied in the industry. feldt, E., 2nd Ed.; Elsevier Science: Oxford, 1991, Vol. 1-2, pp. 395-407. This review will be useful in terms of environmental care and http://dx.doi.org/10.1016/B978-0-08-052349-1.00034-2 [9] Potdar, M.K.; Mohile, S.S.; Salunkhe, M.M. Coumarin syntheses via Pech- development of nontoxic, green catalysts and reagents, which have mann condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahe- been developed for years by many researchers worldwide. Their dron Lett., 2001, 42, 9285-9287. application is getting more prominent every day and their perspec- http://dx.doi.org/10.1016/S0040-4039(01)02041-X [10] Abdel-Wahab, B.F.; Mohamed, H.A.; Farhat, A.A. Ethyl coumarin-3- tive, both for laboratory-scale reactions and industry application, is carboxylate. Synthesis and chemical properties. Org. Comm., 2014, 7(1), 1- very promising. 27. [11] Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. Montmorillonite KSF as an inorganic, water stable, and reusable catalyst for the knoevenagel synthesis CONSENT FOR PUBLICATION of coumarin-3-carboxylic acids. J. Org. Chem., 1999, 64(3), 1033-1035. http://dx.doi.org/10.1021/jo981794r PMID: 11674183 Not applicable. [12] Ouellette, R.J.; Rawn, J.D. Aldehydes and ketones: nucleophilic addition reactions. Organic Chemistry; Elsevier: Oxford, 2018, pp. 595-623. http://dx.doi.org/10.1016/B978-0-12-812838-1.50020-7 FUNDING [13] Valizadeh, H.; Vaghefi, S. One-pot wittig and knoevenagel reactions in ionic liquid as convenient methods for the synthesis of coumarin derivatives. This work has been supported in part by Croatian Science Synth. Commun., 2009, 39(9), 1666-1678. Foundation under the project “Green Technologies in Synthesis of http://dx.doi.org/10.1080/00397910802573163 [14] Dittmer, D.C.; Li, Q.; Avilov, D.V. Synthesis of coumarins, 4- Heterocyclic Compounds” (UIP-2017-05-6593). hydroxycoumarins, and 4-hydroxyquinolinones by tellurium-triggered cycli- zations. J. Org. Chem., 2005, 70(12), 4682-4686. CONFLICT OF INTEREST http://dx.doi.org/10.1021/jo050070u PMID: 15932305 [15] Clarke, C.J.; Tu, W-C.; Levers, O.; Bröhl, A.; Hallett, J.P. Green and sustainable solvents in chemical processes. Chem. Rev., 2018, 118(2), 747-800. The authors declare no conflict of interest, financial or other- http://dx.doi.org/10.1021/acs.chemrev.7b00571 PMID: 29300087 wise. [16] Zhang, S.; Sun, N.; He, X.; Lu, X.; Zhang, X. Physical properties of ionic liquids: database and evaluation. J. Phys. Chem. Ref. Data, 2006, 35(4), 1475-1517. ACKNOWLEDGEMENTS http://dx.doi.org/10.1063/1.2204959 [17] Khandelwal, S.; Tailor, Y.K.; Kumar, M. Deep Eutectic Solvents (DESs) as Declare None. eco-friendly and sustainable solvent/catalyst systems in organic transforma- tions. J. Mol. Liq., 2016, 215, 345-386. SUPPLEMENTARY MATERIAL http://dx.doi.org/10.1016/j.molliq.2015.12.015 [18] Handy, S. Ionic Liquids: Classes and Properties; IntechOpen: Rijeka, 2011. Supplementary material is available on the publisher’s web site http://dx.doi.org/10.5772/853 [19] Su, C.; Chen, Z-C.; Zheng, Q-G. Organic reactions in ionic liquids: knoeve- along with the published article. nagel condensation catalyzed by ethylenediammonium diacetate. 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