An Efficient and Versatile Deep Eutectic Solvent-Mediated Green Method for the Synthesis of Functionalized Coumarins.

Herein, we report a green and efficient synthetic route for the construction of diverse functionalized coumarins in good-to-excellent yields (60-98%) via the Pechmann condensation. The optimized synthetic route involves a biodegradable, reusable, and inexpensive deep eutectic solvent (DES) of choline chloride and l-(+)-tartaric acid in a ratio of 1:2 at 110 °C. Interestingly, phloroglucinol and ethyl acetoacetate, upon reaction, furnished the functionalized coumarin (20) in 98% yield within 10 min. On the other front, the same DES at relatively lower reaction temperature (90 °C) was found to provide the bis-coumarins in decent yields (81-97%) within 20-45 min. Moreover, this particular method was found to be quite effective for large-scale coumarin synthesis without noteworthy reduction in the yields of the desired products. Noticeably, in this versatile approach, the DES plays a dual role as solvent as well as catalyst, and it was effectively recycled and reused four times with no significant drop-down in the yield of the product.

Introduction

Coumarins are notable members of the benzopyrone class of organic compounds, which have recently attracted a great awareness from chemists and biologists across the globe because of their interesting photochemical/photophysical assets[1−4] and substantial biological activities such as antioxidant,[5] anticoagulant, anti-HIV,[6] anticancer,[7] antimicrobial,[8] antiviral, anti-inflammatory,[9] and anticonvulsant.[10] Moreover, they have also been employed as additives in food, cosmetics, perfumes, agrochemicals, and pharmaceuticals.[11,12] Taking note of the indispensable features of the coumarin backbone, development of new coumarin-based pharmacological drugs and fabrication of optical organic devices (lasers, solar cells, etc.) has become a necessity in the current environment.[13−18] On the other hand, coumarin and its congeners by virtue of acting as vital fluorescent probes also exhibit huge potential in diagnostics and drug delivery developments and are thus considered as privileged structures in the biomedical arena.[19,20] In fact, their simplicity, peculiar chemical properties, and the efficiency in their synthesis make them highly appealing and interesting for both medicinal and biological chemists.[21,22] The structures of some vital biologically active coumarin derivatives are listed here (Figure ).

Figure 1

Diverse functionalized coumarins (1–7) of therapeutic significance.

In the recent past, synthesis of the functionalized coumarins has received interest from both synthetic as well as medicinal chemists, which can be underscored by the involvement of diverse named reactions like the Perkin reaction, Claisen rearrangement, Knoevenagel condensation, Reformatsky reaction, Wittig reaction, Kostanecki–Robinson reaction, Pechmann condensation, and so forth in their ease of construction.[23−30] Among these methods, the Pechmann condensation discovered by Hans von Pechmann in 1883 is well known, which leads to the acid-catalyzed preparation of substituted coumarins from commercially available starting materials (i.e., substituted phenols and β-ketoesters/acids). The acid catalysts utilized for the Pechmann condensation reaction are concd H2SO4, trifluoroacetic acid (TFA), P2O5, TiCl4, ZrCl4, phosphotungstic acid, Nafion resin, SnCl2·2H2O, HClO4/SiO2, zirconium phosphotungstate, and ionic liquids, etc.[31−42] In the context of environmental impact, most of these procedures suffer from one or more serious drawbacks like the use of a stoichiometric amount of costly catalyst, production of large acidic wastes, low yields, no reusability of catalyst, and prolonged reaction time. Consequently, there is an urgent need to develop simple, efficient, high-yielding, and eco-friendly Pechmann condensation tactics, where reusable mild acidic catalysts without involving any hazardous volatile organic solvent could be taken into the consideration.

In the modern era, a major focus of the scientific community is toward the development of green and/or sustainable protocols with the prospect of fostering straightforward yet efficient pathways which not only are economical but also safe for both mankind and the environment. These routes, in turn, avoid the involvement of hazardous volatile organic solvents and corrosive catalysts and also eliminate the generation of nonbiodegradable waste products during the reaction under consideration.[43−45] Among various sustainable alternatives,[46−51] the deep eutectic solvents (DESs) have gained a the attention of researchers worldwide after their discovery by Abbott and teammates in 2003 and the subsequent decoding of some interesting properties.[52] These DESs have been utilized in a myriad of vital synthetic transformations by various research groups. For instance, Tavakol and co-workers have used DESs in the preparation of xanthene derivatives, propargylamines, and 4-aminobenzofurans.[53−55] The DESs are generally formed by virtue of complexation between hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs), which are mostly obtained from natural sources and are gifted with numerous interesting characteristics such as being biocompatible, biodegradable, renewable, inexpensive, inflammable, atom economical, thermally stable, etc., besides displaying a dual/triple role (catalyst, solvent, and/or reactant) during the reaction.[56−66] The Pechmann condensation for the synthesis of coumarin and its derivatives has already been reported involving ionic liquids (ILs) as reaction media.[67−78] Generally, ILs are being considered as the green reaction systems, but actually they are not. This is due to the fact that ILs possesses some serious issues such as huge cost, difficult preparation, and environmental unfriendliness, as they are generally produced from hazardous starting materials involving conventional organic solvents and/or catalysts. Thus, there is an immense urgency to gather diverse functionalized coumarins via Pechmann condensation under environmentally benign conditions having the credentials of green chemistry.

Keeping the remarkable properties of DESs in mind, and also as our major research program in the construction of simple yet architecturally interesting molecules[79−86] employing green protocols,[87−91] we envisioned involving DES of choline chloride (ChCl) and l-(+)-tartaric acid (TA) for the Pechmann condensation reaction to generate a variety of substituted coumarin derivatives by reacting several substituted phenols with different β-ketoesters under operationally simple reaction conditions. To the best of our knowledge, this is the first report where DESs have been taken into the consideration toward the successful synthesis of coumarins. Hopefully, this versatile protocol will open new opportunities not only to construct diverse interesting coumarin derivatives but also to assemble other heterocycles by means of this simple methodology.

Results and Discussion

In order to test the feasibility of DESs for Pechmann condensation, the reaction of cheap and commercially available resorcinol (8) with a β-ketoester, namely, ethyl acetoacetate (9), was chosen as a model reaction for the synthesis of 7-hydroxy-4-methylcoumarin (10). As can be inspected from Table , among the diverse scrutinized DESs, the DES of ChCl/l-(+)-TA (1:2) at 110 °C (Table , entry 19) was realized as the best reaction choice. Interestingly, it was observed that increasing the temperature from 60 to 110 °C displays a profound effect not only on the yield of the desired product but also on the reaction time as well (Table , entries 13–19). Surprisingly, increasing the reaction temperature from 110 to 120 °C slightly lowered the yield of the required product, but a little charring in the reaction mixture was noticed during the progress of the reaction (Table , entry 21). Next, optimization of various amounts of DES (ChCl/l-(+)-TA (1:2)) was tested (Table , entries 17–20); from the studies, we observed that increasing the amount of DES from 1.5 to 3 g increases the yield of the target compound (10) (Table , entries 17–19). A further increase in the amount from 3 to 4 g does not greatly affect the yield of the required product (Table , entry 20). On the other hand, the desired product was also obtained in different ratios of ChCl/l-(+)-TA (entries 11 and 12, Table ) but in lesser amount of yields due to the formation of some unidentified products. Additionally, an almost identical yield was noticed using ChCl/malonic acid (2:1) (Table , entry 22). On the other front, as can be seen from the same table, carbohydrate-based DESs (entries 3–7 and 10) offered the desired product in trace-to-low yields (negligible-29%). In these cases, we noticed the formation of some unidentified complex mixtures along with the desired product. Moreover, almost the same situation happened with other tested DESs (Table , entries 1, 2, 8, 9, and 23). However, in a few cases, we also observed some unconsumed starting materials, even though the reactions were kept for extended times. In order to check the recyclability and reusability, the optimized DES of ChCl/l-(+)-TA (1:2) was isolated from the product after a first successful run through liquid–liquid extraction followed by evaporation of the aqueous layer containing optimized DES.[92] The recovered DES was then reused for the next run for the same reaction. It has been noticed that even after four runs the efficiency of the DES was not significantly decreased in the preparation of compound 10 under similar reaction conditions (Figure ).

Table 1

Optimization of Reaction Conditions for the Preparation of 7-Hydroxy-4-methylcoumarin (10)

entry	DESs	DES amount (g)	reaction temp (° C)	time (h)	yielda (%)
1	DMU/l-(+)-TA (7:3)	3	100	24	25
2	citric acid/DMU (2:3)	3	100	12	28
3	d-(−)-fructose/urea (1:1)	3	100	10	Trace
4	glucose/urea/NH4Cl (6:3:1)	3	100	24	23
5	citric acid/mannitol/urea (3:2:5)	3	100	12	29
6	lactose/DMU/NH4Cl (5:4:1)	3	100	24	11
7	maltose/DMU/NH4Cl (5:4:1)	3	100	24	13
8	ChCl/DMU (1:2)	3	100	24	Trace
9	ChCl/urea (1:2)	3	100	24	Trace
10	ChCl/glucose (1:1)	3	100	24	Trace
11	ChCl/l-(+)-TA (1:1)	3	100	24	48
12	ChCl/l-(+)-TA (2:1)	3	100	24	47
13	ChCl/l-(+)-TA (1:2)	3	60	30	45
14	ChCl/l-(+)-TA (1:2)	3g	80	22	54
15	ChCl/l-(+)-TA (1:2)	3	90	17	67
16	ChCl/l-(+)-TA (1:2)	3	100	11	74
17	ChCl/l-(+)-TA (1:2)	1.5	110	12	61
18	ChCl/l-(+)-TA (1:2)	2	110	10	66
19	ChCl/l-(+)-TA (1:2)	3	110	8	90
20	ChCl/l-(+)-TA (1:2)	4	110	8	88
21	ChCl/l-(+)-TA (1:2)	3	120	8	83
22	ChCl/malonic acid (2:1)	3	100	10	40
23	ChCl/ethylene glycol (1:2)	3	100	12	Trace

Isolated yields after column chromatography; DMU = N,N′-dimethylurea; ChCl = choline chloride.

Figure 2

Bar graph showing the recyclability of ChCl/l-(+)-TA (1:2) for the construction of 7-hydroxy-4-methylcoumarin (10).

Encouraged by the above results, we intended to extend the scope of this versatile protocol to assemble a range of other functionalized coumarins under identical reaction conditions. In this line, we have successfully prepared diverse substituted coumarins (20–31) in good-to-excellent yields (60–98%) from various substituted phenols and β-ketoesters (ethyl acetoacetate/ethyl benzoylacetate/ethyl chloroacetoacetate) (Table ). Strikingly, from our experimentations, we observed that phloroglucinol (11) with ethyl acetoacetate (9) provided the best yield where the reaction proceeded cleanly and rapidly to afford the desired Pechmann condensation product (20) in just 10 min (Table , entry 1). More importantly, compound 20 was also obtained on a large scale (5 g, 95%) in just 15 min under similar conditions. To further demonstrate the substrate scope of this method, pyrogallol (12) and catechol (13) upon reaction with 9 also neatly afforded the corresponding coumarins (21 and 22) in respectable yields (Table , entries 2 and 3). Noticeably, it has been observed that phenols with electron-releasing groups (EDGs) at the meta-positions efficiently delivered the Pechmann condensation products (23 and 24) with 9 in decent yields (Table , entries 4 and 5). It has been observed that phenol derivatives consisting of electron donating groups (EDGs) at the meta-position(s) to phenolic −OH (participating in the cyclization step) increase the rate of the reaction because of the mesomeric effect of these substituents on the attacking benzene ring carbon. This effect can be clearly seen from Table , showing that phloroglucinol 11, having two m-OH groups compared to that of phenolic −OH, which participates in the cyclization, or in other words ortho and para with respect to the attacking benzene ring carbon, not only reacts at a faster rate but also furnished the corresponding product in better yield as compared to the pyrogallol 12, having only one such m-hydroxy group. Moreover, we noticed that 3-aminophenol 14 reacted at a faster rate (surprisingly, lower yield obtained) than resorcinol due to the stronger mesomeric effect by the amino group in comparison to the phenolic functionality. On the other hand, a phenol-containing electron-withdrawing group (EWG), for example, 4-chlorophenol (32), failed to undergo the Pechmann condensation reaction, which may be due to low nucleophilicity and/or mild reaction medium under investigation (Table , entry 13). Moreover, as shown in the literature,[93−95] the parent phenol does not react at all to deliver the corresponding desired product 35 (Table , entry 14). As expected, our efforts in this direction were also futile (no starting material was consumed), although we have raised the temperature of the reaction mixture to 140 °C and also stirred the reaction for several days. On the other hand, employing ChCl/l-(+)-TA (1:2) at 110 °C for α/β naphthols (16 and 17) also did not provide the required products (starting materials recovered) even if we attempted the reaction at higher temperatures and for longer times. Pleasingly, use of a catalytic amount of methanesulfonic acid (0.2 equiv) under similar reaction conditions furnished the desired products (25 and 26) from the naphthols (16 and 17) in respectable yields. The use of less reactive ethyl benzoylacetate (18) as a β-ketoester partner with the substituted phenols (8 and 11) furnished the corresponding coumarin derivatives (27 and 28) in comparatively lower yields with protracted reaction times in comparison to the more reactive β-ketoester partner (9) (Table , entries 8 and 9). Moreover, significant yields (76–91%) of the functionalized coumarins (29–31) were isolated from the reaction of the substituted phenols (8–11) with ethyl chloroacetoacetate (19) (Table , entries 10–12). The phenol systems consisting of two/three phenolic groups were found to be ineffective to deliver the corresponding di- and tricoumarins with 2/3 equiv of β-ketoesters even after the reactions were stirred for longer times at higher temperatures. Surprisingly, in all cases, we were able to isolate only the corresponding monocoumarin derivatives, confirmed both by TLC and 1H NMR spectral data. The reason for the formation of only monocoumarins and not the desired di-/tricoumarins with more equivalents of β-ketoester is still unclear and is under investigation. In order to compare the present green protocol with the already existing ones, we put forth an effort to compile the results of the previously published procedures (Table ).[35,75,96−101] From Table , it is clear that our method is not only slightly better from a yield perspective than the others but also involve cheap, biodegradable, and reusable melting mixture. Fascinatingly, bis-coumarins (41–44) were also fruitfully assembled by reacting 7-hydroxycoumarin (36) with aromatic aldehydes (37–40) in respectable yields (81–97%) utilizing ChCl/l-(+)-TA (1:2) at lower temperature (90 °C) (Scheme ). From these studies, we pointed that aromatic aldehyde containing EWG (38) besides reacting at faster rate with 36 also resulted the desired product (42) in better yield (97%) as compared to the aromatic aldehydes having EDGs (39 and 40) as shown in Scheme . More importantly, in most of the cases, the precipitate formation of the desired coumarins by means of adding the water while the reaction was still hot at the end of the reaction limits the unnecessary use of the volatile organic solvents for workup procedures. Interestingly, purification was also not required in some cases of precipitated products, as we obtained reasonably pure compounds for NMR analysis after direct filtration of precipitate.

Table 2

Construction of Vital Coumarin Derivatives (20–31) Utilizing the ChCl/l-(+)-TA (1:2)

NR = no reaction. In these cases, catalytic amount (0.2 equiv) of methane sulfonic acid (MeSO3H) was added.

Table 3

Assessment of the Green Protocol with Previously Reported Ones for the Synthesis of Diverse Coumarin Derivatives (10, 20–31) via Pechmann Condensation

entry	catalysts	time/temp/solvent	yield (%)	ref
1	ZrOCl2·8H2O	24 h/80 °C/solvent free	48–94	(97)
2	phosphotungstic acid	30–90 min/90 °C/solvent free	60–94	(35)
3	BiCl3	1–2 h/75–110 °C/solvent free	81–93	(98)
4	I2	1–2.2 h/85 °C/solvent free	70–90	(99)
5	oxalic acid	35–50 min/80 °C/solvent free	91–96	(100)
6	sulfamic acid	20–55 min/130 °C/solvent free	68–96	(96)
7	acidic ionic liquid	1.5–4 h/85 °C/solvent free	70–80	(75)
8	Zn0.925Ti0.075O	3–5 h/110 °C/solvent free	55–89	(101)
9	ChCl/l-(+)-TA(1:2)	10 min–24 h/110 °C/solvent free	60–98	This work

Scheme 1

Synthesis of Diverse Bis-coumarin Derivatives (41–44) Using ChCl/l-(+)-TA (1:2)

In order to expose the reactivity of various substituted phenols (8, 11, and 12) with β-ketoesters (9, 18, and 19), competitive reactions for the generation of corresponding substituted coumarins (10, 20, 21, 28, and 30) were performed involving the optimized reaction conditions (Scheme ). From these experiments, as detailed in the Scheme , while comparing the substituted phenols (8, 11, and 12), phloroglucinol (11) reacted at fastest rate in comparison to the others (11 and 12) in order to deliver the corresponding product (20) in highest yield. On the other hand, as expected, β-ketoester (9) was found to react with high speed than other β-ketoesters (18 and 19). Furthermore, we also compare the reactivity of three aromatic aldehydes in the synthesis of bis-coumarins by reacting the 4-hydroxy coumarin (36) with benzaldehyde (37), 4-nitrobenzaldehyde (38), and anisaldehyde (39) and pointed out that 4-nitrobenzaldehyde reacted at faster rate due to an obvious reason of having high electrophilicity at the carbonyl carbon hence afforded major product as compared to the benzaldehyde (37) (Scheme ). In the case of anisaldehyde (39), methoxy groups mitigate the reactivity of the carbonyl functionality due to a mesomeric effect. Hence, these findings are in concurrence with the fact that aromatic aldehyde containing EWG reacts at a faster rate with 36 than the aromatic aldehyde containing EDG.

Scheme 2

Competitive Reactions for the Formation of Functionalized Coumarins in ChCl/l-(+)-TA (1:2) Based DES

The plausible mechanism of 7-hydroxy-4-methylcoumarin (10) via DES of ChCl/l-(+)-TA (1:2) is depicted in the Scheme . Initially, the DES (47) is formed via four hydrogen-bonding interactions between hydroxyl groups of l-(+)-TA) and Cl– ions of the ChCl[111] which by providing the proton activate the carbonyl group of the ethyl acetoacetate (9). The protonated ethyl acetoacetate 48 then undergoes nucleophilic attack by resorcinol (8) resulting in the generation of 49, which on subsequent aromatization yield the compound 50. Next, attack of the phenolic group to ester functionality followed by the dehydration provided the required compound 7-hydroxy 4-methylcoumarin (10).[112]

Scheme 3

Plausible Mechanism of the Formation of 7-Hydroxy-4-methylcoumarin (10) via DES of ChCl/l-(+)-TA (1:2)

Conclusions

In summary, Pechmann condensation has been carried out efficiently under the green condition through the utilization of ChCl/l-(+)-TA (1:2) based DES for the construction of diverse privileged coumarins. Moreover, the same DES at relatively lower temperature was also found effective to assemble various bis-coumarin derivatives under similar reaction conditions. Besides the efficient recovery and reutilization of the ChCl/l-(+)-TA (1:2) based DES, the developed green method was also successfully operated for large-scale synthesis. This procedure may be industrialized as functionalized coumarins were cleanly obtained at gram-scale in almost similar time with almost identical yields as in milligram scale. Our methodology is enriched with various salient features like simple-to-use, good-to-excellent yields with mild reaction conditions and no obligation of hazardous volatile organic solvent/external catalyst/inert atmosphere. Thus, the authors believe that the established protocol for coumarins and bis-coumarins synthesis might be beneficial from both environmental as well as industrial viewpoints.

Experimental Section

General Information

All the required chemicals were procured from Sigma-Aldrich, Alfa Aesar, SRL, TCI, GLR, Avra, and Spectrochem. Reaction progress was monitored by thin-layer chromatography (TLC) on silica gel coated aluminum plates using suitable ratio of hexane and EtOAc for development. For the purification of desired compounds, column chromatography using silica gel (100–200 mesh) was carried out with a suitable mixture of EtOAc and petroleum ether. Purified functionalized coumarins and bis-coumarins were characterized by 1H NMR spectra recorded in DMSO-d6 on a Bruker spectrometer (400 and 500 MHz). Melting points of various coumarin derivatives were recorded through Tanco manual melting point apparatus.

General Synthetic Procedure for Functionalized Coumarins (10, 20–31)

In a characteristic experiment, 3 g of ChCl/l-(+)-TA (1:2) mixture was heated at 60–70 °C so as to obtain a transparent melting mixture. Afterward, the temperature of the clear melt was elevated to optimum temperature (110 °C), and at this temperature, substituted phenols (1 mmol) and β-ketoesters (2.1 mmol) were added. The reaction was allowed to stir at 110 °C for 10 min to 24 h. After the completion of the reaction as monitored through consumption of all the starting materials on TLC, 10–15 mL of water was added while still hot. The resulting solid material formed in most of the cases was filtered-off through the sintered glass funnel and washed thoroughly with water. The solid was later dried and purified by column chromatography using appropriate ratio of petroleum ether and ethyl acetate to afford functionalized coumarins (10, 20–31). In the case of no precipitation, workup with ethyl acetate was performed followed by purification through column chromatography.

General Synthetic Procedure for Bis-coumarins 41–44

In an illustrative experiment, 3 g of ChCl/l-(+)-TA (1:2) mixture was heated at 60–70 °C to obtain a clear melting mixture. Later the temperature was raised to 90 °C and 7-hydroxycoumarin (2 mmol) along with appropriate aromatic aldehyde (1 mmol) were added, and the reaction was allowed to stir for 20–45 min. After the completion of the reaction as monitored via consumption of reactants on TLC, 10–15 mL of water was added while the mixture was still hot. The consequent solid material was later filtered through sintered glass funnel and washed thoroughly with water. After proper vacuum drying, purification of crude solid through column chromatography was performed using appropriate ratio of petroleum ether and ethyl acetate to afford functionalized bis-coumarins (41–44).

General Procedure for Recyclability of ChCl/l-(+)-TA (1:2)

After the completion of a particular reaction carried out by using 3 g of ChCl/l-(+)-TA (1:2), water was added to the hot reaction mixture. Wherever precipitation of a product resulted, filtration was carried out via a sintered glass funnel. However, where no precipitation occurred after addition of water, liquid–liquid extraction using ethyl acetate and water was carried out. The aqueous phase containing DES in both cases was evaporated so as to result in a solid DES, which was later dried and reused directly for the next run. The same procedure was followed for further runs.[92]

7-Hydroxy-4-methyl-2H-chromen-2-one (10):

light pink solid; mp 184–186 °C; yield 90%; 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 6.70 (s, 1H), 6.12 (s, 1H), 2.36 (s, 3H). The spectral data are in accordance with the literature.[32,101,102]

5,7-Dihydroxy-4-methyl-2H-chromen-2-one (20):

white solid; mp 280–283 °C; yield 98%; 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 10.32 (s, 1H), 6.29 (s, 1H), 6.20 (s, 1H), 5.87 (s, 1H), 2.51 (s, 3H). The spectral data are in accordance with the literature.[32,101,102]

7,8-dihydroxy-4-methyl-2H-chromen-2-one (21):

light purple solid; mp 240–242 °C; yield 81%; 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 2.34 (s, 3H). The spectral data are in accordance with the literature.[32,101,102]

8-Hydroxy-4-methyl-2H-chromen-2-one (22):

light pink solid; mp 169–172 °C; yield 62%; 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 6.13 (s, 1H), 2.36 (s, 3H). The spectral data are in accordance with the literature.[103,113]

7-Amino-4-methyl-2H-chromen-2-one (23):

brown solid; mp 220–223 °C; yield 82%; 1H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 6.4 Hz, 1H), 6.41 (s, 1H), 6.11 (s, 2H), 5.90 (s, 1H), 2.29 (s, 3H). The spectral data are in accordance with the literature.[102,104]

7-Methoxy-4-methyl-2H-chromen-2-one (24):

wWhite solid; mp 160–163 °C; yield 65%; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.20 (s, 1H), 3.85 (s, 3H), 2.39 (s, 3H). The spectral data are in accordance with the literature.[101,102,104]

4-Methyl-2H-benzo[h]chromen-2-one (25):

light brown solid, mp 154–157 °C; yield 68%; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 9.6 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.73–7.66 (m, 2H), 6.48 (s, 1H), 2.50 (s, 3H). The spectral data are in accordance with the literature.[32,101,102]

4-Methyl-2H-benzo[g]chromen-2-one (26):

pale yellow solid; mp 180–183 °C; yield 60%; 1H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 10.0 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.81–7.53 (m, 3H), 6.39 (s, 1H), 2.39 (s, 3H). The spectral data are in accordance with the literature.[99,105]

7-Hydroxy-4-phenyl-2H-chromen-2-one (27)

brown solid; mp 253–256 °C; yield 75%; 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.52 (dd, J = 15.2 Hz, 3.6 Hz, 5H), 7.26 (d, J = 8.8 Hz, 1H), 6.79–6.76 (m, 2H), 6.13 (s, 1H). The spectral data are in accordance with the literature.[32,101,106]

5,7-Dihydroxy-4-phenyl-2H-chromen-2-one (28):

light pink solid; mp 240–243 °C; yield 83%; 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 10.14 (s, 1H), 7.37–7.33 (m, 5H), 6.27 (s, 1H), 6.17 (s, 1H), 5.75 (s, 1H). The spectral data are in accordance with the literature.[32,101,107]

4-(Chloromethyl)-7-hydroxy-2H-chromen-2-one (29):

gray solid; mp 180–183 °C; yield 80%; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 4.94 (s, 2H). The spectral data are in accordance with the literature.[32,108,109]

4-(Chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (30):

white solid; mp 185–188 °C; yield 91%; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.52 (s, 1H), 6.28 (s, 1H), 6.25–6.18 (m, 2H), 5.03 (s, 2H). The spectral data are in accordance with the literature.[31,32]

4-(Chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (31):

light pink solid; mp 131–134 °C; yield 76%; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.54 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.93 (s, 2H). The spectral data are in accordance with the literature.[32,97,110]

3,3′-(Phenylmethylene)bis(4-hydroxy-2H-chromen-2-one) (41):

white solid; mp 228–231 °C; yield 91%; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 6.8 Hz, 2H), 7.34–7.23 (m, 4H), 7.22–7.16 (m, 2H), 7.14–7.07 (m, 3H), 6.31 (s, 1H). The spectral data are in accordance with the literature.[114,115]

3,3′-((4-Nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (42):

white solid; mp 233–236 °C; yield 97%; 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 9.2 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.58–7.48 (m, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.32–7.20 (m, 4H), 6.35 (s, 1H). The spectral data are in accordance with the literature.[114−116]

3,3′-((4-Methoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (43):

creamy solid; mp 254–256 °C; yield 85%; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 1.6 Hz, 2H), 7.50 (t, J = 8.8 Hz, 2H), 7.24 (q, J = 8.0 Hz, 4H), 7.00 (d, J = 7.6 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.21 (s, 1H). The spectral data are in accordance with the literature.[114,116,117]

3,3′-((4-Hydroxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (44):

Creamy solid; mp 220–223 °C; yield 81%; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 8.4 Hz, 2H), 7.38–7.16 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 6.18 (s, 1H). The spectral data are in accordance with the literature.[114,116,117]