An organocatalyst from renewable materials for the synthesis of coumarins and chromenes: three-component reaction and multigram scale synthesis

Abstract

A new concept of catalysts which are prepared from renewable materials is demonstrated. It is known that amino acids (e.g., proline and hydroxyproline) are robust organocatalysts for several reactions. Bovine tendons which are proteins rich in hydroxyproline and proline were used as a source of amino acids. An acid hydrolysate of tendons (a TH catalyst) could catalyze two reactions: (i) the synthesis of coumarins and chromenes under solvent-free conditions and (ii) the synthesis of densely functionalized 4H-chromenes via a three-component reaction. Moreover, an economical and easily accessible TH catalyst is applicable in a multigram scale synthesis of coumarins and chromenes, as well as in the three-component reaction for chromene synthesis. A catalytic activity of hydroxyproline for the synthesis of 4H-chromenes via the three-component reaction was also discovered. The present work demonstrates not only the green catalysts from renewable materials, but also an environmentally benign preparation of coumarins and chromenes.

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Introduction

The benzopyran chemical class, formed from the fusion of a benzene ring and a pyran ring with various levels of saturation and oxidation, appears in many natural products.¹ 1-Benzopyran skeletons including coumarin 1 and 4H-chromene 2 (Fig. 1) are important scaffolds in many drugs and bioactive natural products.

Fig. 1 Structure of coumarin 1 and 4H-chromene 2.

Coumarins (2H-chromen-2-one derivatives) possess many biological activities including anticoagulant, anticancer, enzyme inhibition, vasorelaxant, antimicrobial, antioxidant, and anti-inflammatory, and anti-HIV activities.^2–12 In addition to the biological properties, they have been used in food additives, cosmetics, optical brightener, and fluorescent and laser dyes.¹³ 4H-Chromene moiety is present in many bioactive compounds and drug leads.^14–18 The examples of drugs currently used are warfarin 3a and cromoglicic acid 3b as anticoagulants and anti-asthmatic agents, respectively (Fig. 2). Because of their important use in pharmaceuticals, there are many synthetic methods towards the synthesis of these privileged structures.

Fig. 2 Structure of warfarin 3a cromoglicic acid 3b.

Several synthetic routes have been reported for the synthesis of coumarins.^19–21 Whereas, chromene derivatives were synthesized by various methods, for example, DBU-catalyzed reaction between salicylic aldehydes and ethyl 2-methylbuta-2,3-dienoate;²² tandem benzylation and cyclization by FeCl₃;²³ Cu(I)-catalyzed domino reactions;²⁴ and triazine functionalized ordered mesoporous organosilica as an organocatalyst.²⁵ However, these procedures are not green methods since metals and hazardous solvents are used in the synthesis. Recently, green methods were developed for the synthesis of chromene and coumarin, for example, four-component catalyst-free reaction in water²⁶ and biocatalytic domino reaction with the enzyme alkaline protease.²⁷ However, the development of new methods and catalysts, which provide economical and environmentally friendly routes, is still required for both coumarin and chromene syntheses.

Among various organocatalysts, amino acids play an important role in asymmetric organocatalysis. L-Proline and derivatives have been extensively used as efficient organocatalysts,^28,29 and they are employed in several asymmetric organic syntheses.³⁰ L-Proline and other amino acids have been demonstrated to be powerful catalysts for various reactions, i.e., aldol reactions, Mannich reactions, Michael reaction, and α-functionalizations of carbonyl compounds.³¹ Utilization of renewable materials for fine and industrial chemicals is one of the important topics in green chemistry,^32–36 because renewable resources provide not only the reduction of environmental impacts, but also economical feasibility and sustainable productions. Normally, tendons are composed of various collagen fibers, which are proteins rich in hydroxyproline and proline;^37–39 both amino acids are known as robust organocatalysts.^28–31,40 In the present work, we demonstrate a new concept of catalysts which are prepared from renewable materials. We used bovine tendons as a source of amino acids, and found that a tendon hydrolysate (TH) served as an excellent organocatalyst, catalyzing the synthesis of coumarins and 4H-chromenes under solvent-free conditions. The TH catalyst also efficiently catalyzed the three-component reactions for the construction of densely functionalized 4H-chromenes, recently reported by Gu and coworkers.⁴¹ Moreover, the cheap and easily accessible TH catalyst was applicable in a multigram scale synthesis of coumarins and chromenes, as well as in a multigram scale chromene synthesis via the three-component reactions.

Results and discussion

The TH catalyst was simply prepared from the acid hydrolysis of bovine tendons. The hydrolysate obtained from acid hydrolysis was neutralized by base, and then extracted with MeOH to give the TH catalyst. The reaction between salicylaldehyde (4a) methyl acetoacetate (5) catalyzed by the TH catalyst under solvent-free condition (at 55 °C) was initially investigated; this reaction gave coumarin 6a and two diastereomers of chromene 7a as products (Fig. 3). We also found that methyl acetoacetate provided better yields of products than that of ethyl acetoacetate. To ensure that the reaction was not catalyzed by the residue of base or acid which was probably present in the prepared catalyst, portions of the TH catalyst were dissolved in water, and pH of solutions were found to be at 6.5–7.2, confirming that the reaction was not due to the activity of base or acid.

Fig. 3 Reaction of salicylaldehyde (4a) and methyl acetoacetate (5) catalyzed by the TH catalyst.

Next, we investigated the influence of the molar ratio of substrates (salicylaldehyde 4a to methyl acetoacetate 5) on the product ratios of coumarin (6a) to chromene (7a). As shown in Table 1, increasing the molar ratio of methyl acetoacetate (5) gave a slightly increase in chromene (7a) production. We next investigated the effect of temperature for the reaction, and the reactions were conducted at room temperature (26–28 °C), 55 °C, and 80 °C. It was found that the times used for the reaction at room temperature, 55 °C, and 80 °C were 96 h, 29 h, and 19 h, respectively (the yields were >96% as indicated by ¹H NMR spectrum). Although increasing temperature could shorten the time for the reactions, performing the reaction at 55 °C was more reasonable, in term of the reduction of energy consumption, than that at 80 °C. We therefore decided to carry out the reaction at 55 °C for further experiments.

Table 1 Effects of the molar ratio of 4a : 5 on the yield of 6a and 7a^a

Entry	4a : 5	Time (h)	6a : 7a^b
a Reactions were performed using salicylaldehyde (50 mg, 0.41 mmol) and 20% (by weight) of the TH catalyst.b The ratio of 6a : 7a was determined by ^1H NMR spectrum.
1	1 : 1	65	15 : 8
2	1 : 3	65	3 : 4
3	1 : 5	65	7 : 11
4	1 : 7	65	1 : 2

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Next, we investigated the reaction of methyl acetoacetate (5) and a variety of salicylaldehyde derivatives (4), using the molar ratio 1 : 3 of salicylaldehyde derivatives (4) to methyl acetoacetate (5) with 20% of the TH catalyst (at 55 °C). As shown in Table 2, both coumarins and chromenes were obtained in low to moderate yields (3–54%). Unsubstituted salicylaldehyde and those bearing electron-donating groups (Table 2, entries 1–4 and 8) favored the formation of chromenes (7a, 7b, 7c, 7d, and 7h) with respect to coumarins (6a, 6b, 6c, 6d, and 6h). In contrast, salicylaldehyde bearing an electron-withdrawing group (Table 2, entries 5 and 6) provided coumarins (6e and 6f) more than chromenes (7e and 7f). 5-Nitrosalicylaldehyde and 2-hydroxy-1-naphthaldehyde did not provide chromenes (7i and 7k), therefore only coumarins (6i and 6k) were obtained (Table 2, entries 9 and 11). This could be because the nitro group increases the acidity of the hydroxyl group, which is likely to be deprotonated, and thus reducing the electrophilicity of the aldehyde group. It was found that 4-(diethylamino)salicylaldehyde (4j) did not give both coumarin (6j) and chromene (7j) (Table 2, entry 10). This could be because a diethylamino group of 4j probably makes an aldehyde group less reactive via para-donating electron from a nitrogen atom.

Table 2 Synthesis of coumarins and chromenes from salicylaldehyde derivatives (4) and methyl acetoacetate (5) using the TH catalyst^a

Entry	4	Coumarin (% yield)	Chromene^f (% yield)	Time (h)	Entry	4	Coumarin (% yield)	Chromene^f (% yield)	Time (h)
a Reactions contained ca. 4.09 mmol of salicylaldehyde derivatives (4), ca. 12.28 mmol of 5, and 20% of the TH catalyst (at 55 °C).b Yield of the product that was precipitated and obtained without chromatographic separation.c Yield from product precipitation and chromatographic separation.d Yield from crystallization and chromatographic separation.e Yield from chromatographic separation.f Before crystallization, the ratios of ca. 1.5–2.0 to 1 for the major diastereomer to minor diastereomer were observed.g Substrate was recovered.h Yield of the major diastereomer of chromene.i Yield of two diastereomers of chromene.
1				29	7				72
		23%^e	38%^h^,^d				40%^b	17%^i^,^e
2				25	8				72
		28%^c	46%^h^,^d				3%^e	21%^i^,^e
3				72	9				24
		14%^c	26%^h^,^b				41%^b	0%
4				25	10				72^g
		28%^c	42%^h^,^d				Trace amount	0%
5				72	11				36
		54%^b	31%^h^,^d				42%^c	0%
6				72
		39%^b	33%^h^,^d

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As mentioned earlier, this reaction gave two diastereomers of chromene products with the ratio of ca. 1.5–2.0 to 1 for the major diastereomer to minor diastereomer. ¹H NMR spectrum (ESI, Fig. 1S†) of the two diastereomers (0.429 g) of chromene 7b indicated the ratio of 2 to 1 (a major isomer to a minor isomer). However, after crystallization from EtOH–CH₂Cl₂, a large amount (0.397 g) of the major diastereomer of chromene 7b was obtained, leaving only 0.029 g of the filtrate containing the two chromene diastereomers at the ratio of 5 : 3 (ESI, Fig. 2S†). This result suggested that only the major diastereomer could be crystallizable, and that the minor diastereomer was converted to the major diastereomer during crystallization. As shown in Table 2 (entries 1–6), large amounts of the major diastereomer of chromenes 7a–f (26–46% yield) were obtained after crystallization. It should be noted that chromenes 7g and 7h could not be crystallized, and unfortunately they could not be separated by chromatographic techniques; therefore, percentage yields of chromenes 7g and 7h were of a mixture of the two diastereomers (Table 2, entries 7 and 8).

The structure of a major diastereomer of chromene 7a was elucidated by analysis of spectroscopic data; extensive analysis of 2D NMR data established a planar structure of 7a. Fortunately, appropriate crystals of the major diastereomer of chromenes 7a, 7b, 7e, and 7f were obtained, and they were subjected to a single crystal X-ray analysis, which conclusively disclosed the relative configuration of S* and R* for the positions 4 and 2′, respectively (Fig. 4). We proposed that the isomerization between the two chromene diastereomers proceeds via an enol intermediate (ESI, Fig. 3S†). It is worth mentioning that this is the first report on the preparation of a single 4S,2′R-diastereomer of chromenes (e.g. 7a–f), particularly under environmentally benign conditions.

Fig. 4 ORTEP plots (30% probability level) of chromenes 7a, 7b, 7e, and 7f (color codes: C = cyan, O = red, Br = orange, Cl = green, H = white).

Tendons are proteins rich in hydroxyproline and proline amino acids.^37–39 The fact that both proline and hydroxyproline are robust organocatalysts,^28–31,40 we therefore propose that the two amino acids in the TH catalyst are possibly responsible for the catalytic activity. Analysis of an amino acid content in the TH catalyst revealed that, among 20 natural amino acids, the percentage of proline and hydroxyproline were 15.89% and 13.12%, respectively (ESI, Table 2S†), which were relatively high as compared to other amino acids, except glycine (19.23%). To prove our hypothesis, we then used L-proline (20% mol) as a catalyst for the reaction entries 1, 2, and 5 (Table 2). Indeed, we found that L-proline gave the same coumarins and chromenes as that obtained from the TH catalyst; respective yields of coumarins 6a, 6b, and 6e were 29%, 28%, and 50%, while those of chromenes 7a, 7b, and 7e were 40%, 18%, and 24%, respectively. However, hydroxyproline (20% mol) did not catalyze such reaction, possibly due to the insolubility of hydroxyproline in solvent-free conditions (its precipitate was observed). This result conclusively indicated that hydroxyproline did not involve in the reaction under solvent-free conditions. We then performed the reaction in EtOH : H₂O (9 : 1), in which hydroxyproline could be completely dissolved; the reaction proceeded under this condition, giving respective yields of 23%, 14%, and 24% for coumarins 6a, 6b, and 6e and 9%, 17%, and 8% for chromenes 7a, 7b, and 7e. Therefore, hydroxyproline also had a catalytic activity for the formation of chromenes and coumarins under a relatively polar condition that could dissolve hydroxyproline, but not under solvent-free conditions as shown in Table 2. A proposed mechanism for the formation of coumarin and chromene catalyzed by amino acids is shown in Fig. 5. The reaction starts with a condensation of an aldehyde and a catalyst (represented as L-proline), giving rise to an iminium intermediate A, which subsequently reacts with methyl acetoacetate (5), to give the intermediate B. Lactonization of B leads to the formation of the intermediate C. A release of a catalyst from the intermediate C gives rise to a coumarin D. Alternatively, a phenolic group of the intermediate B intramolecularly attacks a carbonyl to give the intermediate E; a release of a catalyst from the intermediate E yields the intermediate F. Loss of water assisted by lone pair electrons on oxygen gives the oxonium intermediate G, which in turn reacts with methyl acetoacetate (5) to give a chromene H (Fig. 5).

Fig. 5 A proposed mechanism for the formation of coumarin and chromene.

Since the TH catalyst is inexpensive, we performed multigram scale synthesis of coumarin 6a and chromene 7a with three separated (solvent-free) conditions (Table 3). With ca. 10 g of a substrate 4a, respective yields of 28–41% and 33–37% for coumarin 6a and chromene 7a were obtained (Table 3), indicating that a practical multigram scale synthesis of coumarins and chromenes is feasible with the TH catalyst. The TH catalyst is a green catalyst derived from renewable materials (bovine tendons), and the solvent-free conditions employed for this multigram scale synthesis is also environmentally friendly.

Table 3 Multigram scale synthesis of coumarin 6a and chromene 7a

Entry	Weight of 4a (g)	Ratio of 4a : 5	Temperature (°C)	Time (h)	Yield of 6a (g) (%)	Yield of 7a (g) (%)
1	10.0	1 : 3	55	72	4.3 (28%)	8.6 (33%)
2	10.6	1 : 7	55	72	6.8 (41%)	10.4 (37%)
3	10.4	1 : 7	80	15	4.8 (30%)	9.9 (36%)

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Next we used the TH catalyst for the synthesis of densely functionalized 4H-chromenes via a three-component reaction. Gu et al. reported the elegant green chemistry route for the synthesis of densely functionalized 4H-chromenes via a three-component reaction of salicylaldehydes, 1,3-cyclohexanediones, and nucleophiles, employing L-proline as catalyst, and some products could be easily isolated by filtration, avoiding the use of chromatographic separations.⁴¹ We followed Gu method for the synthesis of 4H-chromenes, using our TH catalyst. As shown in Table 4, the reaction of salicylaldehyde derivatives (4), dimedone derivatives (8), and nucleophiles (NuH) gave chromenes (9a–j) with yields of 43–95%. It should be noted that chromene products (9a–j) were obtained by filtration and washing with ethanol (without chromatographic separations). Chromenes 9a–c were previously synthesized by Gu and coworkers with respective yields of 98, 88, and 87%,⁴¹ however, these chromenes (9a–c) obtained from the present work (by the TH catalyst) were 67, 79, 56%, respectively (Table 4, entries 1–3). It should be noted that Gu and coworkers cooled the reaction mixture to 0 °C before filtration and washing with ethanol,⁴¹ however, in the present work, this process was performed at room temperature (26–28 °C). This may be the reason that the yields of 9a–c were lower than Gu method.⁴¹ Compounds 9d–j were new chromenes (Table 4, entries 4–10) obtained from the TH catalyst with yields ≥ 70%, except 9f (43%) and 9g (66%). Although chromene products were simply obtained by filtration and washing with ethanol, we observed that the derivatives that are relatively polar (e.g., 9c and 9f, Table 4, entries 3 and 6) had substantial yield losses from ethanol washing. Whereas non-polar products (e.g., 9d) did not have much yield losses from ethanol washing, and thus providing good yield (95%).

Table 4 Three-component reaction of salicylaldehyde derivatives (4), dimedone derivatives (8), and nucleophiles (NuH) by the TH catalyst

Entry	NuH	Product	Time (h)	Yield (%)
1			24	67
2			24	79
3			24	56
4			24	95
5			24	76
6			24	43
7			16	66
8			16	73
9			16	73
10			4	70

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Apart from the chromene synthesis reported by Gu and coworkers,⁴¹ there were other works recently reported for the synthesis of densely functionalized 4H-chromenes using ZnO nanoparticles,⁴² tetrabutylammonium fluoride,⁴³ L-proline,⁴⁴ and iron(III) chloride and triphenylphosphine⁴⁵ as catalysts. The TH catalyst is much cheaper than those catalysts previously employed for such chromene synthesis,^41–45 and we therefore used the TH catalyst for multigram scale synthesis of chromenes. As shown in Fig. 6, a scale of ca. 10 g salicylaldehyde derivatives was used with 20% of the TH catalyst. After stirring the reaction mixture at 80 °C for 15–18 h, chromene products (9k–p) were simply obtained by filtration and washing with ethanol, giving yields of 56, 91, 74, 85, 96, and 97%, respectively (Fig. 6). This result indicates that the economical and green TH catalyst is applicable in the multigram scale synthesis of chromenes; the products were easily obtained without chromatographic separations.

Fig. 6 Multigram scale synthesis of chromenes 9k–p.

Since hydroxyproline was also present in the TH catalyst (ESI, Table 2S†), we then performed the three-component reaction for the synthesis of 4H-chromenes 9n and 9p using hydroxyproline as a catalyst. Surprisingly, quantitative yields of the chromenes 9n (99.5%) and 9p (99.8%) were obtained from the reaction; this result indicated that hydroxyproline in the TH catalyst should also involve in the formation of chromenes. This is the first report on a catalytic activity of hydroxyproline for the synthesis of 4H-chromenes via the three-component reaction.

Overall, the present study highlights a feasible eco-friendly multigram scale synthesis of coumarins and chromenes with a green catalyst from renewable materials, bovine tendons. It should be noted that bovine tendons are used as food ingredients in some countries in Asia, but they are waste from meat industry in Western countries. The multigram scale synthesis of coumarins and/or chromenes reported here could be performed under solvent-free conditions (Table 3) or without chromatographic separations of the products (Fig. 6). Therefore, both the catalyst and the synthetic method are green and friendly to the environment.

Conclusions

The economical, easily accessible, and environmentally friendly TH catalyst was prepared from the acid hydrolysis of bovine tendons which are renewable materials. The TH catalyst catalyzed the synthesis of coumarins and chromenes (e.g., 7a–h) under the solvent-free conditions, and it also catalyzed the synthesis of densely functionalized 4H-chromenes via the three-component reaction. Moreover, the TH catalyst is applicable in the multigram scale synthesis of coumarins and chromenes, as well as in the three-component reaction for the construction of the 4H-chromenes. A multigram scale preparation of chromenes with a single 4S,2′R-diastereomer was demonstrated for the first time. Proline, not hydroxyproline, in the TH catalyst possibly catalyzes the formation of coumarins and chromenes under solvent-free conditions. In addition to proline, hydroxyproline was also found to catalyze the three-component reaction for the synthesis of 4H-chromenes. To the best of our knowledge, this is the first report on the green catalyst prepared from renewable materials.

Experimental section

Instruments

Melting points were measured on Buchi 535 Melting Point Apparatus and reported without correction. UV-Vis spectra were obtained from Shimadzu UV-1700 PharmaSpec Spectrophotometer. FTIR data were obtained using a universal attenuated total reflectance (UATR) attachment on a Perkin-Elmer Spectrum One spectrometer. ¹H and ¹³C NMR spectra were recorded on a Bruker AM 300 NMR instrument (operating at 300 MHz for ¹H and 75 MHz for ¹³C) and a Bruker AVANCE 400 NMR spectrometer (operating at 400 MHz for ¹H and 100 MHz for ¹³C). APCI TOF MS spectra were obtained from a Bruker MicroTOF_LC spectrometer.

Preparation of the TH catalyst

Two batches of the TH catalyst were prepared, and the TH catalysts from both batches had the same catalytic properties. Amino acid content in the TH catalyst is in Table 2S (ESI).†

The first batch. Bovine tendon (135 g) was hydrolyzed in 110 mL of 6 M HCl. A mixture was stirred and refluxed for 12 h; pH of the mixture was adjusted to 7 with saturated NaOH. The mixture was dried by a rotary evaporator, vacuum-dried, and then dissolved in methanol. The methanol soluble part was collected and dried to yield 7 g of the TH catalyst.

The second batch. Bovine tendon (256 g) was hydrolyzed in 90 mL of 6 M HCl. The mixture was stirred and refluxed for 18 h, and its pH was adjusted to 7 with saturated NaOH. The mixture was dried by a rotary evaporator, vacuum-dried, and extracted with 100 mL of MeOH (eleven times, a total volume of 1100 mL). The MeOH extracts were combined and dried, giving 24 g of the TH catalyst.

General procedure for the synthesis of coumarins and chromenes using the TH catalyst

A mixture of a salicylaldehyde derivative (500 mg, 1 equiv.) and methyl acetoacetate (3 equiv.) was added the TH catalyst (20% by weight of a salicylaldehyde derivative). The reaction was stirred at 55 °C, and the progress of a reaction was monitored by TLC. After the reaction was complete (the time for each reaction is indicated in Table 2), if coumarin product precipitated, it was collected by filtration. However, if the coumarin product did not precipitate, the reaction mixture was left at room temperature, in order to crystallize chromene product. In case that both chromene and coumarin did not crystallize or precipitate, the reaction mixture was subjected to chromatographic separations (i.e., Sephadex LH-20 column chromatography (CC), silica gel CC, and preparative TLC). In some cases, chromene or coumarin in the fractions obtained from chromatographic separations were recrystallized from EtOH–CH₂Cl₂.

Multigram scale synthesis of coumarin 6a and chromene 7a was performed with ca. 10 g of salicylaldehyde 4a, using 20% of the TH catalyst. The ratio of substrates 4a and 5, time, and temperature for the reaction were indicated in Table 3. After the reaction was complete, it was added an equal volume of CH₂Cl₂ and H₂O; compounds 6a and 7a were in the CH₂Cl₂ layer, while the TH catalyst was in the H₂O layer. The CH₂Cl₂ layer was left at room temperature, and chromene 7a crystallized from the mixture, followed by coumarin 6a. Finally, a mother liquid was separated by Sephadex LH-20 CC (eluted with MeOH); fractions were left at room temperature, and 6a or 7a individually crystallized from the fractions.

Synthesis of coumarin 6a and chromene 7a

Both 6a and 7a were prepared according to the general procedure. The crude reaction mixture was left at room temperature, and the major diastereomer of chromene 7a crystallized from the mixture. After removing crystals of 7a, the reaction mixture was then washed with water to remove a catalyst, dried under vacuum, and further purified by Sephadex LH-20 CC (eluted with 100% MeOH), followed by silica gel preparative TLC (developed with 20% EtOAc in hexane) to obtain coumarin 6a and a mixture of the two diastereomers of chromene 7a. The mixture of the two diastereomers of chromene 7a was dissolved in a mixture of EtOH–CH₂Cl₂ (2 : 1) and left at room temperature, and the major diastereomer of chromene 7a again crystallized from a solution.

(S*)-Methyl 4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7a). Colorless crystals; mp 119–122 °C; UV (MeOH) λ_max (log ε) 268 (3.68); IR (UATR) ν_max: 3002, 2952, 2840, 1713, 1640, 1584, 1488, 1459, 1434, 1381, 1356, 1291, 1218, 1188, 1154, 1106, 1064, 990, 947, 822, 758 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 2.21 (s, 3H), 2.44 (s, 3H), 3.44 (s, 3H), 3.65 (d, J = 4.5 Hz, 1H), 3.76 (s, 3H), 4.76 (d, J = 4.5 Hz, 1H), 6.98 (dd, J = 1.0 Hz, 8.1 Hz, 1H), 7.05 (td, J = 1.2 Hz, 7.5 Hz, 1H), 7.19 (td, J = 1.1 Hz, 8.0 Hz, 1H) 7.29 (dd, J = 1.5 Hz, 7.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 19.7, 29.5, 34.6, 51.5, 51.9, 66.1, 103.4, 115.8, 121.4, 124.3, 128.2, 129.1, 151.2, 163.9, 167.1, 168.9, 201.6; APCI-TOF MS: calcd for C₁₇H₁₈NaO₆, m/z 341.0996 (M + Na)⁺, found 341.1000.

Synthesis of coumarin 6b and chromene 7b

Compounds 6b and 7b were prepared according to the general procedure. Coumarin 6b precipitated from the reaction mixture. After removing coumarin 6b, the reaction mixture was washed with water to remove a catalyst, dried under vacuum, and further purified by Sephadex LH-20 CC (eluted with 100% MeOH) to obtain additional amounts of coumarin 6b and the mixture of two diastereomers of chromene 7b. The mixture of two diastereomers of chromene 7b was dissolved in a mixture of EtOH–CH₂Cl₂ (2 : 1) and left at room temperature, and the major diastereomer of chromene 7b crystallized from a solution.

(S*)-Methyl 6-methoxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7b). Yellow crystals; mp 97–98 °C; UV (MeOH) λ_max (log ε) 279 (3.83); IR (UATR) ν_max: 2997, 2952, 2838, 1713, 1636, 1601, 1496, 1433, 1380, 1351, 1283, 1244, 1204, 1155, 1106, 1068, 1034, 992, 947, 870, 814, 774, 721, 696 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 2.16 (s, 3H), 2.38 (s, 3H), 3.41 (s, 3H), 3.62 (d, J = 6 Hz, 1H), 3.71 (s, 6H), 4.69 (d, J = 3 Hz, 1H), 6.68 (dd, J = 3 Hz, 9 Hz, 1H), 6.80 (d, J = 3 Hz, 1H), 6.86 (d, J = 9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 19.3, 29.0, 34.4, 51.0, 51.6, 55.0, 65.7, 102.1, 112.6, 114.0, 116.1, 121.7, 144.9, 155.7, 163.8, 166.7, 168.6, 201.3; ESI-TOF MS: calcd for C₁₈H₂₀NaO₇, m/z 371.1101 (M + Na)⁺, found 371.1106.

Synthesis of coumarin 6c and chromene 7c

Compounds 6c and 7c were prepared according to the general procedure. The major diastereomer of chromene 7c precipitated from the reaction mixture. After removing precipitate of 7c, the resulting mixture was left at room temperature, and coumarin 6c was precipitated. After removing coumarin 6c, the reaction mixture was purified by Sephadex LH-20 CC, eluted with 100% MeOH, to obtain fractions that contained coumarin 6c, and these fractions were combined. A combined fraction containing 6c was dried by a rotary evaporator, and dissolved in EtOH–CH₂Cl₂; coumarin 6c crystallized from EtOH–CH₂Cl₂.

(S*)-Methyl 7-methoxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7c). White solid; UV (MeOH) λ_max (log ε) 271 (3.75), 222 (4.21); IR (UATR) ν_max: 3003, 2952, 2841, 1705, 1638, 1583, 1508, 1437, 1385, 1358, 1337, 1288, 1260, 1243, 1206, 1189, 1157, 1140, 1069, 1035, 1005, 952, 849, 805, 778, 715 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 2.21 (s, 3H), 2.43 (s, 3H), 3.47 (s, 3H), 3.64 (d, J = 3 Hz, 1H), 3.76–3.77 (s, 6H), 4.70 (d, J = 3 Hz, 1H), 6.54 (d, J = 3 Hz, 1H), 6.80 (d, J = 3 Hz, 1H), 6.63 (d, J = 9 Hz, 1H), 7.19 (d, J = 6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 19.8, 29.6, 34.2, 51.6, 52.1, 55.4, 66.1, 101.1, 103.8, 110.8, 113.3, 129.8, 152.1, 159.6, 164.0, 167.3, 169.2, 202.0; ESI-TOF MS: calcd for C₁₈H₂₀NaO₇, m/z 371.1101 (M + Na)⁺, found 371.1109.

Synthesis of coumarin 6d and chromene 7d

Compounds 6d and 7d were prepared according to the general procedure. Coumarin 6d precipitated from the reaction mixture. After removing coumarin 6d, the reaction mixture was left at room temperature, and the major diastereomer of chromene 7d crystallized from the mixture. After removing crystals of 7d, the reaction mixture was washed with water to remove a catalyst, dried under vacuum, and further purified by Sephadex LH-20 CC (eluted with 100% MeOH), followed by silica gel CC (eluted with 20% EtOAc in petroleum ether) to obtain additional amounts of coumarin 6d and a mixture of two chromene diastereomers 7d. The mixture of the two chromene diastereomers 7d was dissolved in EtOH–CH₂Cl₂ (2 : 1) and left at room temperature; the major diastereomer of chromene 7d crystallized from EtOH–CH₂Cl₂.

(S*)-Methyl 8-hydroxy-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7d). Colorless crystals; mp 124–126 °C; UV (MeOH) λ_max (log ε) 286 (3.62), 267 (3.65), 205 (4.20); IR (UATR) ν_max: 3420, 3002, 2953, 2845, 1712, 1641, 1617, 1598, 1480, 1435, 1382, 1356, 1211, 1160, 1084, 995, 843, 781, 734 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 2.21 (s, 3H), 2.49 (s, 3H), 3.47 (s, 3H), 3.64 (d, J = 4.9 Hz, 1H), 3.78 (s, 3H), 4.76 (d, J = 4.8 Hz, 1H), 5.44 (s, 1H), 6.79–6.86 (m, 2H), 6.92–6.98 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 19.6, 29.5, 34.7, 51.6, 52.1, 66.0, 104.2, 114.6, 119.9, 122.1, 124.5, 139.1, 143.5, 163.3, 167.1, 168.9, 201.7; ESI-TOF MS: calcd for C₁₇H₁₈NaO₇, m/z 357.0944 (M + Na)⁺, found 357.0952.

Synthesis of coumarin 6e and chromene 7e

Compounds 6e and 7e were prepared according to the general procedure. Coumarin 6e precipitated from the reaction mixture. After removing coumarin 6e, the reaction mixture was left at room temperature, and the major diastereomer of chromene 7e crystallized from the mixture. After removing crystals of 7e, the reaction mixture was then washed with water to remove a catalyst, dried under vacuum, and further purified by silica gel preparative TLC (developed with 25% EtOAc in petroleum ether) to obtain the mixture of two chromene diastereomers 7e. The mixture of the two chromene diastereomers 7e was dissolved in EtOH–CH₂Cl₂ and left at room temperature; the major diastereomer of chromene 7e crystallized from EtOH–CH₂Cl₂.

(S*)-Methyl 6-bromo-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7e). Colorless crystals; mp 119–120 °C; UV (MeOH) λ_max (log ε) 272 (3.73); IR (UATR) ν_max: 3003, 2953, 2922, 1714, 1645, 1578, 1480, 1435, 1382, 1344, 1279, 1221, 1189, 1161, 1116, 1069, 993, 894, 826, 775 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 2.21 (s, 3H), 2.43 (s, 3H), 3.48 (s, 3H), 3.64 (d, J = 3 Hz, 1H), 3.77 (s, 3H), 4.72 (d, J = 3 Hz, 1H), 6.87 (d, J = 9 Hz, 1H), 6.29 (m, 1H), 7.46 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 19.7, 29.5, 34.3, 51.7, 52.2, 65.9, 103.3, 116.7, 117.6, 123.6, 131.2, 131.9, 150.5, 163.9, 166.9, 168.8, 201.24; ESI-TOF MS: calcd for C₁₇H₁₇BrNaO₆, m/z 419.0101 (M + Na)⁺, found 419.0093.

Synthesis of coumarin 6f and chromene 7f

Compounds 6f and 7f were prepared according to the general procedure. Coumarin 6f precipitated from the reaction mixture. After removing coumarin 6f, the reaction mixture was left at room temperature, and the major diastereomer of chromene 7f crystallized from the mixture. After removing crystals of 7f, the reaction mixture was washed with water to remove a catalyst, dried under vacuum, and purified by silica gel preparative TLC (developed with 25% EtOAc in petroleum ether) to obtain a mixture of the two diastereomers of 7f. The mixture of two chromene diastereomers 7f was dissolved in EtOH–CH₂Cl₂ and left at room temperature; the major diastereomer of chromene 7f crystallized from EtOH–CH₂Cl₂.

(S*)-Methyl 6-chloro-4-((R*)-1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7f). Colorless crystals; mp 111–113 °C; UV (MeOH) λ_max (log ε) 271 (3.48); IR (UATR) ν_max: 3003, 2953, 2841, 1716, 1694, 1643, 1582, 1483, 1435, 1381, 1351, 1281, 1223, 1190, 1158, 1116, 1069, 992, 950, 887, 820, 775, 664 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 2.21 (s, 3H), 2.43 (s, 3H), 3.48 (s, 3H), 3.64 (d, J = 4.4 Hz, 1H), 3.77 (s, 3H), 4.72 (d, J = 4.2 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 7.16 (dd, J = 2.5 Hz, 8.7 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 19.6, 29.5, 34.4, 51.6, 52.1, 65.9, 103.2, 117.1, 123.1, 128.2, 129.0, 129.2, 150.0, 163.9, 166.9, 168.8, 201.3; ESI-TOF MS: calcd for C₁₇H₁₇ClNaO₆, m/z 375.0606 (M + Na)⁺, found 375.0603.

Synthesis of coumarin 6g and chromene 7g

Compounds 6g and 7g were prepared according to the general procedure. Coumarin 6g precipitated from the reaction mixture. After removing coumarin 6g, the reaction mixture was washed with water to remove a catalyst, dried under vacuum, and purified by preparative TLC (50% EtOAc in petroleum ether) to obtain the mixture of two diastereomers of chromene 7g.

3-Acetyl-5-bromo-8-methoxy-2H-chromen-2-one (6g). Yellow solid; UV (MeOH) λ_max (log ε) 320 (3.80), 259 (3.62), 213 (4.08); IR (UATR) ν_max: 3084, 2942, 1733, 1686, 1592, 1563, 1466, 1437, 1358, 1328, 1264, 1227, 1202, 1152, 1095, 953, 924, 832, 765 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 2.74 (s, 3H), 3.97 (s, 3H), 7.04 (d, J = 9 Hz, 1H), 7.47 (d, J = 6 Hz, 1H), 8.73 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 30.5, 56.5, 113.9, 116.1, 118.5, 125.3, 128.2, 145.7, 146.5, 146.6, 158.0, 195.0; ESI-TOF MS: calcd for C₁₂H₉BrNaO₄, m/z 318.9576 (M + Na)⁺, found 318.9587.

Methyl 5-bromo-8-methoxy-4-(1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7g). Yellow viscous oil; UV (MeOH) λ_max (log ε) 292 (3.82), 265 (4.01), 202 (4.61); IR (UATR) ν_max: 2997, 2951, 2841, 2172, 1717, 1644, 1602, 1578, 1477, 1435, 1382, 1357, 1312, 1237, 1210, 1155, 1096, 1062, 883, 800 cm⁻¹; The major diastereomer: ¹H NMR (300 MHz, CDCl₃) δ: 2.36 (s, 3H), 2.51 (s, 3H), 3.54 (s, 3H), 3.73 (s, 3H), 3.86 (s, 3H), 3.95 (d, J = 3 Hz, 1H), 4.81 (d, J = 3 Hz, 1H), 6.71–6.75 (m, 1H), 7.27–7.31 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 19.4, 30.0, 36.2, 51.3, 52.0, 56.2, 62.3, 101.5, 111.9, 112.4, 122.4, 127.4, 127.8, 147.3, 163.7, 167.1, 167.8, 201.1; The minor diastereomer: ¹H NMR (300 MHz, CDCl₃) δ: 2.11 (s, 3H), 2.47 (s, 3H), 3.66 (s, 3H), 3.79 (s, 3H), 3.87 (s, 3H), 3.94–3.97 (m, 1H), 4.85 (d, J = 3 Hz, 1H), 6.71–6.75 (m, 1H), 7.27–7.31 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 19.1, 30.1, 36.8, 51.7, 52.3, 56.3, 62.4, 103.8, 111.4, 112.4, 122.4, 127.4, 127.8, 147.2, 162.9, 167.1, 168.2, 201.2; ESI-TOF MS: calcd for C₁₈H₁₉BrNaO₇, m/z 449.0206 (M + Na)⁺, found 449.0215.

Synthesis of coumarin 6h and chromene 7h

Compounds 6h and 7h were prepared according to the general procedure. The reaction mixture was washed with water to remove a catalyst, dried under vacuum, and purified by Sephadex LH-20 CC (eluted with 100% MeOH) to obtain the mixture of two chromene diastereomers 7h and the fractions that contained coumarin 6h. The fractions containing 6h were combined and purified again by preparative TLC (40% hexane in CH₂Cl₂) to give coumarin 6h.

Methyl 6,8-di-tert-butyl-4-(1-methoxy-1,3-dioxobutan-2-yl)-2-methyl-4H-chromene-3-carboxylate (7h). Yellow viscous oil; UV (MeOH) λ_max (log ε) 276 (3.83); IR (UATR) ν_max: 2954, 2870, 1716, 1643, 1598, 1435, 1380, 1361, 1274, 1246, 1213, 1199, 1170, 1074, 994, 883, 832, 774 cm⁻¹; The major diastereomer: ¹H NMR (400 MHz, CDCl₃) δ: 1.28–1.29 (s, 9H), 1.42 (s, 9H), 2.21 (s, 3H), 2.50 (s, 3H), 3.45 (s, 3H), 3.55 (d, J = 6.1 Hz, 1H), 3.75 (s, 3H), 4.72 (m, 1H) 7.15 (m, 1H), 7.22 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 19.5, 29.4, 30.0, 30.4 (3C), 31.4 (3C), 34.8, 36.1, 51.4, 52.0, 66.4, 103.8, 121.6, 122.4, 123.9, 127.3, 136.1, 146.3, 163.9, 167.1, 169.0, 201.7; the minor diastereomer: ¹H NMR (400 MHz, CDCl₃) δ: 1.28–1.29 (s, 9H), 1.42 (s, 9H), 1.78 (s, 3H), 2.49 (s, 3H), 3.64 (d, J = 6.5 Hz, 1H) 3.71 (s, 3H), 3.77 (s, 3H), 4.72 (m, 1H) 7.15 (m, 1H), 7.22 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 19.3, 29.5, 29.7, 30.0 (3C), 31.4 (3C), 34.5, 36.7, 51.4, 52.2, 64.9, 104.2, 121.8, 122.5, 123.7, 127.2, 136.4, 146.6, 163.4, 167.1, 168.6, 202.3; ESI-TOF MS: calcd for C₂₅H₃₄NaO₆, m/z 453.2248 (M + Na)⁺, found 453.2261.

Synthesis of coumarin 6i and chromene 7i

Compound 6i was prepared according to the general procedure. The reaction mixture was added ethanol to precipitate coumarin 6i, and 6i was then collected by filtration. Chromene 7i was not obtained from this reaction.

Synthesis of coumarin 6j and chromene 7j

The synthesis was performed according to the general procedure. However, the reaction did not give coumarin 6j and chromene 7j.

Synthesis of coumarin 6k and chromene 7k

The synthesis was performed according to the general procedure. Coumarin 6k precipitated from the reaction mixture. After removing coumarin 6k, the resulting reaction mixture was then purified by silica gel preparative TLC (100% CH₂Cl₂) to obtain additional amounts of coumarin 6k. Chromene 7k was not formed from this reaction.

General procedure of three-component reactions of salicylaldehyde derivatives (4), 1,3-cyclohexanedione derivatives (8), and nucleophiles (NuH) by the TH catalyst

A mixture of salicylaldehyde derivatives (4) (1.0–1.7 mmol; 1 equiv.), 1,3-cyclohexanedione derivatives (8) (1 equiv.), NuH (1 equiv.) and the TH catalyst (20% by weight) in ethanol (3 mL) was stirred at 80 °C. The time for each reaction was indicated in Table 4. The reaction mixture was cooled to room temperature, and it was filtered and washed with ethanol to yield chromenes. Spectroscopic data of chromenes 9a–c,⁴¹ 9d,⁴³ and 9e (ref. 46) were identical to those reported in the literature.

Multigram scale synthesis of chromenes was performed in the same manner as that mentioned above. Amounts of ca. 10 g of salicylaldehyde derivatives (4), with 1 equivalent of 1,3-cyclohexanedione derivatives (8) and NuH, were used in the experiment; the reaction time was 15–18 h (Fig. 6). Spectroscopic data of chromene 9k were in good agreement with those in the literature.^42,44,45

7-Bromo-9-(1H-indol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one (9f). White solid; UV (MeOH) λ_max (log ε) 280 (4.34) 221 (4.78); IR (UATR) ν_max: 3747, 3403, 3331, 3056, 2949, 2303, 1638, 1575, 1474, 1456, 1422, 1375, 1338, 1233, 1181, 1135, 1097, 1068, 997, 912, 816, 795, 739 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 1.62–2.06 (m, 2H), 2.32–2.36 (m, 2H), 2.57–2.79 (m, 2H), 5.28 (s, 1H), 6.96–7.01 (m, 2H), 7.07–7.14 (m, 2H), 7.22–7.30 (m, 3H), 7.36 (d, J = 8 Hz, 1H), 8.15 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 20.3, 27.7, 29.6, 37.0, 111.4, 113.6, 117.2, 118.0, 118.8, 119.5, 119.7, 121.7, 122.7, 125.5, 127.4, 130.5, 132.8, 136.5, 148.6, 165.7, 197.1; ESI-TOF MS: calcd for C₂₁H₁₆BrNNaO₂, m/z 416.0257 (M + Na)⁺, found 416.0256.

9-(1H-Indol-3-yl)-6-methoxy-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (9g). Orange solid; UV (MeOH) λ_max (log ε) 283 (4.09), 223 (4.65), 203 (4.59); IR (UATR) ν_max: 3408, 3336, 3050, 2958, 2869, 1637, 1582, 1542, 1505, 1456, 1421, 1374, 1336, 1284, 1264, 1190, 1167, 1145, 1112, 1096, 1035, 1013, 957, 838, 782, 738, 704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 0.95 (s, 3H), 1.10 (s, 3H), 2.17 (d, J = 16 Hz, 1H), 2.25 (d, J = 16 Hz, 1H), 2.51 (d, J = 18 Hz, 1H), 2.59 (d, J = 17 Hz, 1H), 3.76 (s, 3H), 5.25 (s, 1H), 6.56 (dd, J = 9, 3 Hz, 1H), 6.63 (d, J = 3 Hz, 1H), 6.98 (td, J = 8, 1 Hz, 1H), 7.05 (m, 2H), 7.15 (d, J = 2 Hz, 1H), 7.25 (d, J = 8 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 8.02 (brs, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 27.6, 28.9, 29.0, 32.0, 41.5, 50.9, 55.4, 101.2, 111.2, 111.5, 113.0, 117.3, 119.0, 119.2, 120.5, 121.5, 122.3, 125.6, 130.6, 136.5, 150.0, 158.8, 164.1, 197.4; ESI-TOF MS: calcd for C₂₄H₂₃NNaO₃, m/z 396.1570 (M + Na)⁺, found 396.1574.

3-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1H-indole-2-carboxylic acid (9h). White solid; UV (MeOH) λ_max (log ε) 296 (3.77), 227 (4.01); IR (UATR) ν_max: 3261, 2937, 2877, 1676, 1644, 1579, 1547, 1485, 1446, 1417, 1376, 1350, 1319, 1289, 1257, 1227, 1201, 1183, 1143, 1199, 1034, 1015, 913, 875, 758, 736, 710, 682 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ: 0.87 (s, 3H), 1.05 (s, 3H), 1.98 (d, J = 16 Hz, 1H), 2.24 (d, J = 16 Hz, 1H), 2.60 (d, J = 18 Hz, 1H), 2.68 (d, J = 18 Hz, 1H), 6.25 (s, 1H), 6.87 (t, J = 7 Hz, 1H), 6.99 (td, J = 8, 3 Hz, 1H), 7.09–7.17 (m, 3H), 7.20–7.27 (m, 2H), 7.34 (d, J = 8 Hz, 1H), 11.50 (s, 1H), 13.18 (brs, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 26.8, 27.3, 28.8, 31.5, 40.5, 50.3, 111.5 (2C), 112.7, 116.2, 119.2, 119.9, 123.7, 124.0, 124.7, 124.9, 125.2, 127.7, 129.7, 136.1, 148.6, 163.6, 164.1196.0; ESI-TOF MS: calcd for C₂₄H₂₂NO₄, m/z 388.1543 (M + H)⁺, found 388.1554.

7-Bromo-9-((4-methoxybenzyl)thio)-2,3,4,9-tetrahydro-1H-xanthen-1-one (9i). White crystals; mp 115–117 °C; UV (MeOH) λ_max (log ε) 279 (3.57), 205 (4.13); IR (UATR) ν_max: 2951, 2830, 1641,1608, 1574, 1509, 1474, 1411, 1374, 1301, 1233, 1170, 1133, 1033, 995, 908, 814, 734, 670 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): 1.81–2.02 (m, 2H), 2.27–2.49 (m, 4H), 3.57 (d, J = 14 Hz, 1H), 3.66 (d, J = 14 Hz, 1H), 3.79 (s, 3H), 4.94 (s, 1H), 6.80–6.89 (m, 3H), 7.17–7.20 (m, 3H), 7.28 (dd, J = 9.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): 19.9, 27.6, 34.7, 34.8, 36.8, 55.3, 111.8, 113.8 (2C), 117.5, 117.9, 124.8, 129.9 (2C), 130.2, 131.1, 132.5, 149.5, 158.6, 166.9, 196.2; ESI-TOF MS: calcd for C₂₁H₁₉BrNaO₃S, m/z 453.0131 (M + Na)⁺, found 453.0133.

5-(3,3-Dimethyl-7-nitro-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethylpyrimidine-2,4,6-(1H,3H,5H)-trione (9j). White solid; UV (MeOH) λ_max (log ε) 318 (3.94), 231 (4.23), 203 (4.51); IR (UATR) ν_max: 3744, 3070, 2960, 2869, 1747, 1675, 1651, 1584, 1526, 1446, 1422, 1381, 1343, 1287, 1235, 1209, 1194, 1147, 1127, 1089, 1031, 905, 840, 801, 749, 735, 702 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 1.13 (s, 3H), 1.15 (s, 3H) 2.29 (d, J = 16 Hz, 1H), 2.37 (d, J = 16 Hz, 1H), 2.55 (s, 2H), 3.21 (s, 3H), 3.26 (s, 3H), 3.90 (d, J = 2 Hz, 1H), 4.97 (s, 1H), 7.17 (dd, J = 8.2 Hz, 1H), 8.1–8.2 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ: 26.9, 28.5, 28.6, 29.4, 32.1, 34.6, 41.3, 50.6, 55.4, 108.9, 117.7, 123.2, 124.4, 124.6, 144.5, 151.0, 154.6, 166.6, 166.7, 167.2, 197.5; ESI-TOF MS: calcd for C₂₁H₂₁N₃NaO₇, m/z 450.1272 (M + Na)⁺, found 450.1262.

8-Bromo-9-(1H-indol-3-yl)-5-methoxy-2,3,4,9-tetrahydro-xanthen-1-one (9l). White solid; UV (EtOH) λ_max (log ε) 291 (4.36), 273 (4.40), 221 (4.96), 213 (4.96); IR (UATR) ν_max: 3338, 2319, 1644, 1573, 1471, 1428, 1372, 1311, 1217, 1182, 1135, 1092, 1062, 869, 800, 745 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ: 1.66–1.97 (m, 2H), 2.17–2.36 (m, 2H), 2.60–2.76 (m, 2H), 3.87 (s, 3H), 5.30 (s, 1H), 6.86–7.01 (m, 3H), 7.08 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H), 10.90 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 19.9, 26.7, 29.5, 36.3, 55.9, 111.6, 111.9, 113.7, 114.3, 116.4, 118.3, 118.6, 120.5, 124.7, 125.2 (2C), 128.2, 136.0, 140.2, 147.1, 165.5, 195.9; ESI-TOF MS: calcd for C₂₂H₁₈BrNNaO₃, m/z 446.0362 (M + Na)⁺, found 446.0363.

9-Benzotriazol-1-yl-7-chloro-2,3,4,9-tetrahydro-xanthen-1-one (9m). Yellow solid; UV (EtOH) λ_max (log ε) 265 (4.45); IR (UATR) ν_max: 3747, 2942, 1732, 1648, 1583, 1480, 1421, 1383, 1240, 1182, 1079, 1001, 823, 747 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 2.03–2.17 (m, 2H), 2.39–2.44 (m, 2H), 2.73–2.97 (m, 2H), 7.02 (s, 1H), 7.18–7.31 (m, 3H), 7.36 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 20.1, 27.8, 36.4, 48.2, 109.3, 109.6, 118.7, 120.0, 120.9, 123.9, 127.6, 128.8, 130.3, 130.5, 132.3, 145.7, 148.6, 169.2, 196.0; ESI-TOF MS: calcd for C₁₉H₁₄ClN₃NaO₂, m/z 374.0667 (M + Na)⁺, found 374.0658.

9-Benzotriazol-1-yl-8-bromo-5-methoxy-2,3,4,9-tetrahydro-xanthen-1-one (9n). White solid; UV (EtOH) λ_max (log ε) 293 (3.96), 264 (4.26), 207 (4.61); IR (UATR) ν_max: 2962, 2940, 2838, 1659, 1609, 1578, 1476, 1443, 1386, 1332, 1312, 1278, 1263, 1231, 1205, 1187, 1158, 1149, 1139, 1125, 1101, 1092, 1064, 1002, 941, 917, 873, 818, 802, 776, 764, 735, 743, 702, 657 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 1.95–2.10 (m, 2H), 2.36–2.40 (m, 2H), 2.80–2.97 (m, 2H), 3.96 (s, 3H), 6.85 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.32 (td, J_t = 8.1 Hz, J_d = 0.7 Hz, 1H), 7.55 (td, J = 7.9 Hz, J_d = 0.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 20.0, 27.6, 36.4, 48.1, 56.4, 111.2, 111.7, 112.9, 114.1, 119.3, 120.4, 123.6, 127.2, 128.4, 133.5, 142.2, 144.8, 147.7, 168.8, 196.2; ESI-TOF MS: calcd for C₂₀H₁₆BrN₃NaO₃, m/z 448.0267 (M + Na)⁺, found 448.0267.

5-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethyl-pyrimidine-2,4,6-trione (9o). White solid; UV (EtOH) λ_max (log ε) 267 (3.30), 222 (3.38), 204 (3.50); IR (UATR) ν_max: 3749, 2957, 2886, 1746, 1675, 1643, 1582, 1457, 1421, 1387, 1319, 1289, 1230, 1185, 1114, 1034, 775, 756 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 1.13 (s, 3H), 1.18 (s, 3H), 2.30 (d, J = 17.3 Hz, 1H), 2.36 (d, J = 16.3 Hz, 1H), 2.48 (d, J = 17.7 Hz, 1H), 2.56 (d, J = 17.6 Hz, 1H), 3.07 (s, 3H), 3.21 (s, 3H), 3.85 (d, J = 2.7 Hz, 1H), 4.87 (s, 1H), 7.03 (d, J = 8.22 Hz, 1H) 7.08–7.09 (m, 2H), 7.22–7.29 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 27.2, 28.1, 28.2, 29.2, 32.0, 36.3, 41.4, 50.5, 54.9, 108.8, 116.6, 120.5, 124.9, 127.9, 129.0, 150.4, 151.1, 166.9, 167.2, 168.0, 192.7; ESI-TOF MS: calcd for C₂₁H₂₂N₂NaO₅, m/z 405.1421 (M + Na)⁺, found 405.1430.

5-(7-Chloro-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethyl-pyrimidine-2,4,6-trione (9p). White solid; UV (EtOH) λ_max (log ε) 265 (4.24), 225 (4.31), 206 (4.42); IR (UATR) ν_max: 2959, 2876, 1734, 1677, 1645, 1449, 1420, 1382, 1287 1234, 1187, 1119, 1033, 827, 757 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ: 1.12 (s, 3H), 1.14 (s, 3H), 2.28 (d, J = 15.9 Hz, 1H), 2.35 (d, J = 16.1 Hz, 1H), 2.47 (d, J = 18.5 Hz, 1H), 2.54 (d, J = 17.8 Hz, 1H), 3.16 (s, 3H), 3.24 (s, 3H), 3.85 (d, J = 2.5 Hz, 1H), 4.84 (s, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.21 (dd, J_a = 8.7 Hz, J_b = 2.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 27.1, 28.3, 28.4, 29.3, 32.0, 35.5, 41.4, 50.5, 55.1, 108.5, 118.0, 122.9, 127.9, 129.0, 130.0, 148.9, 151.1, 166.8, 167.0, 167.8, 197.4; ESI-TOF MS: calcd for C₂₁H₂₁ClN₂NaO₅, m/z 439.1031 (M + Na)⁺, found 439.1036.

Single crystal X-ray analysis

X-ray diffraction data for chromenes 7a, 7b, 7e, and 7f were collected at 296(2) K on a Bruker X8 APEX II KAPPA CCD diffractometer using graphite monochromatized Mo-Kα radiation (λ = 0.71073 Å). The structures were solved using SHELXS-97⁴⁷ and refined using full-matrix least squares on F² with SHELXL-97.⁴⁷ Final R-values and selected refinement details of 7a, 7b, 7e, and 7f are given in Table 1S (ESI).†

Acknowledgements

P. K. is supported by The Thailand Research Fund and the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education. T. A. acknowledges financial support by the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, Ministry of Education. R. S. thanks the Ministry of Science and Technology for a student grant.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 952576–952579. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra00673a

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